Nutrition, Anabolism, and the Wound Healing Process: An Overview Citation Demling, Robert H. 2009. Nutrition, anabolism, and the wound healing process: an overview. ePlasty 9. Permanent link http://nrs.harvard.edu/urn-3:HUL.InstRepos:4791063 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA Share Your Story The Harvard community has made this article openly available. Please share how this access benefits you. Submit a story . Accessibility Nutrition, Anabolism, and the Wound Healing Process: An Overview RobertH.Demling,MD HarvardMedicalSchool,BurnandTraumaCenter,BrighamandWomen’sHospital,Boston,MA Correspondence:[email protected] PublishedFebruary3,2009 Objective:Todevelopaclear,concise,andup-to-datetreatiseontheroleofanabolism from nutrition in wound healing. Special emphasis was to be placed on the effect of the stress response to wounding and its effect. Methods: A compilation of both the most important and most recent reports in the literature was used to also develop the review.Thereviewwasdividedintosectionstoemphasizespecificnutritionconceptsof importance.Results:Generalandspecificconceptsweredevelopedfromthismaterial. Topicsincludedbodycompositionandleanbodymass,principlesofmacronutritional utilization,thestressresponsetowounding,nutritionalassessment,nutritionalsupport, anduseofanabolicagents.Conclusions:Wefoundthatnutritionisacriticalcomponent in all the wound healing processes. The stress response to injury and any preexistent protein-energy malnutrition will alter this response, impeding healing and leading to potential severe morbidity. A decrease in lean body mass is of particular concern as thiscomponentisresponsibleforallproteinsynthesisnecessaryforhealing.Nutritional assessmentandsupportneedstobewellorchestratedandprecise.Theuseofanabolic agents can significantly increase overall lean mass synthesis and directly or indirectly improveshealingbyincreasingproteinsynthesis. Optimum nutrition is well recognized to be a key factor in maintaining all phases of wound healing. There are 2 processes that can complicate healing. One is activation of the stress response to injury, and the second is the development of any protein-energy malnutrition(PEM). Any significant wound leads to a hypermetabolic and catabolic state, and nutritional needs are significantly increased. The healing wound depends on adequate nutrient flow (Fig1).OfparticularconcernisthepresenceofanyPEM,PEMbeingdefinedasadeficiency ofenergyandproteinintaketomeetbodilydemands.PEMinthepresenceofawoundleads to the loss of lean body mass (LBM) or protein stores, which will in and of itself impede the healing process. Early aggressive nutrient and micronutritional feeding is essential to control and prevent this process from developing. PEM is commonly seen in the chronic wound population, especially the elderly, disabled, or chronically ill populations where chronicwoundstendtodevelop.1–5 Hunter,in1954,followedbyCulbertsonandMoore,identifiedthefactthatawoundbe- ingathreattohumanexistencetakespreferencefortheavailablenutrientstoheal,especially 65 ePlasty VOLUME9 Figure1. Balancebetweenadequacyofmacronutrientsandnetanabolismandcatabolismand itsimpactonwoundhealing. aminoacids,attheexpenseofthehostLBM.6–8 Thisprocessleadstoanautocannibalism ofavailableLBMtoobtainthenecessaryaminoacidsfortherequiredproteinsynthesisin thewound.Ifinadequateintakeispresenttokeepupwithneeds,thenPEMcandevelop.If inadequateglucoseisavailableforthehealingwound,proteinswillbreakdownintoamino acids and through the alanine shunt lead to glucose synthesis by the liver. However, with severelossesofLBM,thehosttakespreferenceoverthewound.9–13 This entire process is the result of the activation of the “stress response” to injury or wounding with its hormonal imbalance favoring body protein catabolism for substrate, neededforproteinsynthesis.Thereisalsoincreasedmetabolicorcaloriedemand.9–13 Thereisafundamentaldifferencebetweentheadequateintakeseenintheunstressed patientandonewheretraumaorinfectionhasactivatedthehoststressresponse.14,15Starva- tionaloneproducesaself-protectivehormonalenvironment,whichsparesLBMwithmore than90%ofcaloriesobtainedfromfat.14–16 To optimize healing, a substrate that is more dependent on intake than on the bodily breakdownofproteinneedstobeavailable.Chronicwoundsaremorecomplicatedbecause the biology of the healing process is significantly altered. However, a stress response is activated with any wound and any existing PEM will accentuate the already poor healing process.17–19 For the above reasons, one cannot dissociate the normal process of healing fromthenutritionalstatus. 66 DEMLING Table 1. Conditionsassociatedwithdevelopmentofprotein-energymalnutrition Catabolicillness,“thestressresponse,”eg,trauma,surgery,wounds,infection,corticosteroids Involuntaryweightlossexceeding10%ofideal,foranyreason Chronicillnesses,eg,diabetes,cancer,mentalimpairment,arthritis,renalfailure Wounds,especiallychronic Increaseinnutritionallosses;openwounds,enteralfistulas Intestinal-tractdiseasesimpairingabsorption BODYCOMPOSITIONANDLBM Componentsofbodycomposition TobetterunderstandtheimpactorerosionofLBMandthenormalorabnormalutilizationof proteinandfatforfuel,ageneralunderstandingofnormalbodycompositionisrequired19–21 (Table1). Bodycompositioncanbedividedintoafatandafat-freecomponentorLBM.LBM containsallofthebody’sproteincontentandwatercontent,makingup75%ofthenormal bodyweight.Everyproteinmoleculehasaroleinmaintainingbodyhomeostasis.Lossof any body protein is deleterious. The majority of the protein in the LBM is in the skeletal musclemass.LBMis50%to60%musclemassbyweight. It is the loss of body protein, not fat loss, that produces the complications caused by involuntaryweightloss.Proteinmakesupthecriticalcellstructureinmuscle,viscera,red cells,andconnectivetissue.Enzymesthatdirectmetabolismandantibodiesthatmaintain immune functions are also proteins. Skin is composed primarily of the protein collagen. Proteinsynthesisisessentialforanytissuerepair.Therefore,LBMishighlymetabolically activeandnecessaryforsurvival. There are only 40,000 calories in the LBM compartment in a 70-kg individual; each gram of protein generates 4 calories (Fig 2). It is not possible to burn more than 50% of LBM.22 Fat mass comprises about 25% of body composition. For all intents, the fat compartment is a calorie reservoir where day-to-day excess calories are stored and fat is removedwhendemandsneedtobemet.Thereare,however,somenecessaryessentialfats, whichmakeupasmallfractionofthiscompartment. Forthemostpart,fatisnotresponsibleforanyessentialmetabolicactivity.Thisenergy reservoircontainsabout110,000caloriesstored,as1goffatgenerates10calories(Fig2). There are a number of body adaptations that attempt to maintain normal LBM or body protein(Table2).23 There is an ongoing homeostatic drive to preserve LBM as a self-protective process since lost protein is deleterious. However, activation of the stress response, caused by a wound,willblocktheseadaptiveresponsesandbodyproteinwillbeburnedforfuel.6–9 Measuringbodycomposition(commonapproaches) Involuntaryweightlossisamarkerofpotentialproblems,andweightrestorationisapoten- tialsolution.However,therealkeydiagnosticinformationisthestatusofbodycomposition (Table3).Sincenormalbodycompositionfortheindividualofconcernisnotknownprior to the insult, a host of normalized tables and equations, with an assumed normal value, 67 ePlasty VOLUME9 Figure2. Body composition is divided into lean mass containing all the protein in the body plus waterandfatmasscomposedmainlyofafatstore, foradepositionofexcessenergy. Table 2. Whatmaintainsleanmass Intensegeneticdrivetomaintainessentialproteinstores Anabolichormonesthatstimulateproteinsynthesis Resistanceexercise Adequateproteinintaketomeetthedemands areused.Therefore,theactualalterationofbodycompositioncausedbyaninsultorpoor nutrition(orusuallyboth)isnotknown.Thecomplications,forexample,theweaknessseen in the patient, as well as the presence of a catabolic state that will lead to LBM loss, are oftenthebestclinicalmarkers.Oftheavailablemethods(Table3),skin-foldthicknessand bioelectiveimpendencearevaluableiftakensequentiallyovertime,butsomeformofbase- lineisneeded;ontheotherhand,nitrogenbalanceprovidesdirectinformationastowhether thepatientwascatabolicoranaboliconthemeasurementday,andhowcatabolic.22–28 LossofLBM LossofanyLBMisdeleteriousastherearenospareproteins.ThelossofLBM,relativeto normal,correspondswithmajorcomplications.Alossofmorethan15%oftotalwillimpair woundhealing,thegreatertheloss,themorethehealingdeficit.Alossof30%ormoreleads tothedevelopmentofspontaneouswoundssuchaspressureulcers,andwounddehiscence atalatestage.Deathoccurswith40%LBMloss,usuallyfrompneumonia(Table4).22 68 DEMLING Table 3. Methodsroutinelyavailabletoassessbodycomposition Precision (coefficient Method Description Advantage Disadvantage ofvariation),% Measurementof Thicknessof Easilyperformed Possibilityoferror 5–10 skin-fold subcutaneous withportable andinterobserver thickness equipment variabilityin measurement Bioimpedance Low-levelcurrent Easilyperformed Results will be af- <5 analysis isintroduced,and withportable fectedbyhydration measurementsof equipment,used impedanceare tocalculatebody usedtocalculate cellmass fatandfat-free mass Nitrogenbalance Measurementof Easytoperform, Nottotallyreliable, 10–15 nitrogenintake indicatesareal asthereareother minusurinary timeevaluation nitrogenlosses nitrogenlossto ofleanbody besidesurine determinenet mass nitrogengainor loss ∗ Table 4. Complicationsrelativetolossofleanbodymass Leanbodymass Complications(relatedto Associated, ∗ (%lossoftotal) lostleanmass) mortality,% 10 Impairedimmunity,increasedinfection 10 20 Decreasedhealing,weakness,infection,thinningofskin 30 30 Tooweaktosit,pressuresoresdeveloppneumonia,nohealing 50 40 Death,usuallyfrompneumonia 100 ∗ Assumingnopreexistingloss. This table assumes no preexisting involuntary weight loss.17,18 Someone with PEM willalwayshaveapreexistingloss,whichneedstobeaddedaspartoftotal.Onecanassume that with any stress-induced PEM, LBM loss is about half of the involuntary weight loss. TherelationshipbetweenLBMandwoundhealingisbasedonthemannerofutilizationof availableproteinforeitherthewoundormaintainingtheoverallLBMcompartment(Fig3). Woundclosureisanimportantgeneticallydetermineddriveforsurvival.Withaloss oflessthan20%ofLBM,thewoundtakespriorityfortheproteinforhealing.Withaloss of 20%, there is equal competition for the protein between the wound and the restoration of LBM, so the healing rate will slow down. With a loss of 30% or more, where risk to survivalishigh,theLBMtakescompletepriorityforproteinintake.Thewoundessentially stopshealingtillLBMisrestoredatleastpartially.6–8 Bodycompositionalchangesbeforeandafterawound,therefore,haveamajorimpact on healing irrespective of the local wound care. In addition, nutritional support needs to be increased in both calories and protein (1.5 g/kg body weight) if there is a preexisting 69 ePlasty VOLUME9 Figure3. With a loss of lean mass less than 10%, the wound takes priority over the available protein substrate. As lean mass decreases, more consumed protein is used to restore LBM, with less being available to the wound. Wound healing rate decreasesuntilleanmassisrestored.Withalossofleanmassexceeding30%oftotal, spontaneouswoundscandevelopduetothethinningofskinfromlostcollagen. Figure4. Lean mass loss 20% of the total: Clean but poorly healingacutewoundrespondingtoLBMloss. deficit,aswouldbepresentwithanypreviousPEM.Therateofhealingisdirectlyrelated totherateofrestorationofbodycomposition(Fig3).Woundhealingisdirectlyrelatedto thedegreeofLBMloss(Figs4–7).29 PRINCIPLESOFMACRONUTRIENTUTILIZATION (ADAPTIVEMETABOLISM) Before discussing the principles of nutritional support for healing, it is important to un- derstand the normal utilization of nutrients and the normal metabolic pathways to energy productionandproteinsynthesis,whichmaintaintheLBMcompartment.30–37 70 DEMLING Figure5. Leanmassloss25%thetotal:thinningofskinwith lossofcollagenasLBMdecreases. Figure6. Leanmassloss25%to30%ofthetotal:dehiscence stumpclosurenowwithopennonhealingwound. Understanding the metabolic concept of macronutrient nutrient partitioning into an energyandproteincompartmentandmethodstooptimizeanefficientnutrientchanneling into either energy production or protein synthesis is the first step to understanding the nutritionalsupportprinciples.Inaddition,theroleofanabolicagentsbecomesclearerwhen consideringtheirroleasagentschannelingproteinsubstrateinproteinsynthesis. Ingeneral,normalmetabolismisdirectedbyhormonesthatadjustwhenneededtoand alterenergyproductiontomeetneedsandalsotorestoredailyproteinbalancethroughthe naturaltissuesynthesisandbreakdownpathways.30,31,34–37 Energypathway Normally,theenergypathwayisfueledalmostcompletelybycarbohydratesandfat.31–33 71 ePlasty VOLUME9 Figure7. Lean mass loss 30% of the total: sponta- neouspressureulceronthesacrum. Proteinpathway Proteinwhenconsumedismetabolizedintoaminoacidsandpeptides.Withnormalanabolic hormone activity, nearly all of the protein by-products are used for protein synthesis, not forenergy.Only5%istypicallyusedforenergy.However,energyisrequiredfortheprotein synthesisprocess(Fig8).34–37 With starvation, there is preservation of LBM compartment, as the majority of the calories come from the fat mass and only about 5% from protein.16,33 Metabolic rate and energy demands are decreased, cortisol levels (catabolic) decrease, and human growth hormone(HGH)levels(anabolic)increase(Fig9). THE“STRESSRESPONSE”TOWOUNDING The host response to severe illness or infection is an amplification of the fright-flight reaction.11,12,38–40 Theinsultleadstothereleaseofinflammatorymediatorsthatactivatea very abnormal (Table 5) hormonal response, led by a marked increase in catecholamines andotherhormonesthatproduceahypermetabolic-catabolicstate.38–41 Anentirespectrumofabnormalitiescanbeseenafterinjuryandinflammationdueto degreesofthemanifestationofthehost“stressresponse”toabodywound.Ifuncontrolled, the stress response can progress with loss of body protein and impaired wound healing. The once protective response then becomes autodestructive, and intense autocannibalism (catabolismforfuel)occurswithrapidlossofLBM38–41 (Fig10). Controlling the degree of ongoing injury requires both controlling the host response and at the same time supporting the metabolic needs to avoid further deterioration. How- ever,catabolismstilloutweighsanabolismasthecatabolichormonespredominateandthe anabolichormones,growthhormone,andtestosteronearestilldecreased.Massiveprotein depletioncanoccurindaystoweeksafterasevereinjurywithwoundsuntilthewoundhas beenclosedandthestressresponsehasbeenremoved.14,38–44 72 DEMLING Figure8. Macronutrients enter the metabolic pathways directly by hormones. Carbohydrates and fatsentertheenergysystemorarestoredasfat,whilemorethan90%ofconsumedproteinenters theproteinsynthesisprocess.Normalskinpreventsanyenergydrainthroughawound. NUTRITIONALASSESSMENT ThemaintenanceofoptimumnutritioninthepresenceofawoundorPEMisamultifactorial process.Assessmenthasthefollowingobjectives(Tables5–8).31,45 ASSESSINGTHENUTRITIONALNEEDS Tooptimizesubstrateflowtothehealingwound,anassessmentofrequiredintakeismade. Therearemanypresentvalues,whichhavebeenscientificallydefinedoverthepast3decades (Table7). Thereareanumberofspecificprocessesthatneedtobecompletedbeforethecalories andproteinintakecanbedetermined.Assessmentofnutritionalneedscanbedividedinto thefollowing3components46–48 (Tables6and8): (cid:2) Energyorcalorierequirements (cid:2) Proteinrequirements (cid:2) Micronutrientrequirements 73