In our center, a parenteral fish oil-based lipid emulsion used as monotherapy in a subset of pediatric PN dependent patients at a dose of 1 g.kg−1
has been shown to be safe and efficacious in reversing PN associated liver disease and normalizing EFAD status (14
). In addition to previously published papers by our group, this report adds important data regarding the safety of parenteral fish oil as monotherapy. In contrast to our earlier studies, we present a unique population of 10 parenteral nutrition dependent infants who received no significant enteral calories and received all fats derived from intravenous fish oil. Although this patient population is even more prone to develop EFAD, our results are in line with our previously published data that patients on parenteral fish oil monotherapy do not develop EFAD (14
). Also, we previously demonstrated that fish oil, when used at sufficient concentrations, can be used as the sole source of fat, displaying no adverse effects on growth and no evidence of EFAD in a 9-week murine model (18
). Despite these results, skepticism had remained that a fish oil-based lipid emulsion may not contain sufficient amounts of LA and ALA to prevent EFAD when used as a monotherapy. Our results show, for the first time, that Omegaven® monotherapy as the sole source of fat in a subset of PN dependent patients does not lead to the onset of clinical or biochemical EFAD.
Although physical signs and symptoms of EFAD in infants may not appear for 4-6 weeks, biochemical abnormalities generally appear in only 1-2 weeks (12
). In our study, however, all patients were followed for a minimum of 6 weeks and none of them showed clinical signs of EFAD. A cut-off point for the upper limit for the triene:tetraene ratio as a biochemical marker for EFAD was based on early experiments on rats, that initially suggested it to be 0.4 (21
). Further work in humans using the more accurate gas liquid chromatography, however, showed that the upper limit should be 0.2 (22
). Although others have argued that the upper limit should be as low as 0.025 (23
), this distinction is somewhat semantic since clinical evidence of EFAD is not seen when the triene:tetraene ratio is <0.2. The upper limit, therefore, should be 0.2 as a lower ratio would actually over-diagnose patients with EFAD.
We also demonstrated that these patients did not experience growth retardation, indicated by gestational age adjusted Z-scores for length, weight and head circumference, while on the fish oil based lipid emulsion. In a state of EFAD where ω-3 and ω-6 PUFA stores are depleted, MA is produced by de novo lipogenesis. Data from the fatty acid profiles showed that while being on Omegaven®, MA levels remained within the normal range, and the triene:tetraene ratios remained below 0.2. Also, the relative amount of ω-3 to ω-6 increased in all patients.
Although the median follow-up time was only 3.8 months, this period should exceed the time window for the onset of EFAD. By including only those with a minimum of 4 weeks on exclusive PN and intravenous Omegaven®, we hope to eliminate any false negatives in detecting EFAD. Also, by censoring these patients as soon as they advanced to any enteral feeding, we eliminated any possible confounding from enteral fat calories.
At baseline, all patients had significant liver disease (median direct bilirubin 6.8 mg/dL), as well as multiple other comorbidities, justifying their enrollment in the Omegaven® monotherapy under a compassionate use protocol. At baseline, patients' fatty acid profiles represented the composition of the parenteral lipid emulsions that they had been receiving. It has been suggested that patients with severe liver disease are deficient in long chain PUFAs, and that supplementation may improve patients' clinical condition by correcting this deficiency (24
). Although none of the 8 patients that had received the soybean-based lipid emulsion were deficient in the total amount of long chain PUFAs, they experienced a low, suboptimal ω-3:ω-6 ratio. Already after 1 week, fatty acid profiles had changed to the composition of fish oil, which has been shown to be less pro-inflammatory and less hepatotoxic (26
Breast milk, which contains considerable amounts of long chain PUFAs, is considered to provide the optimal form of nutrition for young infants. Since long chain PUFAs accumulate mainly during the last trimester of pregnancy, preterm infants have very limited body stores at birth, at a time when its requirement is high due to their rapidly growing state (29
). Although a fish oil-based lipid emulsion does not provide the same amounts of fatty acids as breast milk, it contains relatively high levels of EPA and DHA that may play an important role in development of critical organs and cognitive function (29
). These effects may be particularly important in preterm infants who receive their entire caloric intake from PN and a parenteral lipid emulsion.
In our study, we calculated that an estimated daily caloric intake of 0.09-0.63% LA, <0.18% ALA, 1.15-2.54% EPA, 1.30-2.78% DHA and 0.09-0.36% AA was enough to prevent EFAD. The estimated amount of ω-3 PUFAs that we provided is higher than reported by Bjerve et al., who estimated that the minimal daily requirement of ω-3 PUFAs was approximately 0.1-0.2% (30
). Our patients, however, were growing, young infants (some premature), with significant co-morbidities and a higher need for ω-3 PUFAs, whereas the patients that Bjerve et al. described were relatively healthy, immobile adults fed by gastric tube. Although we provided <0.18% of ALA, our patients received a significantly higher amount of the downstream ω-3 PUFAs EPA and DHA assuring proper physical and mental development (29
). Our data does require a note of caution, because we calculated an estimated daily caloric intake based on the median data derived from our study sample. Since this calculation is dependent on infants' weight, height and age, our numbers are presented as a representative snapshot of our study sample, and may not be generalized to the pediatric population as a whole.
In conclusion, we have demonstrated for the first time that a fish oil-based lipid emulsion as monotherapy contains sufficient amounts of essential fatty acids to prevent EFAD and sustain adequate growth in children completely dependent on PN. A randomized, controlled, double-blind clinical trial, such as the one that is currently underway at our institution (NCT00512629), comparing the conventional soybean-based Intralipid® to the fish oil-based Omegaven® as the sole source of parenteral lipid will be imperative in the current debate about the efficacy and safety of parenteral fish oil-based lipid emulsions (31
). The results will also determine its role as monotherapy in PN-dependent patients.