Effects unrelated to anti-inflammation of lipid emulsions containing fish oil in parenteral nutrition for adult patients

Efectos no relacionados con la antiinflamación de las emulsiones lipídicas que contienen aceite de pescado en la nutrición parenteral para pacientes adultos

Javier Mateu-de-Antonio¹ and Marta Florit-Sureda²

¹Pharmacy Department. Hospital del Mar. Barcelona, Spain.
²Pharmacy Department. Corporació Sanitària Parc Taulí. Sabadell, Barcelona. Spain

Correspondence

ABSTRACT

Several reviews and meta-analyses on modulated inflammatory and immunologic responses after the administration of omega-3 polyunsaturated fatty acids (PUFAs) in different diseases and conditions have been published. However, omega-3 PUFAs exert several other actions which are not directly related to immunologic or inflammatory responses. The aim of this paper was to review the effects which are not directly related to immunologic and inflammatory responses of intravenous lipid emulsions (IVLEs) containing fish oil (FO) in parenteral nutrition (PN) for adult patients. IVLEs containing FO could have a role in the prevention of alterations in liver enzyme tests (LETs) or PN-associated liver disease (PNALD). Studies using FO doses of ≥ 0.150 mg/kg/day or IVLEs with high FO concentration reported more positive results than those with lower doses. Once PNALD was developed, the use of IVLEs exclusively composed of FO at doses of 0.25-1 g of FO/kg/day for several weeks could attenuate or even eradicate cholestasis and liver alteration. IVLEs containing FO seemed to have faster blood clearance, and this could be beneficial for some patients. Some studies also suggested a possible improvement of respiratory function by the administration of these IVLEs. In general, IVLEs containing FO were safe. Their use did not increase oxidative stress but, in contrast, increased plasma tocopherol content. They did not alter insulin sensitivity or glycemic control, and studies have found no relevant clinical effect on platelet aggregation or hemostasis. In conclusion, the use of IVLEs containing FO in PN may be beneficial with regard to older IVLEs, in addition to the modulation of systemic inflammation response.

Key words: Fish oils. Intravenous fat emulsions. Parenteral nutrition. Omega-3 fatty acids.

RESUMEN

Se han publicado varias revisiones y metaanálisis sobre la modulación de las respuestas inflamatorias e inmunológicas por la administración de ácidos grasos poliinsaturados (AGPI) omega-3. Sin embargo, los AGPI omega-3 ejercen otras acciones no directamente relacionadas con estas respuestas. El objetivo de este trabajo es revisar los efectos de las emulsiones lipídicas intravenosas (ELIV) que contienen aceite de pescado (AP) en la nutrición parenteral (NP) de pacientes adultos. Estas emulsiones pueden tener un papel importante en la prevención de las alteraciones del perfil hepático o de la enfermedad hepática asociada a la NP (EHANP) en comparación con las ELIV sin AP. Los estudios que usaron dosis ≥ 0,150 mg/kg/día presentaron resultados más positivos que aquellos con dosis menores. Una vez se ha presentado la EHANP, el uso de una ELIV compuesta exclusivamente de AP, a dosis de 0,25-1 g de AP/kg/día durante varias semanas, podría atenuar o incluso revertir la alteración hepática y la colestasis cuando la administración de la NP es crónica. Las ELIV con AP parecen tener un aclaramiento plasmático más rápido, lo que podría suponer una ventaja en ciertos pacientes. Algunos estudios también sugieren que estas emulsiones podrían mejorar la función respiratoria. En general, estas ELIV que contienen AP son muy seguras, no aumentan el estrés oxidativo e incluso incrementan el nivel de alfa-tocoferol plasmático. Asimismo, no alteran la sensibilidad a la insulina o el control glicémico y tampoco se ha demostrado que afecten clínicamente a la agregación plaquetaria o a la hemostasia. En conclusión, el uso de ELIV con AP en la NP podría suponer algunas ventajas frente a la ELIV sin AP, además de la modulación de la respuesta inflamatoria sistémica.

Palabras clave: Aceites de pescado. Emulsiones lipídicas intravenosas. Nutrición parenteral. Ácidos grasos omega-3.

Introduction

These effects have been related to the immunomodulatory and anti-inflammatory action of omega-3 PUFAs. Their use, especially by parenteral route, diminishes several inflammatory biomarkers in both acutely and chronically ill patients (4). They also reduce interleukin-6, increase albumin and, additionally, decrease the C-reactive protein to albumin ratio in colorectal cancer patients (5).

However, omega-3 PUFAs from FO exert several other actions which are not directly related to immunologic and inflammatory responses. To our knowledge, these effects have not been reviewed in sum.

The aim of this paper was to review the effects which are not directly related to immunologic and inflammatory responses of intravenous lipid emulsions (IVLEs) containing FO as part of parenteral nutrition (PN) in adult patients. We divided these effects in potential benefits and possible concerns.

Potential benefits

PREVENTION OF ALTERATIONS IN LIVER ENZYME TESTS (LETS) OR PARENTERAL NUTRITION-ASSOCIATED LIVER DISEASE (PNALD)

Several prospective studies have been published assessing the preventive effect of IVLEs containing FO on alterations in LETs or PNALD (6-21). Characteristics of these studies are shown in table I. Most of the studies were focused on middle-aged surgical or critically ill patients. Seven (44%) of the 16 studies found some positive results for LETs or liver ultrasound tests in patients receiving IVLEs containing FO (8,11,12,15,16,19,21). Studies using FO in doses of ≥ 0.150 mg/kg/day presented more positive results than those with lower doses. In five (63%) of the eight articles using doses ≥ 0.150 mg/kg/day some positive results in LETs were observed, whereas only two (25%) of the eight studies using lower doses reported some positive results. This hypothesis could be reinforced by two recent retrospective studies. In a large retrospective study including more than 1,500 patients receiving PN, a higher FO dose was associated with a greater decrease in gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) in a multivariate adjusted model (22). Additionally, in a propensity score-matched study, a higher percentage of FO administered by PN was associated with lower LET elevation during PN (23).

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In relation to the IVLE used, the most studied one is a multicomponent oil emulsion containing soybean oil (SO) 30%, middle-chain triglycerides (MCT) 30%, olive oil (OO) 25%, and FO 15%. Four (50%) of the eight studies using this IVLE resulted in positive outcomes (8,11,16,21). The second most studied IVLE is an emulsion containing SO 40%, MCT 50%, and FO 10%. Two (40%) of the five studies with this IVLE rendered some positive results (15,19). Only one study tested an IVLE containing exclusively FO 100% administered in high doses, which lead to improved liver ultrasound test and better lactate dehydrogenase (LDH) in septic patients (12). Two additional studies tested a combination of an IVLE exclusively composed of FO 100% and an already marketed IVLE without FO. No differences in liver parameters were found (9,13).

These studies have several limitations regarding clinical practice. The first limitation is the length of the study period. PN lasted from four to eight days in most trials. This lapse could be shorter than the usual PN course in clinical settings. Only one study had a four-week duration, resulting in an improved LET using a multicomponent oil emulsion containing FO 15% in doses of > 0.150 g/kg/day (16). Another important limitation is the age of the patients under assessment, who were younger than many patients requiring PN nowadays, usually older than 70.

In summary, IVLEs with FO in doses of FO > 0.150 g/kg/day or with high proportion of FO could reduce the incidence of alterations in LETs or PNALD.

TREATMENT OF PNALD

Treatment with IVLEs containing FO has not been thoroughly studied in adults after the development of PNALD. The first case was described by Jurewitsch et al. (24). A 75-year-old female required PN after a massive intestinal resection that led to short bowel syndrome. She developed hepatomegaly, altered LET, and an abnormal liver biopsy after ten weeks of PN containing an IVLE of SO 100%. After replacing the initial IVLE by an IVLE of FO 100%, in doses of 0.25 g FO/kg/day, liver span decreased, LET dropped, and liver biopsy normalized in approximately 20 weeks. To our knowledge, two additional cases have been described so far in patients requiring chronic PN (25,26). They developed severe liver alterations that could not be reversed except by replacing the initial IVLE (SO 100% and OO/SO 80%/20%, respectively) with an IVLE of FO 100%. The doses of FO used were about 1g/kg/day.

Three studies focused on patients presenting LET alteration and PNALD. The first one is a retrospective study in 54 patients receiving long term PN that assessed the effect of adding taurine to PN on LET (27).

Authors concluded that a synergistic effect could exist between taurine and a multicomponent IVLE of SO/MCT/OO/FO 30%/30%/25%/15% by reducing an altered LET. However, this effect was not accurately analyzed.

The last study focused on the effect of different IVLEs in ten adults with PNALD secondary to long-term PN. Additionally, an in vitro study assessed the effect of these IVLEs on human hepatocytes (29). The use of an IVLE of FO 100% at 1 g/kg/day for four months restored LET, fibrotic and inflammatory markers to normal values. This FO 100% emulsion showed not only a potent in vitro anti-inflammatory effect but also a possible direct antifibrotic effect in the liver.

As a concern, it has been hypothesized that the administration of IVLE with FO 100% as an exclusive source of fat does not provide the required essential fatty acid amount when used for long periods (29). However, it has not been possible to prove this point clinically (25).

The substitution of the initial IVLE by one exclusively composed by FO or with high amounts of it and administered at doses of 0.25-1 g of FO/kg/day during several weeks could attenuate or even revert LET alterations or PNALD in patients under chronic PN.

PLASMA LIPID CLEARANCE

Prospective studies collecting data on plasma clearance of IVLEs containing FO are presented in table II (6-8,12-14,16,17,19-21,30-34).

Three studies on healthy subjects assessed lipid oxidation or lipid plasma clearance specifically (31-33). These studies resulted in a 15-25% faster clearance or 25-45% shorter half-life of the experimental IVLE containing FO, although emulsions under assessment had different composition and FO content.

Thirteen clinical studies assessed clearance of IVLE with FO in hospitalized patients. Six of them (46%) reported higher clearance in the FO group as well (8,12,13,17,19,21).

Regarding the rest of clinical studies, six (46%) resulted in similar clearance to control emulsions (6,14,16,20,30,34), and only in one (8%) of them (7) triglyceridemia increased in the experimental group.

The most studied control IVLE was composed by MCT/SO 50%/50%. Seven (88%) of the eight studies which used this control resulted in faster lipid clearance of the IVLE containing FO. The remaining eight studies used control emulsions of SO 100% or OO/SO 80%/20%, three (38%) of them resulting in faster clearance for the IVLE containing FO.

Taking all studies together, five (38%) out of 13 clinical studies and the three experimental studies resulted in faster clearance or shorter half-life in the IVLEs containing FO. The inclusion of FO in IVLEs could be beneficial to some patients as it improves lipid clearance.

RESPIRATORY GAS INTERCHANGE

Few trials have investigated the effect of IVLEs with FO in gas exchange and the oxygenation index (ratio PaO₂/FiO₂). In two studies respiratory function was improved, and a tendency to a shorter LOS during five days of PN in the group receiving an IVLE of MCT/SO/FO 50%/40%/10% in comparison to those being administered an IVLE of SO 100% (10,36) was observed. Doses of FO were 0.09 to 0.2 g/kg/day. Two more studies analyzed respiratory parameters in cardiac surgery patients. In one of them, 40 patients subject to elective coronary artery bypass grafting were randomized to receive a preoperative IVLE of FO 100% at doses of 10 g (about 0.11 g/kg) or saline. The results of this study showed that the extraction of oxygen and the uptake of lactate were markedly increased in the FO pretreated patients compared to the control group (37). In the second study, 23 patients were randomized to receive FO 100% 0.2 g/kg or saline administered two times on the evening before cardiopulmonary bypass and immediately before surgery. The FO group presented shorter ventilation time but no significant impact on the oxygenation index was observed (38).

On the other hand, no differences in relation to gas exchange parameters were found in a study on 16 patients with acute respiratory distress syndrome who were randomized in two different groups receiving IVLE containing either SO 100% or MCT/SO/FO 50%/40%/10%, administered at a dose of 0.12 g/kg/hour during 12 hours. The lack of beneficial results was attributed to the short duration of the treatment (39).

The mechanism by which FO could improve respiratory function was not clear (10).

OTHER EFFECTS

In a randomized controlled clinical trial, patients who had undergone orthotopic liver transplantation and received PN with an IVLE of SO/MCT/FO 40%/40%20%, at doses of FO 0.2 g/kg/day for seven days, presented better alanine aminotransferase (ALAT) profile and prognostic nutritional index, more reduced hepatic cell injury and higher prealbumin than patients receiving a similar PN without FO. In addition, the FO group had a decreased incidence of infectious complications and their post-transplant hospital stay was shorter (40). It has been hypothesized that IVLEs containing high amounts of FO are of benefit to patients who have undergone kidney transplantation and may require PN after severe complications (41).

In a single-arm phase II trial on patients with advanced pancreatic cancer, an IVLE containing FO (MCT/SO/FO 50%/40%/10%) was used to augment chemotherapy activity and improve quality of life. It was administered weekly as a standard intravenous infusion of 500 mL (FO 10 g) after the antitumor agent gemcitabine 1,000 mg/m² for three weeks, followed by a rest week. The study showed improved activity of the antitumor agent and improvement of the quality of life (42).

OXIDATIVE STRESS

FO contains a high percentage of long chain omega-3 PUFAs, such as eicosapentaenoic acid and docosahexaenoic acid, susceptible to oxidation that could increase oxidative stress. To counteract peroxidation reactions, IVLEs containing FO are enriched with higher doses of alpha-tocopherol, a lipophilic antioxidant (43).

Several studies have demonstrated that IVLEs partly or totally composed of FO increase plasma levels of alpha-tocopherol in comparison to IVLEs with SO 100% due to their high content of this vitamin (7,16,21,44,45). Doses used in these studies ranged from 0.7 to 2 g of fat/kg/day. Comparisons with other IVLEs without FO have not been made.

In addition, some studies assessed the effect of IVFEs with FO on oxygen radical production, peroxidation capacity or antioxidant capacity. No differences have been detected in oxidative status using IVLEs with FO in comparison to control IVLEs, mostly SO 100% (17,44-46). However, these studies used different techniques and oxidation markers, and had small samples and short time lipid administration. Thus, the use of IVLEs with high PUFA content did not seem to increase oxidative stress.

INSULIN SENSITIVITY AND GLUCOSE METABOLISM

Elevated plasma free fatty acid levels are known to contribute to peripheral insulin resistance by impairing insulin-receptor signaling, which leads to decreased cellular glucose uptake and serum hyperglycemia, and can also reduce insulin secretion in subjects with impaired glucose tolerance (47). So far, three studies have examined glycemic control as a primary objective when administering IVLEs with FO. In the first study, 24 patients were randomized to receive an IVLE containing either FO 100% or SO 100%, in doses of 0.25 g of fat/kg/day, as part of PN for four days. No differences were detected in glucose metabolism in patients receiving FO (30). In the second study, 44 patients were randomized to receive PN containing an IVLE with SO 100% or an IVLE with SO/FO 80%/20% at doses of 1 g fat/kg/day for five days. Blood glucose levels normalized to the insulin doses applied and did not differ significantly between both groups. However, blood glucose levels fell significantly over time in the SO group, whereas they remained high in the SO/FO group (34). In the third study, 11 subjects with type 2 diabetes mellitus received infusions of SO 100% or SO/FO 89%/11% randomly by four-hour isoglycemic hyperinsulinemic clamps. Both IVLEs similarly decreased insulin-mediated glucose utilization. The IVLE with FO increased plasma free fatty acids. However, no difference regarding glucose utilization, insulin secretion and total energy production was observed between groups (46).

Two additional studies had glycemic control as a secondary outcome. In a randomized trial with 44 patients comparing a multicomponent emulsion of SO/MCT/OO/FO 30%/30%/25%/15% (FO dose 0.15 g/kg/day) versus OO/SO 80%/20% for five days, glucose levels and insulin dosage did not differ significantly between groups (8). Another study assessed 23 patients who were randomized to receive FO 100% 0.2 g/kg or saline administered twice on the evening before cardiopulmonary bypass and immediately before surgery. The average glycemia during the first 24 hours after surgery was significantly lower in the FO group. However, insulin requirements and endogenous glucose production were similar in both groups in the first 24 hours (38).

In a retrospective study, the substitution of an IVLE of SO/OO 80%/20% by a multicomponent IVLE containing SO/MCT/OO/FO 30%/30%/25%/15% in patients presenting moderate hypertriglyceridemia during PN resulted in a slight increase of insulin requirements, but it was attributed to the previous hypertriglyceridemia (35).

IVLEs with FO seemed not to alter significantly insulin sensitivity or glycemic control in clinical practice.

Omega-3 PUFAs contained in FO have an antithrombotic effect mainly mediated by inhibiting cyclooxygenase, which transforms arachidonic acid into thromboxane A2, a platelet activator, and reducing its formation, thus leading to decreased platelet aggregation. Early studies raised concern about the safety of high doses of these lipids due to an increased risk of bleeding (48) that could not be proved later. However, this concern still persists nowadays.

Several studies assessed hemostasis parameters in patients receiving IVLEs with FO. In an early study mainly focused in hemostasis, 44 patients were randomly administered IVLEs with SO 100% or SO/FO 80%/20% in a dose of 1 g of fat/kg/day (FO 0.2 g/kg/day) for five days. However, no differences were found between groups in relation to thromboplastin time, activated partial thromboplastin time, fibrinogen, antithrombin III, factors VIIa and XIIa, and platelet function (49). In a more recent study already mentioned above, 40 patients undergoing coronary artery bypass graft surgery were randomized to receive either FO IVLE as single doses of FO 10 g (about 0.11 g/kg) 100% or saline solution before surgery and again four hours before starting extracorporeal circulation. The results showed no differences in international normalized ratio (INR), activated partial thromboplastin time, bleeding volume, blood transfusion or fresh frozen plasma requirements, platelet count in postoperative period, and heparin or protamine use. Only in one of four tests platelets activity was statistically lower in the FO group, but with no negative effect (50).

Three additional studies evaluated certain hemostasis parameters, but lacking a detailed analysis. They found no differences in INR (16), partial thrombin time (10), and prothrombin time (7). Two of them showed no differences in platelet counts (10,16), but a moderate difference regarding platelet count recovery after surgery was found in the FO group in the earliest study (7). FO doses ranged from 0.09 to 0.195 g/kg/day.

In general, studies have found no relevant clinical effect on platelet aggregation or hemostasis when administering IVLE with FO.

Conclusions

The use of IVLEs containing FO in PN may have some advantages with respect to earlier IVLEs, not only in terms of modulation of systemic inflammation but in relation to further benefits. There are some evidences that IVLEs with FO may reduce the incidence of LET alterations during PN, eradicate PNALD, increase plasma lipid clearance, and improve respiratory gas exchange. Their use is safe, and possible concerns as alterations in oxidative stress, insulin sensitivity or hemostasis have not been confirmed so far.

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Correspondence:
Javier Mateu-de-Antonio.
Pharmacy Department.
Hospital del Mar.
Passeig Marítim, 25-29.
08003 Barcelona, Spain
e-mail: 92976@hospitaldelmar.net

Received: 14/12/2016 ]]> Accepted: 23/12/2016