The efficacy of fish-oil based fat emulsion administered from the first day of life in very low birth weight newborns.
Efekty stosowania emulsji tłuszczowej opartej na oleju rybim w żywieniu pozajelitowym od pierwszej doby życia u noworodków z bardzo małą urodzeniową masą ciała
Dorota Pawlik, Ryszard Lauterbach, Joanna Hurkała
Department of Neonatology
Head of Department: Professor R. Lauterbach MD.
Jagiellonian University, Collegium Medicum, Kraków, Poland
Background: DHA has been shown to be important for foetal brain development, optimal development for motor skills and visual acuity in infants. Newborns born prematurely are at increased risk for DHA (docosahexaenoic acid) insufficiency because they may not have benefited from a full trimester of the mother’s lipid stores and have very limited ability to synthesize DHA. Moreover, within the first 2-3 weeks of life, the main sources of lipids for most prematurely delivered infants are soyabean/safflower/olive oil emulsions which are rich in n-6 fatty acids and do not contain DHA.
Aim: To perform a retrospective analysis, which compares the safety and efficacy outcomes of an intravenous fat emulsion based on fish-oil (containing docosahexaenoic acid- DHA), and is administered from the first day of life in very low birth weight newborns, with data obtained in preterm neonates with birthweight below 1500 g, receiving soyabean/olive oil emulsion, which do not contain DHA.
Materials and methods: Infants from the two groups (the study group n=152; the control group n=185) were comparable with regard to demographic and clinical characteristics and were subjected to the same conventional therapy. Determination of plasma and erythrocytes DHA concentrations in newborns was made using a high-performance liquid chromatography-mass spectrometry (LC-ESI/MS) method. Detection of parent ions with negative ionization mode, m/z 327.5 amu. Method validation was according to the ICH and FDA requirements.
Results: There was a significantly lower risk of cholestasis in infants, who were receiving the soyabean/ olive oil/fish-oil emulsion (p=0.025). Also, there was a markedly lower risk of laser therapy in infants, who were receiving a fish-oil emulsion however, the difference did not reach statistical significance.
Conclusions: Fish-oil-based fat emulsion administered as a component of total parenteral nutrition from the first day of life is safe in the prophylaxis of cholestasis and severe retinopathy of prematurity. Further clinical investigations are needed.
Key words: models of nutrition, children, adolescents
Uzasadnienie: Kwas dokozaheksaenowy (DHA) jest niezwykle ważnym lipidowym składnikiem błony komórkowej. Szczególnie duża ilość tego lipidu znajduje się w błonach komórek ośrodkowego układu nerwowego oraz siatkówki. Powszechnie uważa się, że niedobór tego składnika w organizmie rozwijającego się dziecka może spowodować istotne zaburzenia w rozwoju neurologicznym a także wpłynąć niekorzystnie na funkcje narządu wzroku. Szczególnie zagrożone niedoborem DHA są noworodki urodzone przedwcześnie, u których, zachodzący intensywnie w trzecim trymestrze ciąży transport tego kwasu od matki przez łożysko, zostaje przerwany w chwili wystąpienia porodu. Noworodki urodzone przedwcześnie nie są również w stanie syntetyzować odpowiednich ilości DHA w ciągu pierwszych tygodni po urodzeniu a często jedynym źródłem tłuszczu w tym okresie życia jest dla nich dożylna emulsja, nie zawierająca w składzie kwasu dokozaheksaenowego.
Cel pracy: Autorzy przedstawiają rezultaty analizy retrospektywnej, przeprowadzonej w dwóch grupach noworodków z bardzo małą urodzeniową masą ciała, otrzymujących emulsje tłuszczowe w trakcie stosowania żywienia pozajelitowego, które zawierały DHA bądź były całkowicie pozbawione tego składnika.
Materiał i metodyka: W grupie 152 wcześniaków wykorzystano w żywieniu pozajelitowym roztwór lipidów oparty na oleju rybim (zawierającym kwas dokozaheksaenowy) oraz oleju sojowym i oleju z oliwek. Natomiast w grupie 185 dzieci, w żywieniu pozajelitowym podawano emulsję lipidową opartą wyłącznie na roztworze tłuszczu sojowego i oleju z oliwek. Obie grupy noworodków były porównywalne pod względem dojrzałości masy urodzeniowej oraz stanu klinicznego a także stosowano u nich takie same metody terapii. Oznaczenie stężenia DHA w osoczu i erytrocytach noworodków metodą wysokosprawnej chromatografii cieczowej sprzężonej z detekcją masową (LC-ESI/MS). Detekcja jonów macierzystych w trybie jonizacji ujemnej, m/z 327,5 amu. Walidacja metod zgodnie z wytycznymi ICH i FDA.
Wyniki: U noworodków żywionych parenteralnie emulsją tłuszczową zawierającą DHA stwierdzono znamiennie statystycznie niższą częstość występowania cholestazy wątrobowej (p=0,025) oraz znacznie obniżone ryzyko wystąpienia postaci retinopatii wcześniaczej wymagającej stosowania laseroterapii (bliskie znamienności statystycznej: p=0, 06).
Wnioski: Zastosowanie u noworodków z bardzo małą urodzeniową masą ciała od pierwszej doby życia w żywieniu pozajelitowym emulsji tłuszczowej zawierającej w składzie olej rybi jest bezpiecznym sposobem postępowania, mogącym mieć istotny wpływ na obniżenie ryzyka występowania cholestazy oraz zaawansowanej postaci retinopatii wcześniaczej, wymagającej zastosowania laseroterapii. Zagadnienie to wymaga dalszych badań klinicznych.
Słowa kluczowe: retinopatia wcześniacza, kwas dokozaheksaenowy (DHA), cholestaza, noworodek z bardzo małą urodzeniową masą ciała
Docosahexaenoic acid (DHA) is a ω-3 fatty acid that falls into the category of polyunsaturated fatty acids (PUFAs). It has been shown to be important for foetal brain development, optimal development for motor skills and visual acuity in infants (1, 2, 3, 4). Retina contains rods and cones, highly enriched with docosahexaenoic acid (DHA). In the membranes, DHA is a source of docosanoids, which are chemical messengers with potent anti-inflammatory actions (5). The three known classes of docosanoids – docosatriens, resolvins and protectins – are produced mainly from controlled oxidative breakdown of DHA within the membrane. The resolvins appear to be involved in the physiological resolution of inflammatory response which is essential to maintain homeostasis (6). In vitro studies demonstrate that DHA inhibits the expression of inflammatory markers such as pro-inflammatory cytokines, monocytes adhesion to endothelial cells and cell-adhesion molecules, particularly vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and E-selectin (7).
Perinatally, the premature infant is exposed to plenty of factors, which trigger an inflammatory cascade and may cause an injury. Either bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) or necrotizing enterocolitis (NEC) are examples of clinical condition, when uncontrolled inflammation appears to be essential for development of disease. Recently, a role of inflammatory reaction in the pathophysiology of retinopathy of prematurity (ROP) has been suggested (8).
DHA is transferred preferentially from mother to foetus and its transportation depends on fatty acid transport protein-4 (FATP-4) expression in human placenta. During the last trimester of gestation, total foetal accretion of ω-3 LCPUFA was estimated to be about 50 mg of ω-3 LCPUFA/kg/day (5). Infants born prematurely are at special risk for DHA insufficiency because they may not have benefited from a full trimester of the mother’s lipid stores. Moreover, preterm infants have very limited ability to synthesize DHA from the alpha-linoleic acid (ALA) (9). The exclusive source of DHA after birth for preterm newborns is breast milk or DHA-enriched formula. However, within the first 2-3 weeks of life, the main sources of lipids for most prematurely delivered infants are fat emulsions, administered as components of total parenteral nutrition. These are usually soybean/safflower/ olive oil emulsions which are rich in n-6 fatty acids and do not contain DHA. Consequently, supply of DHA is interrupted for a relatively long period of time, which is dependent either on the immaturity of infants or the incidence of feeding complications. On the other hand, a fish-oil emulsion contains ω-3 fatty acids, DHA and eicosapentaenoic (EPA) acid, an eicosanoid precursor. This emulsion also contains arachidonic acid (AA), a ω-6 fatty acid. Recently Gura KM et al. (10) showed the safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition associated liver disease in infants. Patients tolerated the therapy well, and no adverse effects attributed to the use of that emulsion were observed. In our previous observational study (11), carried out in small groups of patients we found significantly lower risk of laser therapy in newborns with retinopathy, who were receiving a fish-oil emulsion in amount equal to one third of total daily intravenous lipid intake from the first day of life. The aim of the study was to confirm these preliminary results in the larger groups of patients and compare the incidence of severe retinopathy of prematurity and cholestasis in all VLBW newborns, hospitalized in 2009 and receiving a fish-oil emulsion in amount equal to one third of total daily intravenous lipid intake, with the results obtained in all VLBW newborns, admitted to neonatal department in 2007 who were treated with conventional soybean/olive oil emulsion.
PATIENTS AND METHODS
All very low birth weight newborns, delivered prematurely before the 32nd week of gestation and admitted to the neonatal intensive care unit of the Neonatal Department of the Collegium Medicum, Jagiellonian University in Cracow between 1st January and 31st December 2009 and who needed total parenteral nutrition were recruited for the analysis. However, for further evaluation only newborns without major congenital malformation or inborn metabolic errors and symptoms of congenital infection were enrolled. Finally, 152 of the 171 admitted infants in 2009 were enrolled and analyzed as group I. For comparison purposes, the group of 185 very low birth weight newborns, separated from 201 infants who were born and admitted to the neonatal department between 1st January and 31st December of 2007, was reviewed (group II). The exclusion criteria were identical in both groups of infants. Infants in the group I were treated with a volume composition of lipid emulsions consisting of 50% of soybean/olive oil emulsion (20% Clinoleic, Baxter S.A.) and 50% of fish-oil emulsion (10% Omegaven, Fresenius Kabi AG). The treatment protocol was approved by the Ethical Committee of the Jagiellonian University and informed written consent was obtained from parents of all treated infants. A source of lipid emulsion, administered parenterally in infants in the group II was exclusively a 20% soybean/olive oil emulsion (20% Clinoleic, Baxter).
The following data were collected in infants of both groups: birth weight, gestational age, Apgar score, sex and antenatal cortico steroid administration. The diagnosis and routine medical management of respiratory insufficiency and/or sepsis in the two groups was comparable. Also, the criteria either for ventilatory support or for weaning from the ventilator and/or CPAP were comparable in infants of both groups.
In both groups of infants, the lipid emulsions were administered from the first day of life as a continuous infusion 24 hours/day. The initial daily dose was 0.5 g (for infants with birth weight <1000 g) or 1.0 g (for infants with birth weight >1000 g) of lipids/kg body weight. It was increased by 0.5-1.0 g of lipids/kg body weight every 24 hours to a maximum of 3.0-3.5 g of lipids/kg body weight/ day. With regard to enteral feeding, infants in both groups were fed initially and advanced at 20 ml of breast milk and/or formula (Bebilon Nenatal Premium, Nutricia) enriched with ω-3 LCPUFA/kg per day, according to feeding tolerance. One hundred and twenty one infants in group I (80%) and one hundred thirty eight infants in group II (75%) received their own mother’s breast milk. The intravenous lipid infusion as a component of total parenteral nutrition was progressively replaced with enteral intake so as to maintain the total daily lipid dose at 3.0-3.5 g of lipids/kg body weight (except the first few days after birth). The dosage and schedule of lipid administration were identical in both groups.
The primary study outcomes were the following: a development of ROP and the need for ophthalmologic intervention (laser photocoagulation), as well as the occurrence of cholestasis during hospitalization. The cholestasis was defined as the serum direct bilirubin value greater than 1.0 mg/dL if the total bilirubin was less than 5 mg/dL or a direct bilirubin more than 20% of the total bilirubin if the total bilirubin was greater than 5 mg/dL, found in two consecutive measurements (12). Laboratory values were prospectively measured approximately biweekly. The historical group had all the bilirubin tests available, recorded retrospectively.
Secondary study outcomes, including blood stream infections, treatment for patent ductus arteriosus (PDA) pharmacological or surgical, the occurrence of intraventricular haemorrhage (IVH), bronchopulmonary dysplasia (BPD), a length of hospitalization and total parenteral nutrition (in days) were analyzed in both groups. BPD was defined as an oxygen requirement and/ or respiratory support at 36 weeks corrected gestational age. The final diagnosis of IVH was established within the first month of life according to Papile’s criteria (13).
In infants of both groups, the monitoring of level of oxygen saturation with pulse oximetry was initiated within the first minutes after birth and was continued until the infant was breathing ambient air and did not require ventilatory support (ventilator or CPAP) for more than 48 hours. Adjustments in supplemental oxygen to maintain the target level of oxygen saturation between 88 and 93 (ranges identical for both groups) were performed by the clinical nurses. All infants either in the both groups were screened for ROP (screening criteria of <32 weeks gestational age or <1500 g) by the same ophthalmologist (blinded of interventions) trained in the diagnosis of ROP. Examinations continued until the study outcome was reached or resolution occurred.
Statistical analyses were performed with the use of Statistica for Windows (version 8.0) with probability <0.05 considered significant. Statistical significance of differences in categorical values was analyzed by the Chi-square test with two degrees of freedom. In Chi-squared comparison, the Yates correction for continuity statistic was used to prevent overestimation of the significance, and the Fisher’s exact probability test was applied when examining variables of low incidence. The unpaired Student’s t-test was used to examine the differences between body weight and gestational age in the two groups. The Mann-Whitney U test was performed to examine the differences between demographic and clinical characteristics in the groups. The regression analysis was used to estimate possible correlations between analysed factors and the incidence of ROP.
The overall mortality rate between the two groups did not differ significantly (20.3% in group I and respectively 23.9% in group II).
Table I show that patients in the two groups were comparable with regard to the birth weight, gestational age, Apgar score, and the frequency of antenatal cortico steroid administration. The cholestasis was diagnosed in 9 of 185 infants in the group II whereas it occurred only in one patient in the group I. The difference was statistically significant (p=0.025). The rate of the secondary outcomes: blood stream infections, treatment for PDA (pharmacological or surgical), and the occurrence of BPD, IVH, a length of hospitalization or total parenteral nutrition (in days) did not differ significantly between the two groups. Ophthalmologic intervention (laser therapy) was performed in 9 (5.9%) subjects in group I and in 23 (12.4%) infants in group II. In fact, in two of the infants in group II, laser therapy had to be repeated within the next two weeks. The difference in rates of ophthalmologic interventions in infants who developed retinopathy between the two groups was close to statistical significance (p=0.06; two tailed Fisher Exact Test). The comparison of demographic (birthweight, gestational age) and clinical characteristics (Apgar score, neonatal sepsis in general – bacterial or fungal, BPD, IVH – according to number and grades) of patients who developed ROP did not show significant differences between infants of the two groups. Among patients with ROP in group II the only factors which significantly increased risk of laser therapy was gestational age (gestational age: OR – 0.37; 95%CI: 0.16 to 1.01; p=0.047; However, similar correlation was not found in group I.
The occurrence of undesirable safety effects in infants receiving fish-oil emulsion was comparable with that found in group II. Twelve patients in group I and seventeen infants in group II developed hypertriglyceridemia (triglyceride level: >350 mg/dl). No patient in either group developed coagulopathy (international normalized ratio: >2), the mean platelet count as well as central venous catheter infection and new infection rates were comparable in the two groups of infants during the intravenous administration of both types of lipid emulsion.
In this retrospective analysis, we found statistically significant lower incidence of cholestasis among patients who received fish-oil emulsion in amount equal to one third of total daily intravenous lipid intake from the first day of life. Also, there was a lower risk (not statistically significant) of laser therapy in infants, who were receiving a fish-oil emulsion. As shown in the table, demographic and clinical characteristics of the patients in the two analyzed groups were comparable. Thus, differences in severity of clinical condition of patients in the two groups could be ruled out. Also, in order to exclude the possible bias, the ophthalmologist who performed screening examination in all infants was blinded to the differences in composition of lipid emulsions.
It seems to us that intravenous intake of the fish oil based lipid emulsion was the most important difference between the two groups of infants, which might influence the significant difference in the incidence of cholestasis and lower risk of laser therapy. It is well known that, soyabeanderived lipids contain phytosterols that may be the cholestatic components and are linked with impairment of biliary secretion. Concerning retinopathy, it is generally accepted that between 23rd and 40th week of pregnancy, the weight of brain increases from about 75 to 400 grams. DHA, which is present in sufficient amount in fish oil-based lipid emulsion, is the one nutrient absolutely required for the development of the sensory, perceptual, cognitive and motor neural system during the brain growth spurt (5). Also retina, functionally an extension of the brain, contains rods and cones whose membranes are highly enriched with DHA. It was established that DHA comprises 20% of total fatty acid content of the infant retina. In the outer segments of rod photoreceptors DHA comprises 35% of total fatty acids (9). Rodents, primates with experimentally induced DHA deficiency show deficit in retinal structure, visual acuity development, and cognitive performance. It was also found that modulation of TNF-α production influences vascular growth through endothelial cell cycle regulation. Moreover, mice which are lacking TNF-α have less oxygen-induced retinopathy (14). The ω-3-PUFA diet potently suppresses retinal expression of TNF-α by ≈ 90%. The results of experimental data obtained by Connor et al. (15), indicate that DHA, EPA and their potent bioactive products at physiological levels, reduce pathologic neovascularization through enhanced vessel regrowth after vascular loss and injury and that enriching the sources of ω-3-PUFA may be an effective approach to help prevent proliferative retinopathy. On the other hand, higher dose of DHA in the neonatal period improves visual acuity of preterm infants (16, 17, 18, 19). The fact that very low birth weight infants are minimally fed by enteral route and receive routine parenteral nutrition which does not contain DHA might be the major causative factor of different pathologies, including cholestasis and retinopathy.
We do not know if this is the optimal dosage or preferential fish-oil emulsion. It is important that we did not find undesirable effects in infants treated with the modified lipid emulsion.
Fish-oil-based fat emulsion administered as a component of total parenteral nutrition from the first day of life is safe in the prophylaxis of cholestasis and severe retinopathy of prematurity. Further clinical investigations are needed.
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Adres do korespondencji / Address for correspondence:
Department of Neonatology
Collegium Medicum, Jagiellonian University
ul. Kopernika 23, 31-501 Kraków
Phone/fax: (48 22) 42-48-587