Transcript Olive oil-based intravenous lipid emulsion in pediatric patients

Olive oil-based intravenous lipid emulsion
in pediatric patients undergoing bone
marrow transplantation: A short-term
prospective controlled trial
Received 11 August 2008;
accepted 28 April 2009.
Available online 3 June 2009.
Clinical Nutrition
營養師鄭秀英9901
Introduction
• Nutritional support has become an integral part
of the supportive care of bone marrow
transplanted (BMT) patients. In recent years,
use of parenteral nutrition (PN) has markedly
decreased in favor of enteral nutrition .
• PN is indispensable when the gastrointestinal
toxicity induced by high-dose chemotherapy and
radiotherapy precludes optimal nutrient intake
and utilization.
• Intravenous lipid emulsions (ILE) are important
components of PN solutions that allow delivery
of increased energy supply, provision of
essential fatty acids (linoleic and α-linolenic
acids) and fat-soluble vitamins .
• The concern that excess of ω-6 polyunsaturated
fatty acids (PUFA), present in the classic
soybean or safflower-based ILE, might be
immunosuppressive and proinflammatory, has
led to the development of alternative lipid
emulsions .
• Lipid emulsions based on mixtures of long-chain
triglycerides (LCT) and medium-chain
triglycerides (MCT) were formulated in order to
reduce the ω-6 PUFA content. The ω-6 to ω-3
PUFA ratio is similar in both soybean and
MCT/LCT lipid emulsions but the linoleic and αlinolenic content of MCT/LCT mixtures is half of
that of soybean based ILE.
• The MCT/LCT lipid emulsions have the
theoretical advantage of faster clearance from
the blood stream, are less susceptible to
peroxidation, have less impact on the
reticuloendothelial system and cause less
systemic inflammatory response due to lower ω6 PUFA content .
• There are no studies comparing the use of
olive oil-based lipid emulsions to LCT/MCT
emulsions in pediatric BMT patients. The
objectives of this prospective, randomized
study were to assess short-term safety
and metabolic effects of olive oil-based
(OO) lipid emulsions compared with
MCT/LCT (M/L) lipid emulsions in the
clinical setting of pediatric bone BMT
patients.
• 而已上市的脂肪乳劑中含有50 %中鏈脂肪酸
（MCTs），研究證實中鏈脂肪酸（MCFAs）代謝速
率較長鏈脂肪酸（LCFAs）快，中鏈脂肪酸（MCFAs）
無需carnitine作為媒介，而長鏈脂肪酸（LCFAs）快則
需carnitine作為媒介；另外中鏈脂肪酸（MCFAs）較
不易蓄積，反之長鏈脂肪酸（LCFAs）只有30%被代
謝，剩餘部分則被儲存。
飽和脂肪酸
單元不飽和脂肪
酸
多元不飽和脂
肪酸
理想的脂肪乳
劑
25%
50%
25%
大豆油
15%
25%
60%
橄欖油
(ClinOleic)
15%
65%
20%
• 以大豆油為原料所製成的長鏈三酸甘油脂（LCT）已超過30年，
長鏈三酸甘油脂（LCT）可提供熱量且少有急性的副作用發生。
然而，與脂肪酸建議攝取量比較，它含有過多的不飽和脂肪酸
（PUFA），也就是過多的ω-6系列的脂肪酸，因此細胞膜中的
磷脂質所含linoleate, ω-6及ω-3的數量與輸注長鏈脂肪酸（LCT）
有關，
• 另外，大豆油製成的乳劑富含γ-tocopherol，但僅含少量αtocophererol，然而α-tocophererol是維生素E中最具抗氧化功
能的同分異構物，同時也是唯一可藉肝內特殊的蛋白質再合成
的物質，持續輸注大豆油製成的乳劑會使得血漿蛋白中的αtocophererol減少，也就是將減少體內抗氧化的能力。
• 使用不飽和脂肪酸（PUFA）較低的脂肪乳劑，例如以50：50
比例的中鏈脂肪酸（MCT）和大豆油（LCT），或80：20比例
的橄欖油和大豆油，不會明顯地改變脂肪酸在細胞膜上的形式，
因此可避免因過氧化對細胞造成的傷害，尤其是含豐富的αtocophererol的脂肪乳劑，而且中鏈脂肪酸（MCT）有助於血
漿的廓清。
• 長期補充魚油對ω-3的保護以對抗發炎、血栓反應、癌症
及惡病質，同時報告也指出ω-3可維持器官移植後的組織
灌流。
• 近年來更發現ω-3可避免心律不整及血管纖維化；其中
EPA具上述功能，而DHA則與神經系統的成熟度及因早產
而引起的視網膜病變有關。
• 在前列腺素等的生成上，必需脂肪酸（EFA）直接與
arachidonic acid（AA）對抗，因為arachidonic acid (AA)
直接與eicosanoids的生成相關，花生四稀酸中的
eicosanoids為引起發炎、血栓的化學誘質前驅物，而相
對的從EPA調停的作用產生影響非常的微弱。
• 使用混合中鏈脂肪酸（MCT）的靜脈注射脂肪乳劑、大豆
油長鏈脂肪酸（LCT）及魚油三酸甘油脂之混合比例為5：
4：1
Patients and methods
• 2.1. Patient selection
• We prospectively enrolled 28 children, aged 1–18 years
who underwent BMT at the BMT Unit of Pediatric
Oncology-Hematology Department, Meyer Children's
Hospital, Rambam Health Care Campus, during 2003–
2004 and needed PN support for at least 2 weeks. We
expected that children with more severe mucositis and
feeding difficulties that started earlier during conditioning
will need longer periods of PN.
• Children who received PN less than 8 days, had
abnormal liver function tests before initiation of PN (total
bilirubin >2.5 mg/dL, SGOT/SGPT >2.5× upper limit of
normal) and enteral daily intake of more than 50% of
total calories were not included in the study.
• The protocol of the study was approved by the human
ethical committee of Rambam Health Care Campus.
Written informed consent was obtained for each patient.
2.2. Bone marrow transplantation
• BMT was carried out according to standard protocols for
autologous and allogeneic procedures. Total body
irradiation and graft versus host disease (GVHD)
prophylaxis were administered to allogeneic BMT
recipients. Furthermore, patients were treated with highdose chemotherapy (busulfan and/or cyclophosphamide),
followed by infusion of bone marrow from a
histocompatible donor (allogeneic) or by re-infusion of
previously cryopreserved autologous bone marrow
(autologous). In addition to nutritional support, standard
supportive care during the recovery phase included
reverse isolation, antimicrobial therapy, GVHD and venoocclusive disease prophylaxis and blood products
support.
2.3. Study protocol
• The children included in the study were randomly
assigned to PN containing one of two lipid emulsions,
1.M/L lipid emulsion (Lipofundin 20%, B. Braun,
Melsungen, Germany) which was composed of 50%
MCTs and 50% LCTs
2.OO lipid emulsion (Cinoleic 20%, Baxter SAS,
Maurepas, France).
• PN solutions were supplied by TEVA Pharmaceuticals
Inc., Israel, to the pharmacy of Rambam Health Care
Campus. Allocation of individuals to groups was done by
following a table of computer-generated random
numbers.
• The investigators, attending and primary physicians,
patients, the nursing staff and the study pharmacist who
received coded PN solutions were blinded to
randomization and treatment scheme.
• 商品名：10% 500 MCT/LCT
Lipofundin
• 成分名：Soybean Oil/Triglycerides
Medium Chain/Egg Phosphatides/Glycerin
infusion 100 mg/100mg/12mg/25mg/ml
20% 250ml
• The other PN constituents were similar in both groups.
All patients received individualized ‘all-in-one’ PN
solution containing appropriate amounts of fluid,
dextrose, l-amino acids (Primene 10%; Baxter Clintec,
Maurepas, France), electrolytes, vitamins (MVI
Pediatric; Mayne Pharma, USA) and trace elements
(Peditrace; Fresenius Kabi, Bad Homburg, Germany).
• The basal energy needs were calculated on the basis
of WHO standards. Because of the controversies
regarding the REE and energy requirements in
patients with cancer or those undergoing BMT, we
chose to supply 100% to 120% of REE according to
nutritional and clinical status of each individual.23
• Non-protein energy was provided as 70%
dextrose and 30% lipid emulsion. The protein
needs were calculated according to
recommended protein intakes with PN (including
energy from amino acids) and adjusted for each
patient depending on clinical and nutritional
status.24
• Water and electrolytes content of PN solutions
were adjusted daily on the basis of age
requirements, intestinal losses and of serum
chemistry test results.
• PN support was initiated when patients’
oral/enteral intake decreased to less than 50%
of estimated energy requirements. PN was
discontinued when oral intake was >50% of the
calculated maintenance energy needs for 3
consecutive days.
2.4. Assessment of nutritional status
• Weight, height and weight for age z-scores
were calculated for each patient at the
start of PN.
• Afterwards, only weight was measured
daily.
• Energy and macro-nutrients intake from
patient food records and PN were
calculated daily by the ward dietitian.
2.5. Laboratory investigations
• Daily complete blood count, urea, electrolytes,
serum bilirubin, liver transaminases, alkaline
phosphatase, serum proteins, creatinine,
inorganic phosphate, albumin, total cholesterol,
triglycerides and coagulation status were
routinely performed.
• Serum Vitamin E, 25(OH)D3 and plasma fatty
acids profile were evaluated at the start of PN
and on day 14 on PN. Plasma concentrations of
thiobarbituric acid reactive substances (TBARS),
an index of lipid peroxidation and oxidative
stress, were assayed at the start and on the 14th
day of the study.
2.6. Statistical analysis
• Continuous variable are expressed as means ± SEM.
Data were recorded at study entry (baseline) and at day
14. Statistical analyses were performed using SPSS for
Windows (15.0).
• Comparisons between the two groups were performed
using Student's t-test.
• Change differences between groups were analyzed
using analysis of covariance on change scores with
baseline levels serving as covariates.
• Because of the groups’ heterogeneity it was felt that the
use of this statistical method would better measure the
changes in the assessed variables.
• Significance level for all comparisons was set at
α = 0.05.
3. Results
• Patients’ age, sex, body weight and primary
diagnosis were not significantly different
between the two PN protocols (Table 1).
• Five of the 13 (38%) children in the M/L and 3/15
(20%) in the OO group underwent autologous
BMT (NS).
• The number of days on PN and the daily energy
and macro-nutrients supply from enteral and PN
were not different in the two groups (Table 2).
• Means and SEMs of outcome variables at
baseline and at day 14 on PN are presented in
Table 3. Skewness and kurtosis analyses
indicated no significant deviation from normality
for all study variables.
3.1. Safety results
• There were no differences between the groups with regard to
the success of engraftment, that occurred in 11/13 (85%) and
14/15 (93%) children from the M/L and OO group respectively,
or post-transplantation time to engraftment.
• There were no differences in the routine laboratory
parameters including complete blood count, urea, electrolytes,
serum bilirubin, transaminases, alkaline phosphatase, serum
proteins, creatinine, inorganic phosphate and albumin and
coagulation studies between the two groups at baseline or
follow-up.
• At the end of follow-up (day 14) the M/L group weight z-score
was −0.43 ± 0.4 compared to −0.86 ± 0.4 at the start of PN
(50% change in weight z-score) and the OO group weight zscore was −0.26 ± 0.3 compared to −0.35 ± 0.3 at the start of
PN (26% change in weight z-score), p = 0.03, meaning that
compared to children in the OO group, the children in the
M/L group gained more weight during the study period
3.2. Lipid and fat-soluble vitamins profile
and peroxidation status
• The baseline serum triglycerides were higher in the OO
group but not statistically significantly different from the M/L
group.
• Total serum cholesterol levels decreased significantly in the
OO group at the end of the study period and there was a
trend towards lower blood levels for triglycerides in the OO
group when compared to the baseline levels.
• Fatty acids profiles showed significant differences
between the two groups. The results revealed that, with
baseline levels controlled for, oleic, linoleic and arachidonic
acids serum levels increased significantly at 14 days in the
OO group. Eicosapentanoic (EPA) and docosahexanoic
acids (DHA) levels were not different in the two groups at
baseline or follow-up.
• Serum vitamin E, vitamin E/cholesterol ratio, 25(OH)D3 and
plasma concentration of TBARS were not different within
and between the groups at baseline or follow-up.
4. Discussion
• This is the first study that assessed short-term
safety and metabolic effects of OO lipid
emulsion (Clinoleic) compared with M/L
emulsion (Lipofundin) in the clinical setting of
pediatric BMT patients.
• We found no significant differences for
hematological parameters, liver enzymes,
vitamins concentration, plasma TBARS or
success of engraftment.
• The OO group had significantly higher plasma
oleic acid and showed a favorable lipids profile
as reflected by the decreased cholesterol and
triglyceride levels. Therefore, our study suggests
that OO lipid emulsions might be a safe and well
tolerated alternative ILE for short-term use in
children undergoing BMT.
• Plasma oleic acid concentration was, predictably,
significantly higher in the OO group at follow-up.
• In addition, linoleic acid and its long-chain homologue
arachidonic acid levels also increased significantly after
14 days.
• It is possible that the differences in the patients’ primary
diagnoses, pre-transplantation treatments and
conditioning regimens can be accounted for by the
higher linoleic and arachidonic acid levels in the OO
group.
• the data suggest that essential fatty acids deficiency is
not a limitation in the short term and even during longer
treatment periods in spite of lower PUFA content of OO
lipid emulsions
• Excessive ω-6 PUFA may alter the metabolism
of ω-3 PUFA due to enzymatic competition for
the desaturation and elongation; however, there
was no appreciable effect on the plasma EPA
and DHA levels that were similar in the two
groups.
• It was previously shown that premature infants
had increased linoleic and linolenic acids but
decreased plasma arachidonic and
docosahexanoic acids after 8 days of Clinoleic
infusion. That reflects probably the impaired
capacity of premature infants to synthesize longchain PUFA
• In spite of evident differences in the fatty acid lipid
profiles, due to different fatty acids composition of
the two ILE, we found no disturbances in the
metabolic profiles, plasma peroxidation status or
clinical endpoints such as number of children who
achieved engraftment or the time to engraftment.
• Serum triglycerides levels were marginally lower in
the OO group, suggesting that plasma clearance of
olive oil-based ILE is at least as good, if not better
than that of M/L emulsions.
• The children in the OO group showed a significant
reduction in cholesterol levels after the period of PN
supplementation. A similar result has been reported
previously by Goulet et al. in children treated with
olive oil-based PN for 2 months.15
• In the limited studies available in BMT patients, the
administration of standard PN did not prevent decreases
in plasma micronutrient antioxidants, such as vitamin E
and β-carotene.30
• As Clinoleic has a lower content of PUFA than MCT/LCT
emulsions and supplies the α-tocopherol naturally found
in olive oil, it has been suggested that it may have a
positive impact by lowering the risk of lipid
peroxidation.32
• In our study no significant differences were recorded in
vitamin E and vitamin E/cholesterol ratio that were within
the normal range in both groups at baseline and day 14,
although a higher plasma α-tocopherol/total lipid ratio
was reported in a study in premature infants given olive
oil-based lipid emulsions.14
• The limitations to our study are mostly related to the
small size and the heterogeneity of the study groups, the
time-limited duration of the PN and short-term follow-up
that could have decreased our ability to show the full
impact of the intervention.
• Our group included children with different primary
diagnoses who receive either autologous or allogeneic
BMT, have been through different treatments before BMT
and followed different BMT protocols according to their
primary diagnosis and stem cells source.
• Although there was a relatively comparable distribution
for types of primary disorders and BMT procedures, this
was a heterogeneous group, which may account for the
differences, even if not significant, observed in some of
the clinical and laboratory parameters of the two groups.
Because the study evaluated the outcomes at day 14,
just at the time of engraftment, no child developed
GVHD during the study.
• Therefore for the purpose of our study we
considered the two groups as similar enough for
comparison of the two lipid emulsion solutions.
• Finally, the children in both groups received
relatively low parenteral lipids supply.
• It is possible that higher doses of OO lipid
emulsions given for longer periods are
associated with adverse effects, although Goulet
et al. did not record such effects with 2 g/kg/day
of OO lipid emulsion provided during a 2-month
period.15
• With all these limitations, we can conclude that
in children who underwent BMT and were in
need of PN support, short-term provision of OO
lipid emulsion was well tolerated as was the M/L
lipid emulsion.
• No adverse events were observed during the
study period, suggesting that short-term use of
olive oil-based intravenous lipid emulsions might
be safe.
• Larger studies and safety data during longer
treatment periods are needed to confirm our
data.