rt Lipid Intolerance in Neonates Receiving Dexamethasone for Bronchopulmonary Dysplasia ‘Sanjiv B. Amin, MD; Robert A. Sinkin, MD; Michael P. McDermott, PRD; James W. Kendig, MD Background: We hypothesized that dexamethasone induces hypertrighyceridemia (triglyceride levels >2.82 mmol/L [250 mg/dL]) and increases free fatty acid (EFA) levels and that steroid-induced hypertriglyceride- mia is associated with hyperinsulinemia and elevated PPA levels, Objectives To study the effect of dexamethasone sodium phosphate on lipid metabolism in neonates receiving intravenous lipids Design: A prospective cohort study with patients serving as their own controls ‘Setting: Neonatal Intensive Care Unit, Children’s Hospital at Strong, Rochester, NY. Methods: All neonates younger than 29 weeks’ gesta- tional age at birth receiving 3 g/kg per day of intrave- nous lipids who were to start dexamethasone therapy for bronchopulmonary dysplasia were eligible. Exclusion eri- teria included neonates with active infection, prior hy pertriglyceridemia, bleeding manifestations, recent sur- ‘gery, thyroid medication, and human recombinant insulin intravenous infusion therapy. Ten neonates were stud- ied. Blood was drawn for triglyceride, FFA, and insulin assays before initiating and at 1, 2, 3, and 5 days after starting dexamethasone therapy. On day 3, dexametha- sone dosage was decreased as per protocol. Intravenous lipid intake was kept constant. Statistical analysis was done using a paired ¢ test Results: Six of 10 neonates reached a state of hypertri- glyceridemia (05% confidence interval, 26.2%-87.8%). The mean average increase in triglycerides, insulin, and FFA levels in neonates receiving 3 g/kg per day of intrs- venous lipids after initiation of dexamethasone therapy was 0.75 mmol/L (66.6 mg/dL) (P =.007), 127 pmol/L, (P=.006), and 47.5 ymoVL (P =.65), respectively. Sixneo- nates who developed hypertriglyceridemia had signifi canily elevated mean peak FFA levels (918.3 pmol/L) prior to developing hypertrigyceridemia compared with + neo- nates (mean peak FFA levels, 380.2 jimol/L) who had tri glyceride levels lower than 2.82 mmoV/L (250 mg/dL) (P2002) Conelusion: We conclude that dexamethasone in- duces hypertriglyceridemia in the presence of hyperin- sulinemia and increased FPA levels Arch Pediatr Adolese Med. 19995153:795-800 weight infants dditor’s Note: At this point, we can only guess at the long-term consequences of this double whammy therapy for very low-birth- infection.** Elevated lipid concentra- tions have been associated with a deterio- ration of pulmonary function,” impair- ment of neutrophil function,” and Catherine D, DeAngelis, MD From the Department of Pediatrics, Division of ‘Neonatology, Childrens Hospital at Strong, University of Rochester School of Medicine and Denustry, Rochester, NY. OST PREMATURE neo- nates need intrave- nous (IV) lipids dur- ing the first few weeks of life to acquire ad- equate energy intake and prevent essen- tial fatty acid deficiency before they can tolerate all nutrition via enteral feeds.! Lipid intolerance has been described in in- fants who are extremely premature, small for gestational age, or who have an active displacement of bilirubin from albumin binding sites, with an inereased risk for kernicterus.'°!" Bronchopulmonary dysplasia (BPD) fs the most common form of chronic lung, disease in neonates. Dexamethasone, asyn- thetic corticosteroid, has been used for the prevention and treatment of BPD."=? How- ever, administering dexamethasone therapy to neonates is not benign and is associated with multiple side effects, sn- cluding poor weight gain." Administe ing dexamethasone therapy to premature {nlants may cause an impairment in glu- (©1909 American Medical Association, All sights reserved. Downloaded From: http:/jamanetwork.com/ on 08/09/2017SUBJECTS, MATERIALS, AND METHODS STUDY DESIGN ‘The cohort study was prospective with patients serving as their own controls. The stidy was reviewed and approved by the University of Rochester Medical Center Research Sub- jects Review Board, Rochester, NY. For the purpose of the study, hypertriglyceridemia was delined a tnglycerde val- tues equal to or higher than 2.82 mmol/L (250 mg/dl.) INCLUSION CRITERIA All premature neonates 24 1 29 weeks gestational age at thrhadmited tothe Children's Hospital at Strong, Neona- taltntensive care Unit, Rochester who were selected ore Ceivea long course (>7 days) of dexamethasone therapy for BPD and who were receiving > pg per day of lipids were considered eligible or this study. The diagnosis of BPD was dkermined by the clinical ta Based on ndings rom ches radiographs and increasing fraction of inspired oxygen re- Glrements, Gestational age was determined by obstetric is {ory or, obstetric history was unreliable, by Ballard exam hun’ Dexamethasone therapy was administered atthe discretion of the attending neonatologis. Eligible patients swere enrolled inthe std following parental consent EXCLUSION CRITERIA Exclusion criteria included known genetie disorders active {infections treated with antibiotics; triglyceride levels equal to or higher than 2.82 mmol. (250 mg/dL): thyroid prob Jems requiring medications: surgery performed within 72 hours of study enrollment; bleeding manifestations or ab- normal findings on a coagulation profile, which prechaded the routine use of heparin sullate in 1 fluids; and/or pa- tients requiring an epinephrine 1V infusion or insulin drip METHODS, Patients receiving 3 g/kg per day of 1V lipids (Liposyn Ul Abbott Laboratories, Abbott Par, I) who wereto start dex ‘methasone therapy for BPD were identified 24 1048 hours before dexamethasone therapy was initiated. Parental con- sent was oblained ifthe research subjects did not meet the exclusion criteria. Baseline values for triglyceride, FFA, and insulin levels were measured 1 to 2 hours before initiating dexamethasone therapy, Baseline values were measured at {er patients had heen receiving 3 g/kg per day of 1V lipids forat least 2 consecutive days, Dosage for dexamethasone therapy followed the protocol of Avery et al which in- cluded 0.25 mg/kg every 2 horsforthe frat doses, Ol lowed by 0.13 mg every 12 hours for the next 6 doses. The I lipids were continued a3 gf per day and were ‘nosed continua the same Row rate Atl, 2 3, ‘nd 3 days following snitation of dexamethasone therapy, Blood was drm ate same time of day to measure the teglcerde, FFA, and insulin levee. The same source of Hidod was used forthe whole stndy period for individual patients Beeause FFA levelsdilfer between arterial and ve- Tous blood: Blood specimens were immediately cent figed aed acm vr aeparte Sen war rp faz at “4c unl analyst: Free fay acd levels were measured ‘sing an enzymatic analysis (Waco Chemicals USA Ine, Richmond, Va): insulin levels were meanired ving 3° dhoimnonsny (Linco Rescate, St Charles Mo} and te tdyecrde eves wer mens tng estan colon tne method (Ortho Clinical Diagnostics, Ranan,N). Both FFA and nslin levels were measred in pit, andthe mean values were considered fo statistical analy Si. The mean coeicient of vanattons for duplicate mer Surementsof each sample for insulin and FEA levels were Sioand 1%, spectively Daring the sty period (1) heparin intake was kept constant and infsed continual (2) no teatnent ith few medications, sich ns epinephne, broncho- diltors or disretie, as initiated and (3) id intake was heptconstant,nlesehypertrigyecrdemiadeveloped It glyceride leven were 282 mmol. to 4.52 mma (250- $0 mg/d, 1V pd intake wanderer 1 gg per day ITuighyceride levels continued to increase, even when the Patient vas receiving 1 glkg of 'V lipids por day. 1 pad Intake ws decreased 19 0. pk per dy. However, fSyestle els decreed lente patient ws reciving 1 g/kg per day. IV iid intake was comtined at! kg pet day He patcnt was receiving 0 pkg per day of ‘deand rlycende levels increased, Vii intake ws d= Continued At any time, igyceride levels were bgher than #52 mmol (400 mp1 ip amination vas discontinued. STATISTICAL ANALYSIS ‘The paired # test was used to test the null hypothesis that the mean changes average serum levels of triglycerides, FEA, and insulin while the patient is receiving 9 glk pet day of TV lips rom baseline to after inition ef dexa- tmethasone therapy were equal to zero. In addition, the {est wa used to analyze continous variables (laa Pro- frame Sata Corporation, College Station, Tex). tests twere 2 lalled, and P05 was considered statistically nificant. ‘cose and protein metabolism." To our knowledge, dexs- methasone-induced lipid intolerance has not been pre- viously deseribed in neonates, although there are animal data to support the association of steroid use and hyper triglyceridemia,!™ Steroids are catabolic and cause fatty acid mobilization from adipose tissue, leading to an in- ‘crease in free fatty acid (FFA) levels in serum. Elevated PPA levels increase triglyceride synthesis and secre- tion.” Steroids are also known to produce hyperinst- linemia.*” Insulin prevents fatty acid mobilization from adipose tissue and decreases FFA levels. However in the liver, insulin, like dexamethasone, increases de novo fatty acid and triglyceride synthesis.°25°" We performed a retrospective chatt review of pre ‘mature infants with BPD and a history of hypertriglye- cridemia and compared them with a control group of in- fants with BPD and normal triglyceride levels. We found that patients with hypertriglyceridemia were 17 times more likely to be receiving dexamethasone therapy than patients with normal triglyceride levels. (©1909 American Med Downloaded From: http:/jamanetwork.com/ on 08/09/2017 Association, All rights reserved.Al aus are gen as mean «SO. ‘Patents eceng 3 9 of pds per dy, intravenous Based on the animal data and our experience from. this retrospective analysis, we hypothesized that dexa- methasone induces hypertriglyceridemia and increases PFA levels and that steroid-induced hypertriglyceride- mia is associated with hyperinsulinemia and elevated FFA levels. Our objectives were to determine (1) the inci dence and intensity of hypertrighyceridemia in prema- ture neonates receiving dexamethasone therapy; (2) the incidence and intensity of increased FFA levels in pre- mature neonates receiving dexamethasone therapy; and (3) the possibility of an association of hypertriglyceri- demia with hyperinsulinemia and elevated FFA levels Es} ‘Ten neonates were enrolled in the study. Two neonates could not complete the fifth day of the study: one be- ‘cause insulin therapy was initiated for hyperglycemia (blood glucose level >10.0 mmol/L [180 mg/dL]); an- other because not enough blood was available to ana lyze the insulin levels, The mean postmensteual age of allstudy patients atthe time of enrollment was 28%; weeks, ‘with a mean chronological age of 17.3 days. The mean postmenstrual age for the group of neonates with ti- alyceride levels lower than 2.82 mmol/L (250 mg/dL) (n=4) was 204/ weeks. The mean postmenstrual age for the group of neonates who developed hypertriglyceride- la (n=6) was 28% weeks. Six of 10 research subjects, ‘were female. Nine of 10 neonates were an appropriate size for gestational age. Only 1 infant was small for ges- tational age; however, the triglyceride levels for this particular patient while receiving 3 g/kg per day of LV ip- ids and prior to starting dexamethasone therapy were all normal, Intake rates for 1V lipids, glucose, energy, and hep- arin did not change between baseline (prior to start of dexamethasone therapy) and the time of peak values of triglyceride levels after initiating dexamethasone therapy, 4s given in the Table, ‘The mean serum triglyceride, insulin, and PPA lev- cls at baseline (0 hour) and 1, 2,3, and 5 days after int Uiation of dexamethasone therapy are shown in Figure ¥ ‘The mean average increase in triglyceride, insulin, and PFA levels for patients receiving 3 g/kg of LV lipids per Tigris Ls maT Ge rin oes pelt Fron Fy AL et, Figure +. Sem thse (0 our and 2:3 ard days ater Solan phosphate thay fr theresa subjects. Tighe aa sain lees were Sonat elated in neonates undergoing dexamethasone therapy ld sy if (ean), inten of exameasone day after initiation of dexamethasone therapy was 0.75 mmoV/L (60.6 mg/dL.) (P=.007), 127 pmol/L (P=.000), and 47.5 pmol/L (P=.65), respectively. Daily individual serum triglyceride levels for each patient are shown in Figure 2. Six (60%) of 10 re- search subjects developed hypertriglyceridemia, Even those neonates with triglyceride levels lower than 2.82 mmoVL (250 mg/dL) had higher triglyceride levels after starting dexamethasone therapy. All6 neonates with hy- pertriglyceridemia required a decrease in IV lipid intake according o the protocol outlined in the “Methods” sub- section of the "Subjects, Materials, and Methods” sec- tion. In 3 of 6 neonates with hypertriglyceridemia, t slyceride levels decreased as the IV lipid intake was decreased because of hypertriglyceridemia, However, in 3 other neonates with hypertriglyceridemia, triglycer- ide levels decreased only alter day 3 when the dexameth- asone dosage was decreased, The triglyceride levels also decreased with the decrease in dexamethasone dosage in 2 of 3 neonates with triglyceride levels lower than 2.82 mmoV/L (250 mg/d). Daily serum insulin levels for individual patients are shown in Figure 3. Nine of 10 neonates had an in- crease in insulin levels alter starting dexamethasone therapy. All neonates with hyperteiglycericemis had el- evated insulin levels (mean peak insulin level, 342 pmol/L) while receiving dexamethasone therapy. Four neonates (©1909 American Med Downloaded From: http:/jamanetwork.com/ on 08/09/2017 Association, All rights reserved.co é 89. Tigyeicaves anal aia) 108 Figure 2. Sem tighcende lees or did pats poted against std. Sic of 10 neonates had hypetighendema,represeted by so lines. Dased nes epreset neanaes wt tighezre kes ove han 22 mma. (280 mpl) hon bar, ihe dosage of exametasone Sdlum phosphate atminstered dug thes days. Tiycende eels erenced (open sures) with he decrease atavenous Ip ee ft ‘neonates wth ypertigcerdemt Io 3 other neonates with hype ig and 2 nenaes with geile eves ager tan 282 ‘nmol (250 mg tigheende levels decreased (open cles) an th the decrease in dexametasone dosage Trainee pra BEE EE s ‘ oy Figure 3. Serum sun lve orig patents ploted against study ay. Dashed ies preset inal eels fo neonates wt geri els lower tan 282 mmol (250 mot) sold ines, nul eel for neonates ith hypertgycenemi Mie of 1 neonates had crease nul eels {fer sng deanetasone sodium phosptate therapy. Heoates ih hyperthermia ad elated isn eves Inu vk peaed ior ‘or concomiant ote nreace a tere vs. Insulin els essed yy 5 ie dese exacts cosa or ravenous pid nak. with triglyceride levels lower than 2.82 mmol/L (250 mg/dL.) also had elevated insulin levels (mean peak insu- lin level, 404 pmoVL). There was no difference between the insulin levels in the neonates who developed hypper- triglyceridemia and the neonates with triglyceride levels lower than 2.82 mmol/L (250 mg/dL) (P =-69). The insu- lin levels peaked 1 day prior to or concomitantly with the peak in triglyceride levels, Insulin levelsin 5 of 6 neonates with hypertriglyceridemia decreased concomitantly with the decrease in dexamethasone dosage or the decrease in 1V lipid intake. One neonate who had persistent hyperin- sulinemia, despite a decrease in dexamethasone dosage and 1V lipid intake, also had persistent hypertriglyceridemia. In 3 neonates with triglyceride levels lower than 2.82 mmol/L (250 mg/dL), the insulin levels decreased with the decrease in dexamethasone dosage. Daily serum FFA levels for individual patients are shown in Figure 4. The FFA levels increased in 7 of 10 Figure Serum fe fat acd (FF) evel for indndualpatents plone agaist tay day. Dashed ies represent FA eves for neonates ington 282 mmol. 250 mg ld nes lel for asonates wth ypertighendema, Sern of YO neonates had {an nereae FFA ves after Starting deanetasone sodum phosphate ‘heragy The PA levels wer sgnieanty elevated neonate th Iypertighceiem compared wth azontes wth taycend lev over ‘an 22 mmol (250 mg). The FFA ees decrased by ay 5 wih he crease in detaethasate dosage or ravenous ip tale neonates alter starting dexamethasone therapy. Two ne nates had high baseline FFA levels (mean baseline FFA value, 1020.2 pmol/L) compared with 8 other neonates (mean baseline PPA value, 3345 ymoVL). Ifthese 2 neo- nates are not accounted for, the mean average FPA values (678.2 ymoV/L) for neonates receiving 3 g/kg of 1V lipids per day after initiation of dexamethasone therapy are sig- nificantly elevated above the baseline FPA values (334.5 mol/L), P=.02. All 6 neonates with hypertriglyceride- ‘mia had elevated PPA levels after starting dexametha- sone therapy. Mean peak PPA values for 6 neonates with hypertriglyceridemia and 4 neonates with triglyceride lev- cls lower than 2.82 mmol/L (250 mg/dL) were 918.5 mol, and 4045 jmol/L, respectively. The PFA levels were sig- nificantly higher in neonates with hypertrighyceridemia than inneonates with triglyceride levels lower than 282 mmol/L. (250 mg/dL.) (P<.004). As with triglyceride and insulin levels, the FFA levels decreased concomitantly with the decrease in dexamethasone dosage oF IV lipid intake. a Premature infants with BPD have high energy requir ‘ments to sustain postnatal weight gain, and IV lipids are fan important energy source for them. Infants with BPD who are treated with dexamethasone have poor Weight gain.!* Treatment with dexamethasone impairs not only glucose but protein metabolism in premature in- fants."*! From this review we have demonstrated that infants with BPD who receive both IV lipids and dexa- methasone also have altered lipid metabolisn, Triglycerides, the major component of lipid emul- sions, are hydrolyzed by lipoprotein lipase into FFA and alycerol. Heparin releases the lipase from the capillary endothelium.” The faty acids bound to albumin are trans- {erred to various issues, mainly adipose and liver, where they are oxidized to provide energy or are reesteriied and stored as triglycerides. An infant's ability to use lipids as an energy source depends on appropriate enzyme activ- lty in the liver and adipose cells to metabolize the FFA. (©1909 American Med Downloaded From: http:/jamanetwork.com/ on 08/09/2017 Association, All rights reserved.In premature infants, about 30% of energy is derived from the Broxidation of faty act." ‘Numerous fetors have been associated with byper- lipidemia in neonates Diminished tolerance to 1V ip- idshas been described in infants who are extremely pre mature. As these infants mature, riglyeride levels usually fallwith the increase in lipoprotein lipase activity." The rate of lipid infusion also allects serum concentrations of wiglycerides and FFAs; the maximum recommended lipid infusion rate is less than 0.25 g/kg per hour Lipid metabolism may also be altered during the immediate postoperative period,” and by administering an epineph- Fine drip." thyroid medications,” oF glucose. ‘Numerous animal studies have demonstrated that steroid use is also associated with hypertriglyeeride- mia." The inducible ellect of steroids on triglyceride synthesis in the liver is affected by the presence of insti lin Inslin inereases triglyceride synthesis in the liver Steroids induce hyperinsulinemia by 2 separate mecha- nisms. (1) Steroids havea pronounced pancreatropic ef feet, causing arise in insulin levels» 2) inaddiion, ste roids inbibit glucose uptake into cells and decrease glucokinase activity, thereby causing hyperglycemia. In response to hyperglycemia, more insulin isscerced, cause ing hyperinsulinemia.” In our study, 9 of 10 neonates had increased insulin levels alter starting dexamctha- sone therapy, 4(old above baseline valies, There was no dillerence in glicose intake between the baseline and peak values, which could have caused hyperinsulinemia De novo faty acid symthests is required for synthe- sis of triglycerides.” Dexamethasone increases the ac- tivity ofacetyl-Coa carboxylase, a rate-limiting enzyine for de novo fatty acid synthesis. This ellect is not seen in the absence of insulin, suggesting that insulin has 4 permissive action in increasing the activity of acetyl CoA carboxylase. In our study we found patients whose insulin levels peaked 1 day prior to or concomitantly with the peak in wiglyeeride levels, suggesting that insula lev- cls were high for this permissive action on de novo fatty acid synthests. Inthe presence of dexamethasone and in- ulin, instead of being oxidized for energy production, ost ofthe fatty acids synthesized are resterfied to form wiglyecrides.""**? Though insulin inereasestriglyeer~ ide synthesis in liver, its effect on triglyceride secretion has been demonstrated to be biphasic.” Short-term hy- perinsulinemia (<24 hours) decreases wiglyeeride cretion; however, aconates with hyperinsulinemia for longer than 24 houts lose this inhibitory effect, and se cretion of triglycerides increases." Allof the neonates in our study had hyperinsulinemia for longer than 24 hours; however, only 6 neonates developed hypertrghye~ cridemia. All 4 neonates who did not develop hypertsi slyceridemia in the presence of hyperinsulinemia also had significantly lower FFA levels compared with neonates who developed hypertigyceridemia. Our findings sug gest that not all patients with hyperinsulinemia develop hypertiglyceridcmia and substrate availabilty is a sig- nilicant factor. lasulin levels decreased with the de- crease in dexamethasone dosage oF IV lipid intake eX ‘eptin 1 nconate. This particular nconate also continued tw have hyperteglyeeridemia, despite decreases in dexa- methasone dosage and 1V lipid intake. Dexamethasone increases triglyceride synthesis and secretion in the liver."™ Steroid use also causes hhypertrglyceridemia by decreasing the activity of ipo- protein lipase, which hydrolyzes triglycerides into FFA snd glycerol However, Cole eta" demonstrated in an finimal model that augmented synthesis and secretion of triglycerides largely contribute to steroid-induced hypeririglyceridemia. With dexamethasone therapy wwe found the incidence of hyperteighyceridemia to be 60% with a 2-fold increase in serum triglyceride levels. A much higher triglyeeride level could have been observed ifthe lipid intake had not been decreased because of hypertriglyecridemia. Hypertriglyeeridemia improved with a decrease in dexamethasone dosage of 1V lipid intake oF both. ree faty acid (substrate) availability also affects tr- slyceride synthesis 2” steroids are catabolic and eause fatty acid mobilization from adipose Usstc. Insulin de- creases fatty acid mobilization atthe adipose tisste level and isan antagonist to the steroid elfect. Though 7 of 10 riconates had an increase in PFA levels ltr starting dex methasone therapy, mean average FFA levels for neo- nates receiving 3 y/kg of IV ips per day were nots nificantly clevated above the baseline levels. These may be related o the igh baseline FFA levels found in 2 ne nates. We do not have an explanation for these high ba line FFA levels. Neonates with hypertriglycerideria had higher FFA levels than neonates with wiglyecride levels, lower than 282 mmol/L (250 mg/dl). Our findings sup- port the findings of others who found that elevated FFA levels are associated with the development of hyper slyceridemia™ tn addition, faty acids are potent an- {agonists of the action of insulin to decrease Wiglyeeride secretion.” The lower FFA levels in neonates with t slyceride levels lower than 2.82 mmoV/L (250 mg/dL) may be related to the slightly higher insulin levels in these neonates compared with neonates who developed hypertriglyceridemia Insummary, dexamethasone induces bypertrighy cridemia that occurs in the presence of hyperinsu- Iineria and elevated levels of FFAS, Because of oncom tant hyperinsulinemia, we speculate that dexamethasone therapy is associated with decreased fatty acid oxida- tion. This may partially explain why neonates undergo- ing dexamethasone therapy have poor weight gain, Ne nates receiving IV lipids and dexamethasone therapy shouldbe closely monitored for hypertrglyceridemia and Increased PEA levels, especially if there Is @ risk for bilirubin encephalopathy “Accepted for publication December 22, 1998. This project was supported in part by grant RROO#4- 35AL (General Clinical Research Centers) from the Né tional Institutes of Health, Bethesda, Md. Presented in part al the Pediatric Academic Societies annual meetings, Washington, DC, May 4, 1997. We thank Michael MeDermott, PhD, biostatistician, {Jor his help in the statistical analysis of the data, We thank Charles Sparks, MD, for his support ofthe study Corresponding author: James W. Kendlig, MD, Divi- sion of Neonatology, Children’s Hospital at Strong, 601 Elm- wood Ave, Box 651, Rochester, NY 14642. 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Plums Ii hangs ince bya phi: a study cari uti reat aise wth mus ite Tip eompostion 4 Paar 186074708716 Kayes WG, Vos H, Heenburg MForason ch ery ow esi ipopre- ten and matali of [1-140 ty perused ies ram ts tae wth ‘aodtyronne or ropythioued. Mewtotsm, 181 30:135-145 Regan GM, Chen YD. ole of ns eulatn opp metab in Saba. Dates Metab Ra. 1088 60 52 air Zammit VA Eton ements itso hati pr ‘ning of ty ais betwen oxen and esertcan,pospolié and antl yes, and on ern ae of erton orale inv. Becher J O47. 12 Lala ME. Mayes PA Ivesigaons ite tec ets af isin on pate tgenes,fpproi secretion and praatadyageas evi io chm Bop Acta 184, 795:427 480, Bagcace DYE, Ader, Palo 04 Sheard anighceans- artes onthe ern as, ppt ipsa pla io Pes in th et Meats O76 583502 (©1909 American Medical Association, All sights reserved. Downloaded From: http:/jamanetwork.com/ on 08/09/2017