Original Article J Clin Nutr 2016;8(1):29-35 pissn 2289-0203 ㆍ eissn 2383-7101 http://dx.doi.org/10.15747/jcn.2016.8.1.29 동종조혈모세포이식을받은환자군에서의 Fish Oil 을함유하는정맥지방유제공급의효과 최지형 1, 이영주 1, 배혜정 1, 정선회 1, 한현주 1, 고영일 2 서울대학교병원 1 약제부, 2 혈액종양내과 Effect of Fish Oil-based Intravenous Fat Emulsion with Parenteral Nutrition in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation Ji Hyeong Choe 1, Young Joo Lee 1, Hye Jung Bae 1, Sun Hoi Jung 1, Hyeon Joo Hahn 1, Yungil Koh 2 1 Department of Pharmacy, 2 Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea Purpose: Omega-3 fatty acid is known for immunonutrition in that it has anti-inflammatory properties and improves the patients immune function. The objective of this study was to determine the effects of a fish oil-based lipid emulsion for adult patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Methods: This was a retrospective study of 90 adult allogeneic HSCT patients from July 2011 to June 2015. The patients were divided into two groups according to the lipid type provided; fish oil group (FO group, n=55) and non-fish oil group (NFO group, n=35). The demographics, parenteral nutrition and lipid emulsion duration, length of hospital stay (LOS), weight change, 30 day mortality, survival period, incidence of acute graft-versus-host disease (agvhd), neutropenic fever, sepsis, and re-hospitalization were collected from the electronic medical records. Results: The patients characteristics including age, sex, body mass index, and underlying disease were similar in the two groups. The incidence of agvhd and infectious complications, mortality, LOS, re-hospitalization were also similar. The FO group showed weight gains, whereas the NFO group showed weight loss (FO vs. NFO=0.34% vs. 1.08%, P=0.245). Conclusion: The clinical outcomes were similar in the two groups but there was a tendency for gain weight in the FO group. A large, well designed study, and a dosing study will also be needed to determine the optimal dose range for HSCT patients. Key Words: Fatty acids, Fish oils, Hematopoietic stem cell transplantation, Parenteral nutrition, total Received Apr 5, 2016; Revised Apr 21, 2016; Accepted Apr 21, 2016 Correspondence to Yungil Koh Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-2114, Fax: +82-2-2072-7379, E-mail: youngilerica@gmail.com Sun Hoi Jung Department of Pharmacy, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-3123, Fax: +82-2-766-1443, E-mail: shoijung@snuh.org Conflict of interest: None. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 서론 조혈모세포이식환자는그들의기저질환, 전처치, 그외의치료와관련한독성으로영양결핍상태에빠지기쉽다. 이식후에동반되는구내염, 오심, 구토, 식욕부진및설사등의위장관이상은경구섭취를부족하게하며, 따라서상당수의환자에서정맥영양 (total parenteral nutrition, TPN) 을필요로하게된다. 1-3 최근 TPN의구성성분중 fish oil을함유하는 4세대정맥지방유제 (intravenous fat emulsion) 의효과에대한관심이커지고있으며, 활발한연구가진행되고있다. Fish oil은오메가-3 지 c 2016, The Korean Society for Parenteral and Enteral Nutrition. All Rights Reserved.
Ji Hyeong Choe, et al. 방산인 eicosapentaenoic acid (EPA), docosahexaenoic acid 를풍부하게함유하고있으며, 오메가-3 지방산은환자의면역기능향상과염증반응조절에도움을주는면역영양의한종류로알려져있다. 4-6 현재 fish oil을함유하는정맥지방유제의효과에대한연구는주로중환자와외과적수술환자를대상으로진행되었고, 그외질환에대한연구는아직부족한상태이다. 반면경장영양에포함된오메가-3 지방산은 immune enhancing diet로써외과적수술환자나중환자에서면역세포기능을향상시키고, 염증을조절하여감염합병증을감소시키는효과를갖는다는결과를얻었을뿐아니라, 7-9 암환자를대상으로한다양한연구에서경구또는경장으로의오메가-3 지방산의공급은암악액질상태의환자에서체중감소, 식욕부진, 생존율과삶의질향상에영향을미친다는결과를보였다. 7,8 Takatsuka 등 10 의연구에서는조혈모세포이식을받은환자군을대상으로경구 EPA를공급하였을때, 이식편대숙주병 (graftversus-host disease, GVHD) 이나거대세포바이러스감염합병증의발생이적고사망률또한감소한다고보고하였으나, 조혈모세포이식환자를대상으로정맥으로의오메가-3 지방산공급에대한연구는거의진행된바없다. 본연구에서는정맥영양으로의 fish oil 공급이동종조혈모세포이식환자에서의임상적결과에어떤효과를갖는지확인하고정맥영양을지원하는데도움이되고자한다. 대상및방법 1. 연구대상및기간 2011년 7월부터 2015년 6월까지서울대학교병원에입원하여동종조혈모세포이식을받은 19세이상의성인환자중지방을포함하는정맥영양을 3일이상투여받은환자를대상으로하였다. 다음의경우는제외하였다. 1) 2회이상동종조혈모세포이식을받은경우, 2) 외국인, 3) 사망원인이자살인경우. 4) acute lymphocytic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, myelo-dysplastic syndrome (MDS), severe aplastic anemia (SAA) 이외의기저질환을가진경우, 5) human leucocyte antigen (HLA) type이 5/6, <8/10인경우, 6) 공여자가자녀, 부모, 또는제대혈인경우본연구는서울대학교병원임상연구윤리심의위원회승인하에시행되었으며, 후향적연구로연구대상자에대한동의서는면제되었다 (IRB no. H-1509-002-698). 2. 연구방법전자의무기록을후향적으로검토하여대상환자의기본정보 ( 나이, 성별, 키, 체중, body mass index [BMI]), 이식에대한정보 ( 기저질환, 이식원, HLA type, 이식전질환상태 ), TPN 투여기간, fish oil 투여기간및투여용량자료를수집하였다. 환자의임상적결과로는급성이식편대숙주병 (acute GVHD, agvhd), neutropenic fever, 패혈증발현유무와 30일사망률, 재원기간, 재입원율, 체중변화, 생존기간을조사하였다. 대상환자는투여된지방유제의종류에따라 fish oil을공급한군을 FO군 (fish oil group), fish oil 이외의지방을공급한군을 NFO군 (non-fish oil group) 으로분류하였다. 환자의임상적결과는이식이후 100일이내의 agvhd, neutropenic fever, 패혈증발생여부를확인하였다. GVHD는동종조혈모세포이식이후나타나는주요합병증으로, 피부발진, 간수치이상, 설사와복부통증을동반한위장관이상등의증상을동반하며 11 이식후 100일을기점으로그이전에나타난경우를 agvhd로분류하였다. 12 항진균제로서 amphotericin B, liposomal amphotericin B, voriconazole, caspofungin 4종류중하나이상의약제를사용한경우 neutropenic fever가발생하였다고정의하였으며, 혈액배양검사상균이동정된경우를패혈증으로정의하였다. Transplant-related mortality로 30일사망률을확인하였으며, 재입원율은이식일기준으로 100일이내에혈액종양내과로재입원한경우로하였다. 체중변화는조혈모세포이식을위해무균실에입실한시점을기준으로하였고, 이식후 14일시점에서의체중과그변화율을분석하였다. 3. 통계분석연속형변수에대해서는정규분포를따르는경우는 Student s t-test, 정규분포를따르지않는경우는 Mann-Whitney U test 를사용하였고, 범주형변수는 chi-square test, Fisher s exact test를사용하였다. 생존분석은 Kaplan-Meier 방법으로분석하였다. 자료의분석은 IBM SPSS Statistics ver. 23.0 (IBM Co., Armonk, NY, USA) 을사용하였으며, P값이 0.05 미만인경우통계적으로유의하다고판단하였다. 결과 1. 일반적특성 2011년 7월부터 2015년 6월까지서울대학교병원에입원하여동종조혈모세포이식을받은 19세이상의성인환자는 275명이었으며, 그중 3일이상지방을포함하는 TPN을투여받은환 30 Journal of Clinical Nutrition
Effect of Fish Oil in Patients Undergoing Allogeneic HSCT 자는 146명이었다. 이중제외기준에해당되는환자 56명을제외한 90명의환자군을대상으로연구를진행하였다. 투여된지방의종류에따라 fish oil을공급한 FO군이 55명, fish oil 이외의지방을공급한 NFO군이 35명으로분류되었으며, 대상환자의특성은 Table 1과같다. 대상환자의나이는 FO군과 NFO 군에서각각 46세 (21 64세) vs. 42세 (22 62세) 였고, 성비는남성이각각 61.8% vs. 62.9% 로많았다. BMI는두군에서각각 22.80±4.10 vs. 23.51±3.29였으며, 기저질환으로는급성백혈병이 78.2% vs. 82.9% 로가장많은비율을차지했다. 키이외의대상환자특성은두군에서통계적으로유의한차이를보이지않았다. 관해여부와상관없이이식을진행하는 MDS와 SAA를제외하고나머지기저질환에대하여이식이전의질병상태를확인하였고, FO군과 NFO군에서모두 complete remission (CR) 이 79.5% vs. 83.9% 로가장높은비율을차지했으며두군에서통계적으로유의한차이가없었다 (P=0.171, Fisher s exact test). 2. 영양지원상태 TPN 투여기간의중앙값은 FO군이 23일 (3 144일), NFO 군이 17일 (3 68일) 로 FO군에서유의하게길게나타났다 (P=0.010). FO군에서투여한 fish oil을함유하는 TPN의종류와오메가-3 지방산의함량은 Table 2와같으며, NFO군에서는지방유제로대두유, 중쇄지방산, 올리브유제제를사용하였다. 지방유제투여기간의중앙값은두군간유의한차이가없었으며 (FO vs. NFO=14 (3 95) vs. 14 (3 46); P=0.587), 지방유제의투여용량은체중당일일공급량으로계산하였을때 FO군에서는 0.218 1.193 g/kg, NFO군에서는 0.364 1.451 g/kg 범위였다. FO군에서오메가-3 지방산으로서의공급량은 0.033 0.240 g/kg 범위였다 (Table 3). Table 2. Content of omega-3 triglyceride (n=55) Volume (ml) Omega-3 triglyceride (g) Smoflipid 20% a 100 3.00 Smof Kabiven central a 1,477 8.43 Smof Kabiven peripheral a 1,206 5.10 Winuf central b 1,820 13.84 Winuf peripheral b 1,085 6.12 a Fresenius Kabi, Frankfurt, Germany. b JW Pharma, Seoul, Korea. Table 1. Patients characteristics (n=90) Characteristic Fish oil group (n=55) Non-fish oil group (n=35) P-value Age (y) 46 (21~64) 42 (22~62) 0.266 Sex (male/female) 34/21 (61.8/38.2) 22/13 (62.9/37.1) 0.921 Height (cm) 165.59±8.08 168.96±7.10 0.046 Weight (kg) 62.71±12.98 67.56±12.88 0.087 Body mass index (kg/m 2 ) 22.80±4.10 23.51±3.29 0.390 Disease 0.125 Acute lymphocytic leukemia 12 (21.8) 15 (42.9) Acute myeloblastic leukemia 31 (56.4) 14 (40.0) Hodgkin lymphoma 1 (1.8) 2 (5.7) Myelo-dysplastic syndrome 8 (14.5) 2 (5.7) Severe aplastic anemia 3 (5.5) 2 (5.7) Transplantation source 0.389 Peripheral blood 55 (100.0) 34 (97.1) Bone marrow 0 1 (2.9) Donor HLA typing 0.191 Full match 38 (69.1) 20 (57.1) 1 locus mismatch 13 (23.6) 8 (22.9) 2 loci mismatch 4 (7.3) 7 (20.0) Disease status (n=75) 0.171 CR1 26 (59.1) 21 (67.7) CR2 9 (20.5) 5 (16.1) Partial remission 0 2 (6.5) Persist 8 (18.2) 2 (6.5) Progressive disease 0 1 (3.2) Relapse 1 (2.3) 0 Values are presented as median (range), number (%), or mean±standard deviation. CR = complete remission. Volume 8, Number 1, April 2016 31
Ji Hyeong Choe, et al. Table 3. Nutrition support state (n=90) Fish oil group (n=55) Non-fish oil group (n=35) P-value Total parenteral nutrition duration (d) 23 (3 144) 17 (3 68) 0.010 Lipid duration (d) 14 (3 95) 14 (3 46) 0.587 Lipid dose (g/kg) 0.218 1.193 0.364 1.451 - -3 dose (g/kg) (n=55) 0.033 0.240 0 - Values are presented as median (range) or range only. Table 4. Clinical outcomes (n=90) Fish oil group (n=55) Non-fish oil group (n=35) P-value Acute graft-versus-host disease 26 (47.3) 19 (54.3) 0.517 Neutropenic fever 35 (63.6) 23 (65.7) 0.841 Sepsis (culture) 22 (40.0) 9 (25.7) 0.164 30 days mortality 2 (3.6) 1 (2.9) 1.000 Length of stay 44 (24~323) 43 (23~107) 0.474 Rehaspitalization (n=71) 14/40 (35.0) 12/31 (38.7) 0.748 Values are presented as number (%) or median (range). Table 5. Weight change (n=90) Fish oil group (n=55) Non-fish oil group (n=35) P-value Weight change (%) +0.34±5.61 1.08±5.57 0.245 Values are presented as mean±standard deviation. 3. 임상적결과두환자군에서의임상적결과는 Table 4과같다. agvhd는 FO군에서더낮은비율로발생하였지만, 그유의성은없었다 (FO vs. NFO=47.3% vs. 54.3%; P=0.517). 감염합병증의지표로확인한 neutropenic fever의경우두군에서차이를보이지않았고 (FO vs. NFO=63.6% vs. 65.7%; P=0.841), 패혈증의발생도유의한차이를보이지않았으나 FO군에서더높은경향을보였다 (FO vs. NFO=40.0% vs. 25.7%; P=0.164). 30 일사망률 (FO vs. NFO=3.6% vs. 2.9%; P=1.000) 과재원기간 (FO vs. NFO=44 (24 323) vs. 43 (23 107); P=0.474) 또한통계적유의성은없었다. 이식후 100일이상생존한환자 71명의 100일이내의재입원율을확인하였으며, 두군에서유의한차이를보이지않았다 (FO vs. NFO=35.0% vs. 38.7%; P=0.748) (Table 4). 체중변화는 FO군에서 0.34% 의체중증가를보인반면 NFO 군에서는 1.08% 의체중감소를보였다 (P=0.245) (Table 5). 생존기간의경우에도두군에서유의한차이를보이지않았고, 이식일을기준으로 100일이내에재입원한환자 26명을대상으로생존기간을분석결과 FO군에서생존기간이더긴경향 을보였으며 (FO vs. NFO=675.45±132.74 vs. 481.33±128.99; P=0.473), FO군은 50% 이상이생존하고있음을확인할수있었다 (Fig. 1). 고찰 본연구에서는정맥영양으로의 fish oil 공급이동종조혈모세포이식환자에서의임상적결과에어떤효과를갖는지확인하고자하였다. 연구결과 fish oil을포함하는정맥영양을공급받은군에서체중이증가하는경향을보였지만통계학적인유의성을보이지는않았으며, agvhd, 감염합병증이나재원기간감소에는차이를보이지않았다. 30일사망률이나생존기간에도유의한차이를보이지않았지만, 재입원한환자를대상으로한 subgroup 분석에서는 FO군에서생존기간이긴경향을보였다. 오메가-3 지방산인 EPA는오메가-6 지방산의한종류인아라키돈산 (arachidonic acid, AA) 을감소시키며, EPA의대사산물인류코트리엔 (leukotriene, LT) B5와프로스타글란딘 (prostaglandin, PG) I3는 AA의대사산물이자염증반응을일으키는 32 Journal of Clinical Nutrition
Effect of Fish Oil in Patients Undergoing Allogeneic HSCT FO group (n=55) NFO group (n=35) P-value FO group (n=14) NFO group (n=12) P-value Survival period (d) 676.0 (24 1,138) 632.0 (30 1,406) 0.926 Re-hospitalized (d) 675.45±132.74 481.33±128.99 0.473 Values are presented as median (range). Values are presented as mean±standard deviation. Fig. 1. (A) Survival period of total patients, (B) survival period of re-hospitalized patients. FO = fish oil, NFO = non-fish oil. LTB4, PGI2, PGE2 등과경쟁적으로작용하여항염증효과를갖는다고알려져있다. 4,5,13 실제로중환자를대상으로한메타분석연구에서는오메가-3 지방산을포함하는정맥지방유제를공급하였을때, 감염합병증과 ventilation 기간이감소하였고 9,14 재원기간이단축되었다는결과를얻었다. 9,14,15 수술환자를대상으로한연구들에서도정맥으로의오메가-3 지방산을공급받은환자에서극명한감염합병증감소와재원기간감소를보였다. 16-18 Takatsuka 등 19 의연구에서는이러한항염증반응을갖는 EPA가조혈모세포이식에서의주요한합병증중하나인 GVHD 의치료에이점이있을수있다고제시하고있다. GVHD는주로조혈모세포이식에앞서시행하는전처치에의한세포손상이원인이되어나타나게되는데, Takatsuka 등 19 은감염에의한염증사이토카인의분비로혈관내피세포가손상되면서 GVHD 증상이나타나는것으로보고있으며이를전신염증반응증후군 (systemic inflammatory response syndrome, SIRS) 으로정의하였다. 연구자는이런가설을기반으로하여 EPA는염증사이토카인의분비를억제하고 SIRS로인한혈관내피세포손상을감소시켜 GVHD의치료에사용될수있다고설명하였다. 실제로조혈모세포이식을받은환자군에서경구 EPA를공급하였을때 GVHD, cytomegalovirus (CMV) 감염합병증이적고사망률을감소시키는것으로보고되었으나그표본수가매우작아 (n=16) 임상적유의성을판단하기에는어려움이있다. 한편암환자에서는약 50% 에서암악액질이나타나며, 그로 Volume 8, Number 1, April 2016 인한영양결핍과체중감소는사망의주요원인이된다. 2 따라서암환자에서의영양지원은중요하게생각되며, 상대적으로다양한연구가진행되었다. 암악액질은 tumor necrosis factor-, interleukin (IL)-6, IL-1 등염증사이토카인의증가를동반하는염증반응과그에의한단백분해와지방분해로발생한다. 20 In vitro 실험을통해 EPA는유비퀴틴-프로테아좀단백분해과정의활성을감소시켜골격근량감소를억제할수있음을확인하였으며, 또한당질코르티코이드의신호전달을방해하여 Zinc- 2-glycoprotein의발현을감소시키고, 지방분해를억제함으로써악액질로부터지방조직을보호한다는결과를얻었다. 21 The American Society for Parenteral and Enteral Nutrition clinical guideline에서는경구로의오메가-3 지방산의보충은암환자에서의체중안정화에도움이되며, 오메가-3 지방산을포함하는 immune enhancing enteral formula는주요한암수술을시행한영양결핍환자에게이점을갖는다고제시되어있다. 2 이런연구에서는대부분체중감소나영양결핍을보이는진행성암환자를대상으로하였으며, 경구로오메가-3 지방산을공급하였다. 본연구에서는혈액암환자를대상으로하였고, 상당수의환자가 CR 상태 (FO vs. NFO=79.5% vs. 83.9%) 였다는점, BMI (FO vs. NFO=22.80±4.10 vs. 23.51±3.29) 가정상범위였다는점에서암악액질상태의가능성이낮았고, 따라서체중변화의효과가적었을것으로생각된다. 본연구에서는두환자군의특성을유사하게하여비교가능성 33
Ji Hyeong Choe, et al. 을높였다는데의의가있다. 조혈모세포이식결과에부정적인영향을주는주요한위험인자로는크게 3가지가있는데, 이식시점에서의질환상태, 환자의나이, HLA 일치정도이다. 질환상태는기저질환의종류나공여자의종류등과관계없이가장주요한위험인자이며, 2세이상의환자에서는나이가증가할수록이식후의사망률이증가하고, HLA type 또한일치정도가떨어질수록부정적인결과를야기한다. 22 본연구에서는두군의기저질환, 이식원과공여자뿐만아니라질환상태, 연령, HLA 일치여부를유사하게하여환자의임상적결과에영향을미칠수있는인자를최대한배제하고자하였다. 또한이전에연구된바적은조혈모세포이식환자를대상으로정맥으로의 fish oil 공급에대한연구라는점에서의의가있다. 그러나본연구는다음과같은한계를갖는다. 서울대학교병원에서는 2011년 11월처음 fish oil을함유한정맥지방유제를사용하기시작하였으며, 이후 fish oil를함유한 TNA 제제의사용량이증가하였다. 이시점을전후로하여약 4년간의환자군을대상으로연구를진행하였고, 충분하지못한표본수로인해검정력이감소하여통계적유의성을확인하기어려웠다. 또한후향적연구인점에서임상적결과와 fish oil 공급과의관계를명확하게규정하는데한계가있었다. 오메가-3 공급량의경우, 환자의임상상태또는식이상태변화에따라공급되는 TPN의용량이변화했을가능성이있으며다양한용량범위로사용되었다. Heller 등 23 과 Heller 24 는중환자를대상으로한연구에서 fish oil로서 0.05 g/kg/day 미만으로공급받은군에비하여 0.1 0.2 g/kg/day 투여한군에서생존율이더높았다는결과를얻었으며, 하루 0.15 0.2 g/kg 수준으로 fish oil을공급하였을때, 항생제치료의필요성을낮출수있다는결론을내렸다. 본연구에서는임상적으로효과를보일것이라고예상되는 0.1 g/kg 용량미만을공급한환자가 20명 (36.4%) 으로상당수포함되어있어, fish oil의효과를확인하는데제한점이있을것으로생각된다. 또한경구나경장영양을섭취하는환자에서의영양공급에대한정보가충분하지못하여경구로서의 fish oil 공급은고려되지못했다. 한편 FO군에서패혈증의발생률이더높은경향성을나타내었는데, 이는 TPN 투여기간과관련이있을것으로생각된다. TPN 기간이길어질수록패혈증이나감염합병증의발병률은증가한다고알려져있으며, 25 FO군에서의 TPN 투여기간이 NFO군과비교하여유의하게길었다. 이는환자의임상상태, 질병의중증도, 임상경과등에영향을받았을것으로추정된다. 향후보다많은표본수의전향적무작위임상연구를통해동종조혈모세포이식환자에서정맥으로의 fish oil을공급하는것이 GVHD 발생률, 감염합병증예방과체중변화등임상적결과에 유의한효과를나타내는지에대한확인이필요하며, 또한오메가-3 지방산의용량에따른임상적결과를연구해보는것도의미가있을것이다. 결론 본연구에서는동종조혈모세포이식환자에서 fish oil을포함하는정맥지방유제의공급이환자의임상적결과에유의한영향을미치지못하였다. 그러나 fish oil을투여한군 (FO군) 에서체중증가양상을보였으며, 재입원환자를대상으로한생존기간분석에서 FO군의생존기간이더긴것을확인하였다. 따라서동종조혈모세포이식환자에서의 fish oil의임상적유용성을평가하기위해서는추가적인연구가필요할것으로생각된다. REFERENCES 1. Charuhas PM, Lipkin A, Lenssen P, McMillen K. Hematopoietic stem cell transplantation. In: Merritt R, ed. A.S.P.E.N Nutrition support practice manual. 2nd ed. Silver Spring:ASPEN;2005: 187-99. 2. August DA, Huhmann MB; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr 2009;33(5):472-500. 3. Bozzetti F, Arends J, Lundholm K, Micklewright A, Zurcher G, Muscaritoli M; ESPEN. ESPEN Guidelines on Parenteral Nutrition: non-surgical oncology. Clin Nutr 2009;28(4):445-54. 4. Vanek VW, Seidner DL, Allen P, Bistrian B, Collier S, Gura K, et al; Novel Nutrient Task Force, Intravenous Fat Emulsions Workgroup; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. A.S.P.E.N. position paper: clinical role for alternative intravenous fat emulsions. Nutr Clin Pract 2012;27(2):150-92. 5. Calder PC. Immunonutrition in surgical and critically ill patients. Br J Nutr 2007;98 Suppl 1:S133-9. 6. Ahn HS, Heo SC. Immunonutrition in surgical patients. JKSPEN 2013;5(1):10-4. 7. Marian M, Carlson SJ. Enteral formulations. In: The A.S.P.E.N nutrition support practice manual. 2nd ed. Silver Spring: ASPEN;2005:63-75. 8. van der Meij BS, van Bokhorst-de van der Schueren MA, Langius JA, Brouwer IA, van Leeuwen PA. n-3 PUFAs in cancer, surgery, and critical care: a systematic review on clinical effects, incorporation, and washout of oral or enteral compared with parenteral supplementation. Am J Clin Nutr 2011;94(5):1248-65. 9. Manzanares W, Langlois PL, Lemieux M, Heyland DK. Fish 34 Journal of Clinical Nutrition
Effect of Fish Oil in Patients Undergoing Allogeneic HSCT oil-containing emulsions: when fat seems to improve clinical outcomes in the critically ill. JPEN J Parenter Enteral Nutr 2016;40(3):305-7. 10. Takatsuka H, Takemoto Y, Iwata N, Suehiro A, Hamano T, Okamoto T, et al. Oral eicosapentaenoic acid for complications of bone marrow transplantation. Bone Marrow Transplant 2001; 28(8):769-74. 11. Socié G, Blazar BR. Acute graft-versus-host disease: from the bench to the bedside. Blood 2009;114(20):4327-36. 12. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11(12):945-56. 13. Jho DH, Cole SM, Lee EM, Espat NJ. Role of omega-3 fatty acid supplementation in inflammation and malignancy. Integr Cancer Ther 2004;3(2):98-111. 14. Pradelli L, Mayer K, Muscaritoli M, Heller AR. n-3 fatty acid-enriched parenteral nutrition regimens in elective surgical and ICU patients: a meta-analysis. Crit Care 2012;16(5):R184. 15. Palmer AJ, Ho CK, Ajibola O, Avenell A. The role of -3 fatty acid supplemented parenteral nutrition in critical illness in adults: a systematic review and meta-analysis. Crit Care Med 2013; 41(1):307-16. 16. Li NN, Zhou Y, Qin XP, Chen Y, He D, Feng JY, et al. Does intravenous fish oil benefit patients post-surgery? A metaanalysis of randomised controlled trials. Clin Nutr 2014;33(2): 226-39. 17. Wei C, Hua J, Bin C, Klassen K. Impact of lipid emulsion containing fish oil on outcomes of surgical patients: systematic review of randomized controlled trials from Europe and Asia. Nutrition 2010;26(5):474-81. 18. Chen B, Zhou Y, Yang P, Wan HW, Wu XT. Safety and efficacy of fish oil-enriched parenteral nutrition regimen on postoperative patients undergoing major abdominal surgery: a meta-analysis of randomized controlled trials. JPEN J Parenter Enteral Nutr 2010;34(4):387-94. 19. Takatsuka H, Iwasaki T, Okamoto T, Kakishita E. Intestinal graft-versus-host disease: mechanisms and management. Drugs 2003;63(1):1-15. 20. Aoyagi T, Terracina KP, Raza A, Matsubara H, Takabe K. Cancer cachexia, mechanism and treatment. World J Gastrointest Oncol 2015;7(4):17-29. 21. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009;89(2):381-410. 22. Rzepecki P, Barzal J, Oborska S. Blood and marrow transplantation and nutritional support. Support Care Cancer 2010;18 Suppl 2:S57-65. 23. Heller AR, Rössler S, Litz RJ, Stehr SN, Heller SC, Koch R, et al. Omega-3 fatty acids improve the diagnosis-related clinical outcome. Crit Care Med 2006;34(4):972-9. 24. Heller AR. Intravenous fish oil in adult intensive care unit patients. World Rev Nutr Diet 2015;112:127-40. 25. Sacks GS, Mayhew S, Johnson D. Parenteral nutrition implementation and management. A.S.P.E.N Nutrition support practice manual. 2nd ed. Silver Spring:ASPEN;2005:108-17. Volume 8, Number 1, April 2016 35