Intravenous fish oil lipid emulsions in critically ill patients: an updated systematic review and meta-analysis

Systemic inflammation and immune dysfunction are two key features in critical illness. In this context, it may be that provision of parenteral FO-containing LEs in ICU patients receiving PN or EN (pharmaconutrient strategy) represents a promising and attractive therapeutic option. We have updated our previous systematic review by evaluating the effects of FO-containing LEs on relevant clinical outcomes in ten eligible RCTs [15-18,61-66] involving critically ill patients. The main findings of our meta-analysis are that FO-containing LEs may reduce infections and may be associated with a tendency toward fewer MV days compared with SO-based strategies or administration of other alternative LEs in ICU patients. Nonetheless, contrary to our previous findings [10], we did not find a tendency toward reduced mortality, although in EN-based trials FO-containing LEs as pharmaconutrition may be associated with a tendency toward reduced mortality. The benefit in terms of improvement in recovery times, as indicated by the tendency toward a reduction in MV days and hospital LOS, may be due to reduced infections, generally or specifically a lower incidence of VAP, which is a frequent cause of infection in mechanically ventilated patients and is associated with significant attributable morbidity and mortality [67]. The presently reported results notwithstanding, these outcomes should be explored in further well-conducted and adequately powered RCTs.

So far, our systematic review and meta-analysis is the most updated evaluation of the overall effects of FO-based PN strategies in the critically ill. In addition, it is pertinent for intensive care as, according to our inclusion criteria, it contains only RCTs evaluating clinical outcomes in ICU patients. Unfortunately, with the exception of two trials [63,65], most trials included in this systematic review were relatively small studies with fewer than 100 patients and therefore were inadequate to detect a clinically important treatment effect of FO-containing LEs on mortality. However, the advantage of meta-analytic techniques is that they can combine data across studies to discern a more precise treatment effect. In addition, given the wide variety of clinical diagnoses and the heterogeneous population of ICU patients included in this systematic review (sepsis, severe sepsis and/or septic shock, trauma, cancer, pancreatitis, and systemic inflammatory response syndrome), the results and conclusions may be applied to a broad and heterogeneous group of ICU patients.

Since 2012, different meta-analyses [8,9,60] on FO-enriched PN have been published. The differences with our present review are largely due to the variations in the studies included in the reviews. In 2012, Pradelli et al. [8] statistically aggregated 23 RCTs in elective surgery and critically ill patients, and, similarly to our findings, they demonstrated that FO-based PN strategies were associated with a significant reduction in infections (RR = 0.61; 95% CI, 0.45 to 0.84; P = 0.002). Furthermore, Pradelli et al. [8] showed a statistically and clinically significant effect on LOS, both in the ICU (WMD = −1.92; 95% CI, −3.27 to −0.58; P = 0.005) and in the hospital (WMD = −3.29; 95% CI, −5.13 to −1.45; P = 0.0005), although no effect on overall mortality was found. The results regarding infections in the Pradelli et al. study [8] are very similar to our findings, although the inclusion criteria were different, as Pradelli et al. included ten trials in adult patients undergoing elective major abdominal surgery and not admitted to the ICU (n = 740). Meanwhile, after aggregating nine RCTs on FO-containing LEs in ICU patients receiving PN, Palmer et al. [9] were unable to demonstrate any significant effect on infectious complications (RR = 0.78; 95% CI, 0.43 to 1.41; P = 0.41) or on mortality and ICU LOS. Palmer et al. [9] included studies published by Wang et al. in 2008 [33] and 2009 [61]. However, we excluded the 2008 Wang et al. trial [33] because we included a later version of the study that included more patients [61]. Additionally, we excluded two unpublished trials, one by Leiderman et al. [54] and one by Ignatenko et al. [55]. Both of these trials [54,55] were included in the prior meta-analyses, but they are published only as abstracts, and we were not able to obtain data from the investigators necessary to have these trials included in our review.

In 2014, Chen et al. [60] summarized 12 RCTs that administered ω-3 PUFAs through enteral or parenteral routes in ICU patients and showed a tendency toward a reduction in mortality (RR = 0.82, 95% CI, 0.62 to 1.09; P = 0.18), although the effect on other clinical outcomes was not analyzed [60].

Is it plausible that FO-containing LEs reduce infections? According to current knowledge, ω-3 PUFAs have different effects on the function and gene expression of the immune cells, affecting cellular and humoral immunity [2-4,6], which may explain their effects on infections in the critically ill. DHA generates protectins, D-series resolvins and maresins, whereas EPA generates E-series resolvins. The immunomodulatory effects of EPA and DHA, in contrast to the ω-6 PUFAs, have been largely recognized for the ability of ω-3 PUFAs to modify leukocyte activity, decrease cell membrane fluidity, alter the production of bioactive mediators and cell signaling, and modulate systemic inflammation by inhibition of cytokine release [2,68]. Intravenous infusion of FO-containing LEs rapidly leads to an incorporation of ω-3 PUFAs in leukocyte cell membrane phospholipids, leading to a reduced production of proinflammatory cytokines because of a higher ratio of ω-3 to ω-6 PUFAs [2,6].

In 2008, Liang et al. [32] supplemented patients undergoing radical colorectal cancer resection with FO-enriched PN and showed a reduction in interleukin (IL)-6, a high CD4⁺/CD8⁺ ratio, and higher CD3⁺ and CD4⁺ lymphocytes. These findings suggest that supplementation of EPA and DHA by the parenteral route may support immunocompetent cells in seriously ill surgical patients. Meanwhile, Mayer et al. [52] demonstrated a significant improvement in neutrophil function in patients receiving FO-containing LEs, including leukotriene generation and respiratory burst. More recently, in a rat model of sepsis, Terashima et al. [69] demonstrated that FO-enriched PN may regulate neutrophil functions, restoring delayed apoptosis, which was associated with an increase in leukotriene B5 (LTB5) production from peritoneal neutrophils. Hecker et al. [70], in a very elegant murine model of acute respiratory distress syndrome, demonstrated, among other findings, that parenteral FO decreased leukocyte invasion, protein leakage, myeloperoxidase activity, and cytokine production in the alveolar space. Therefore, they have speculated that ω-3 PUFAs could be beneficial in reducing pulmonary inflammatory complications such as VAP [70]. All of these experimental findings may explain, at least in part, the anti-inflammatory and immunomodulatory effects of ω-3 PUFAs seen in clinical practice.

In sepsis, parenteral FO-containing LEs can result in favorable changes to inflammation and immunity by minimizing inflammation and maximizing resolution of inflammatory response and thus improving patient outcomes. However, resolvin D1 produced from DHA has several actions that stop polymorphonuclear neutrophil infiltration and inhibit microglial cells from expressing inflammatory cytokines in in vitro animal models. In addition, resolvin E1 decreases leukocyte infiltration induced by tumor necrosis factor (TNF)-α [71]. Therefore, oversuppression may potentially lead to immunosuppression, although there are conflicting data on the effect on cytokine expression and immunological markers, as no documented reports of negative hemostatic outcomes from FO-containing LEs in sepsis/severe sepsis have been published.

The investigators in the clinical trials included in our systematic review evaluated mechanistic effects of FO-containing LEs. Hall et al. [17] demonstrated a significant reduction in C-reactive protein (CRP) mean values in the FO-enriched PN group, although Burkhart et al. [18] were unable to find differences in IL-6, IL-8, IL-10 and CRP levels between patients supplemented and non-supplemented with FO. Meanwhile, after comparing two alternative LEs, Gultekin et al. [66] found a significant reduction in LTB4 and CRP levels in FO-supplemented patients, whereas IL-6 and TNF-α levels were not different between groups. Previously, Barbosa et al. [64] demonstrated a significant reduction in plasma IL-6 and IL-10 levels in the FO group. Similarly, Wang et al. [61] showed an increase in IL-10 levels and human leukocyte antigen DR expression, as well as a concomitantly significant reduction in CRP levels, in patients with severe acute pancreatitis.

The strength of our meta-analysis is based on the fact that, as in previous meta-analyses, we used several methods to reduce bias (comprehensive literature search, duplicate data abstraction, specific criteria for searching and analysis) and focused on clinically important primary outcomes in ICU patients. Nevertheless, we are aware that our meta-analysis has several limitations, such as the limited number of trials included to evaluate different outcomes. In addition, the effect on infections is driven mostly by the large RCT by Grau-Carmona et al. (N = 159) [65]. This trial explains 52% of the signal and is thus an unstable estimate, which increases slightly after the sensitivity analysis excluding the Hall et al. study [17] (RR = 0.64; 95% CI, 0.44 to 0.94; P = 0.02; heterogeneity I² = 0%). In addition, most of data about MV days and ICU and hospital LOS were extracted from the original reports, which may underestimate the average duration in those cases where LOS of non-survivors was included in the calculation. Finally, there are two unpublished abstracts [54,55] from which we could not obtain sufficient data to include in our meta-analysis. These factors may limit the reliability of our estimates and weaken the strength of our conclusions.