Alternative Lipid Emulsions in the Critically Ill: A Systematic Review of the Evidence

Abstract

Introduction

Parenteral lipid emulsions (LEs) are commonly rich in long-chain triglycerides (LCT) derived from soybean oil (SO). SO containing emulsions may promote systemic inflammation and therefore may adversely affect clinical outcomes. We hypothesized that alternative oil-based LEs (SO-sparing strategies) may improve clinical outcomes in critically ill adult patients compared to SO emulsion only products. The purpose of this systematic review was to evaluate the effect of parenteral SO-sparing strategies on clinical outcomes in intensive care unit (ICU) patients.

Methods

We searched computerized databases from 1980 to 2013. We included randomized controlled trials (RCTs) conducted in critically ill adult patients that evaluated SO-sparing strategies versus SO-based LEs in the context of parenteral nutrition (PN).

Results

A total of 12 RCTs met inclusion criteria. When the results of these RCTs that were statistically aggregated, SO-sparing strategies were associated with clinically important reductions in mortality (risk ratio RR= 0.83, 95% confidence intervals CI 0.62, 1.11, P = 0.20), in duration of ventilation (weighted mean difference, WMD −2.57, 95% CI −5.51, 0.37, P= 0.09), and in ICU length of stay (WMD −2.31, 95% CI −5.28, 0.66, P= 0.13) but none of these differences were statistically significant. SO-sparing strategies had no effect on infectious complications (RR=1.13, 95% CI 0.87, 1.46, P=0.35).

Conclusion

Alternative oil-based LEs may be associated with clinically important reductions in mortality, duration of ventilation, and ICU LOS but lack of statistical precision precludes any clinical recommendations at this time. Further research is warranted to confirm these potential positive treatment effects.

Introduction

Lipid emulsions (LEs) are an essential constituent of parenteral nutrition (PN) [1] and are considered an important source of energy, essential fatty acids (FA) and vitamins E and K [2,3,4]. However, the current literature suggests that soy-bean oil (SO) and safflower-based LEs which are rich in the ω−6 fatty acid linoleic acid, might promote production of pro-inflammatory prostanoids and leukotrienes resulting in increased oxidative stress and systemic inflammation[5,6] and may be associated with worse clinical outcomes [7].

Over the past three decades, different generations of alternative oil-based LEs have been developed, which could have less proinflammatory effects, less immune suppression, and more antioxidant effects than the standard SO-based LEs [8,9]. These SO-sparing strategies consist of different formulations of SO combined with medium-chain triglycerides (MCTs), olive oil (OO) which contains the ω-9 monounsaturated FA (MUFA) oleic acid, and fish oil (FO) which contains ω-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The purpose of the current study was to provide an up-to-date systematic review and meta-analysis of all randomized clinical trials (RCTs) of alternative oil-based LEs, compared to SO emulsion products evaluating clinically relevant outcomes in the critically ill.

Methods

Study Identification

We conducted a systematic review of the published literature to identify all relevant clinical trials using a strategy found in Appendix 1. We included studies if they met all the following eligibility criteria:

1. Study design: randomized controlled trials (RCTs).

2. Population: critically ill adult patients (>18 years old).

3. Intervention: parenteral strategies to reduce the overall load of ω-6 FA (alternative ω6-sparing LEs) versus ω6 oil-based LEs (LCT in the control group).

4. Study outcomes: mortality was the primary outcome for this meta-analysis. Secondary outcomes were: intensive care unit (ICU) and hospital LOS, infections, and mechanical ventilation (MV) days. We excluded the clinical studies that reported only biochemical, metabolic, immunologic or nutritional outcomes. Critically ill patients were defined as patients admitted to an ICU who had an urgent or life-threatening complication (high baseline mortality rate ≥5%) to distinguish them from patients with elective surgery who are also cared for in some ICUs but have a low baseline mortality rate (<5%).

Data Extraction and Risk of Bias Assessment

Two reviewers independently extracted data using a data abstraction form with a scoring system [10]. We scored the methodological quality of individual trials according to key methodological features outlined in the Appendix 2. Disagreement was resolved by consensus between both reviewers. We attempted to contact the authors of included trials and requested missing or unclear information. We designated as a level 1 study if all of the following criteria are fulfilled: concealed randomization, blinded outcome adjudication and an intention to treat analysis. A study was considered as level 2 study if any one of the above characteristics was unfulfilled.

Data synthesis

The primary outcome of the systematic review was overall mortality. From all trials, we combined hospital mortality where reported. If hospital mortality was not reported, we used ICU mortality or 28-day mortality. Secondary outcomes included infections, MV days, and ICU LOS. We used definitions of infections as defined by the authors in their original papers. We analyzed data using RevMan 5.1 [11] with a random effect model. We calculated pooled relative risks using the Mantel-Haenszel estimator for dichotomous outcomes and weighted mean differences (WMDs) were estimated by the inverse variance approach for continuous outcomes, with associated 95% CIs. The random effects model of DerSimonian and Laird was used to estimate variances for the Mantel-Haenszel and inverse variance estimators [12]. The possibility of publication bias was assessed by generating funnel plots and testing asymmetry of outcomes using methods proposed by Rucker and colleagues [13]. Statistical heterogeneity was assessed by the I² statistic. We considered P< 0.05 to be statistically significant and P< 0.20 as indicator of trend.

A priori hypotheses testing

Given the different ω-6 FA sparing strategies and the heterogeneity of trial design, we performed pre-specified, hypothesis-generating subgroup analyses to attempt to elucidate potentially more beneficial treatment strategies. We compared the results of trials that provided a) LCTs plus MCT to a LCT emulsion; b) ω-3 oil-based LEs to a LCT or LCT/MCT mixture, and c) ω-9 oil-based LEs to a LCT or LCT + MCT mixture.

Results

Study identification and selection

A total of 52 potentially eligible RCTs were identified. Of these, we excluded 40 trials due to the following reasons: 22 trials [14,15,16,17,18,19,20,21,22,23,24,25,26,27, 28,29,30,31,32,33,34,35] trials did not include ICU patients (mostly elective surgery and cancer patients), 12 trials [36,37,38,39,40,41,42,43,44,45,46,47] did not evaluate clinically important outcomes; 2 trials [48,49] did not include SO-based LE in the control group; 1 trial [50] compared LCT vs. another LCT emulsion without reduction in SO; 1 trial [51] was conducted in a pediatric population; 1 trial[52] had a short duration of intervention (12 hour of lipid emulsion infusion during the first day); 1 trial included patients with poisoning and not representative of ICU patients[53]. In the end, 12 RCTs [54,55,56,57,58,59,60,61,62,63,64,65] enrolling a total of 806 patients met the inclusion criteria and were included in this systematic review (see Table 1 and 2). The authors reached 100% agreement for inclusion of relevant trials in this review. The mean methodological score of all trials was 9.8 (6 to 14). Randomization was concealed in 8/12 (67 %) trials, ITT analysis was performed in 11/12 (92 %) trials and 8/12 (67 %) trials were double blinded. There were 5 level 1 studies and 7 level 2 studies.

Table 1.

Randomized clinical trial evaluating type of lipids (PN) in critically ill patients

Study	Population	Methods (score)	Intervention	Mortality # (%)†		Infections # (%)‡
Long Chain Triglyceride (LCT) plus Medium Chain Triglycerides (MCT) vs. LCT
Nijveldt 1998	ICU, septic surgical patients, trauma N = 20	C. Random: not sure ITT: yes Blinding: double (10)	PN + Lipofundin (50% LCT+ 50% MCT) vs. PN + Intralipid (100% LCT, soybean)	LCT + MCT ICU 2/12 (17)	LCT ICU 1/8 (13)	LCT + MCT NR	LCT NR
Lindgren 2001	ICU patients, sepsis, multitrauma N = 30	C. Random: yes ITT: yes Blinding: yes (12)	PN + Structolipid (64% LCT + 36% MCT) vs. PN + Intralipid (100% LCT, soybean)	LCT + MCT 1/15 (7)	LCT 0/15 (0)	LCT + MCT 6/15 (40)	LCT 4/15 (27)
Garnacho-Montero. 2002	Surgical ICU Patients with peritonitis and abdominal sepsis N = 72	C. Random: not sure ITT: no Blinding: no (6)	PN + Lipofundin (50% LCT + 50% MCT) vs. PN with Intralipid (100% LCT, soybean) Both groups received PN with 45 % Branched chain amino acids	LCT + MCT ICU 8/35 (23) Hospital 11/35 (31)	LCT ICU 11/37 (30) Hospital 13/37 (35)	LCT + MCT NR	LCT NR
Iovinelli 2007	Patients with COPD requiring ventilation N = 24	CRandom: yes ITT: yes Blinding: no (7)	PN + Lipofundin (50% LCT + 50% MCT) vs. 100% LCT (100% LCT, soybean). In both received 50% of non-protein calories given as lipids	LCT + MCT ICU 2/12 (17)	LCT ICU 3/12 (25)	LCT + MCT Catheter- related 1/12 (8)	LCT Catheter-related 2/12 (17)
Fish oil (ω 3) containing emulsions in PN fed patients vs. LCT or LCT+MCT
Grecu 2003	Patients with abdominal sepsis N = 54 (15/54 in ICU)	C. Random: yes ITT: yes Blinding: double (12)	PN + Omegaven (10% fish oils) plus LCTs vs. PN with LCT	Omegaven + LCT ICU 2/28 (7)	LCT ICU 3/26 (12)	Omegaven VAP 0/8*	LCT VAP 1/7* (14)
Friesecke 2008	Medical ICU patients N= 166	CRandom: yes ITT: yes Blinding: double (10)	PN + Lipofundin MCT (50% LCT + 50% MCT) + Omegaven (10% fish oil) vs. Lipofundin MCT (50% LCT + 50% MCT)	LCT + MCT + FO 28 day 18/83 (22)	LCT+MCT 28 day 22/82 (27)	LCT+ MCT+ FO 10/83 (12)	LCT + MCT 11/82 (13)
Wang 2009	Severe acute pancreatitis patients in ICU N = 56	C. Random: no ITT: yes Blinding: double (11)	PN + Omegaven (10% fish oils) plus Lipovenos (LCTs, soybean oil) (ω3:ω6 ratio was 1:4) vs. PN with Lipovenos (LCTs, soybean oil). Both received same amounts of lipids (1 gm/kg/day)	Omegaven ICU 0/28 (0)	LCT ICU 2/28 (7)	Omegaven 6/28 (21)	LCT 9/28 (32)
Barbosa 2010	ICU patients with SIRS or sepsis requiring PN N=25	CRandom: yes ITT: yes Blinding: single (10)	PN + Lipoplus (50% MCT, 40% LCTs soybean oil, 10% FOl) vs. Nutriflex LipidSpecial (50% MCT, 50% LCT, soybean oil). Both received same amounts of lipids (~1 gm/kg/day)	MCT+LCT+FO 5 day 2/13 (15) 28 day 4/13 (31)	MCT+LCT 5 day 1/10 (10) 28 day 4/10 (40)	MCT+LCT+FO NA	MCT+LCT NA
Olive oil containing emulsions vs. LCT or LCT+MCT
Garcia-de-Lorenzo 2005	Severe burn patients, burn severity index ≥7, TBSA > 30 % N = 22	C. Random: not sure ITT: yes Blinding: double (10)	PN with ClinOleic 20% (80% olive oil, 20% soybean oil, (63% ω9, 37% ω6= restricted linoleic acid {ω6} content) vs. Lipofundin (50% LCT+ 50% MCT).	Clinoleic ICU 4/11 (36)	Lipofundin ICU 4/11 (36)	Clinoleic 6/11 (55)	Lipofundin 6/11 (55)
Huschak 2005**	ICU trauma patients N = 33	CRandom: yes ITT: yes Blinding: None (7)	PN high fat (lipid:glucose 75:25) + Clinoleic (80% olive oil, 20% soybean oil) + EN Glucerrna (lipid:glucose 60:40) vs. PN high carbohydrate (lipid: glucose 37:63) + Lipofundin (50% LCT + 50% MCT) + EN Fresubin HP Energy (lipid:glucose 44:56)	High fat + Clinoleic ICU 4/18 (22)	Low fat + LCT + MCT ICU 1/15 (7)	High fat + Clinoleic Low fat +LCT+MCT Data Not reported.
Umperrez 2012	Medical surgical ICU pts post op (88% emergency surgeries) N =100	C. Random: yes ITT: yes Blinding: double (14)	PN with ClinOleic 20% (80% olive oil, 20% soybean oil, ω6:ω3=9:1) vs. Intralipid (100% soybean oil, ω6:ω3=7:1)	Clinoleic Hospital 5/51 (10)	Intralipid Hospital 8/49 (16)	Clinoleic 29/51 (57)	Intralipid 21/49 (43)
						Pneumonia
						7/51 (14)	5/49 (10)
Pontes-Arruda 2012	ICU pts requiring PN from 8 ICUs and 3 countries N=204	C. Random: yes ITT: yes Blinding: no (9)	PN with ClinOleic (n=103) vs PN with a MCT/LCT based IVLE (n=101)	ClinOleic ICU 19/103 (24) 28-day 24/103 (27)	MCT/LCT ICU 21/101 (21) 28-day 26/101 (26)	ClinOleic	MCT/LCT
						All infections
						39/103 (38)	35/101 (35)
						ICU acquired infections
						28/103 (27)	23/101 (23)
						VAP/lower respiratory infections
						9/103 (9)	11/101 (11)

Abbreviations: ARDS: acute respiratory distress syndrome; C. Random: concealed randomization; DHA: docosahexaenoic acid; EN: enteral nutrition; EPA: eicosapentaenoic acid; C. Random: concealed randomization; EN: enteral nutrition; FO: fish oil; ICU: intensive care unit; ITT: intention to treat; IV: intravenous; LCT: long chain triglycerides; MCT: medium chain triglycerides; N: number of patients; NA: non attribuible; NR: non referred; PN: parenteral nutrition; SIRS: systemic inflammatory response syndrome; VAP: ventilator associated pneumonia; ω-3: omega 3; ω-6: omega 6; ω-9: omega 9.

^†hospital mortality unless specified;

^‡number of patients with infections unless specified;

^*data obtained from author, 8 out of 28 in Omegaven and 7 out of 26 in LCT group were in ICU;

^**intervention includes high fat low carbohydrates PN plus fish oil;

^aconverted Standard Error Mean (SEM) to Standard deviation (SD)

Table 2.

Outcomes of included trials on omega 6 reducing strategies lipid emulsions

Study	LOS days		Ventilator days		Other
Long Chain Triglyceride (LCT) plus Medium Chain Triglycerides (MCT) vs. LCT
Nijveldt 1998	LCT + MCT 13.8 ± 2.9 (12)	LCT 17.4 ± 3.0 (8)	LCT + MCT NR	LCT NR	NR
Lindgren 2001	LCT + MCT NR	LCT NR	LCT + MCT NR	LCT NR	LCT + MCT	LCT
					Adverse effects
					5/15 (33)	4/15 (27)
					Nitrogen balance at day 3
					2.6 ± 5.6 gms	−11.7 ± 4.8 gms
Garnacho-Montero 2002	LCT + MCT ICU 16.6 ± 6.1 (35)	LCT ICU 15.8 ± 7 (37)	LCT + MCT NR	LCT NR	LCT + MCT	LCT
					Retinol binding protein
					1.7 ± 1	0.8 ± 0.6
					Nitrogen balance
					14.2 ± 2.9	11.6 ± 4
Iovinelli 2007	LCT + MCT NR	LCT NR	LCT + MCT 10.6 ± 3.0 (12)	LCT 13.4 ± 3.5 (12)	LCT + MCT	LCT
					Time before weaning
					52 ± 36 hrs	127 ± 73 hrs
Fish oil (ω 3) containing emulsions in PN fed patients vs. LCT or LCT+MCT
Grecu 2003*	Omegaven ICU 3.32 ± 1.48 (8) Hospital 11.68 ± 2.04 (28)	LCT ICU 9.28 ± 3.08 (7) Hospital 20.46 ± 3.27 (26)	Omegaven 2.83 ± 1.62 (8)	LCT 5.23 ± 2.80 (7)	Omegaven	LCT
					Patients undergoing reoperation for septic episode
					2/28 (7)	8/26 (31)
Friesecke 2008	FO ICU 28 ± 25 (83)	LCT ICU 23 ± 20 (82)	LCT + MCT + FO 22.8 ± 22.9 (83)	LCT+MCT 20.5 ± 19.0 (82)	LCT + MCT + FO	LCT+MCT
					Urinary Tract Infections
					6/83 (7)	4/82 (5)
					Catheter-related infections
					1/83 (1)	3/83 (4)
					Total EN Energy Intake (kcal/kg)
					22.2 ± 5.5	21.6 ± 5.6
Wang 2009	NA	NA	NA	NA	Omegaven	LCT
					Surgery of infected pancreatic necrosis
					3/28 (11)	6/28 (21)
Barbosa 2010	MCT+LCT+FO ICU 12 ± 14.4a (13) Hospital 22 ± 25.2 a (13)	MCT+LCT ICU 13 ± 12.6 a (10) Hospital 55 ± 50 a.6 (10)	MCT+LCT+FO 10 ± 14.4 (13)	MCT+LCT 11 ± 12.64 (10)	MCT+LCT+ FO 2057± 418 kcals	MCT+LCT 1857 ± 255 kcals
Olive oil containing emulsions vs. LCT or LCT+MCT
Garcia-de-Lorenzo 2005	Clinoleic ICU 32.9 ± 10.6a (11) Hospital 57 ± 15.3a (11)	Lipofundin ICU 41.8 ± 16.3a (11) Hospital 64.9 ± 27.2a (11)	Clinoleic 11.0 ± 11.93a (11)	Lipofundin 13.0 ± 16.25a (11)	Clinoleic	Lipofundin
					Multiple organ dysfunction score
					11.0 ± 3.6	13.0 ± 4.9
Huschak 2005**	High fat + Clinoleic ICU 17.9 ± 11.2 (18)	Low fat + LCT+MCT ICU 25.1 ± 7.0 (15)	High fat + Clinoleic 13.0 ± 8.9 (18)	Low fat + LCT+MCT 20.4 ± 7.0 (15)	High fat + Clinoleic	Low fat + LCT + MCT
					Total Energy Intake (kcal/kg)
					17.9 ± 6.3	22.3 ± 4.2
Umperrez 2012	Clinoleic ICU 17 ± 18 (51) Hospital 40.8 ± 36 (51)	Intralipid ICU 15.2 ± 14 (49) Hospital 46.7 ± 48 (51)	Clinoleic NR	Intralipid NR	Clinoleic	Intralipid
					Total Energy Intake (kcal/kg)
					22 ± 6	22 ±5
Pontes-Arruda 2013	Clinoleic ICU 12 (7–17) Hospital 21 (15–25)	MCT/LCT ICU 11 (5–14) Hospital 18 (13–23)	NA	NA	Clinoleic	MCT/LCT
					Nutritional Intake
					Lipids (g/day)
					66 (61–73)	61 (54–67)
					Days on PN
					12 (8–15)	11 (7–15)
					Dextrose (g/day)
					288 (275–303)	281 (273–301)
					AAs (g/day)
					87 (84–90)	87 (83–92)

Abbreviations: EN: enteral nutrition; FO: fish oil; ICU: intensive care unit; LCT: long chain triglycerides; LOS: length of stay; MCT: medium chain triglycerides; NA: non attribuible; NR: not reported; PN: parenteral nutrition;

^†hospital mortality unless specified;

^‡number of patients with infections unless specified;

^*data obtained from author, 8 out of 28 in Omegaven and 7 out of 26 in LCT group were in ICU;

^**intervention includes high fat low carbohydrates PN plus fish oil;

^aconverted Standard Error Mean (SEM) to Standard deviation (SD)

Meta-Analysis of Primary Outcome

When the results of 12 RCTs [54–65] that evaluated mortality were statistically aggregated, ω-6-sparing strategies were associated with a reduction in mortality that was not statistically significant (risk ratio [RR]= 0.83, 95 % confidence intervals [CI] 0.62, 1.11, P= 0.20, heterogeneity I² =0% see Figure 1).

Figure 1.

Overall effect on Mortality of LCT (Omega-6 reducing strategy) vs. LCT

Abbreviations: LCT: long chain triglycerides; MCT: medium chain triglycerides; 95% CI: 95% confidence intervals

Secondary Outcomes

Compared to LCT, when the RCTs reporting ventilator days were aggregated [58,60,61,62,64], overall ω-6 FA-sparing strategies were consistent with a -reduction in duration of MV but differences were not statistically significant (WMD −2.57, 95% CI −5.51, 0.37, P=0.09, heterogeneity I²=25%) (Figure 2). There was a trend towards a reduction in ICU LOS associated with the use of ω-6-sparing strategies when compared to LCT [54,56,58,59,60,61,62,64] (WMD −2.31, 95% CI −5.28, 0.66, P=0.13, I²⁼68%, P< 0.003) (Figure 3). When the data from 5 RCTs [58,60,62,63,65] that reported ICU-acquired infections were aggregated, ω-6-sparing strategy had no effect (RR= 1.13, 95% CI 0.87, 1.46, P=0.35, heterogeneity I²=0%).

Figure 2.

Overall effect on ventilation days of Omega 6 reducing strategy vs. LCT

Abbreviations: LCT: long chain triglycerides; 95% CI: 95% confidence intervals; SD: standard deviation

Figure 3.

Overall effect on ICU LOS of Omega 6 reducing strategy vs. LCT

Abbreviations: LCT: long chain triglycerides; MCT: medium chain triglycerides; 95% CI: 95% confidence intervals; SD: standard deviation

Subgroup analysis

LCTs plus MCT versus LCT emulsion

Four RCTs [54–57] compared LCTs plus MCT to a LCT emulsion. When statistically aggregated, these studies showed no difference in mortality (RR= 0.84, 95 % CI 0.43, 1.61, P=0.59, heterogeneity I²=0%) (Figure 1). Only one trial [57] compared LCT+MCT to LCT that reported duration of ventilation and no significant differences were seen between the two groups. When the data from the two trials [54,56] that report ICU LOS were aggregated, there were no differences in ICU LOS (WMD −1.46, 95 % CI −5.77, 2.85, P= 0.51, heterogeneity was present I²= 78%, P=0.03) (Figure 3).

Fish oil containing emulsions vs. LCT or LCT +MCT

Four RCTs [61–64] comparing ω-3 oil-based LEs to a LCT or LCT+MCT reported mortality. When these data were aggregated, this strategy was not associated with a reduction in mortality (RR= 0.76, 95% CI 0.48, 1.21, P = 0.25 heterogeneity I²=0%) (Figure 1). We found a trend towards a reduction in the duration of mechanical ventilation (WMD −1.81, 95% CI −3.98, 0.36, P= 0.10, heterogeneity I²=0%) (Figure 2). There were no differences between the groups in ICU LOS (WMD −1.13, 95% CI −8.96, 6.69, P = 0.78; heterogeneity I²= 78%, P= 0.01) (Figure 3) and infections (RR= 0.79, 95% CI 0.43, 1.43, P = 0.43, heterogeneity I²= 0%).

ω9 oil-based LEs versus a LCT + MCT mixture

Four RCTs [58,59,64,65] compared a ω-9 oil-based LE to a LCT + MCT mixture. We did not find any difference between the groups in mortality (RR= 0.90, 95% CI 0.58, 1.39, P=0.62, heterogeneity I²= 0%) (Figure 1), however we found a significant reduction in the duration of MV (WMD −6.47, 95% CI −11.41, −1.53, P= 0.01, heterogeneity I²=0%) (Figure 2) but no effect on ICU LOS (WMD −4.08, 95 % CI −10.97, 2.81, P=0.25, heterogeneity I²=59%) (Figure 3). When 3 RCTs [58,60,65] that reported on ICU-acquired infections were aggregated, this strategy showed a tendency towards an increase in infections (RR= 1.23, 95% CI 0.92, 1.63, P= 0.16, heterogeneity I²=0%).

Risk of publication bias

There was no indication that publication bias influenced the observed aggregated results. Funnel plots were created for each study outcome (data not shown) and the tests of asymmetry were not significant for any outcome measure (mortality, P= 0.48; ICU LOS, P= 0.88, and mechanical ventilation days P= 0.78).

Discussion

Our systematic review and meta-analysis is the first in evaluating the overall effects of parenteral ω-6 reducing strategies in the critically ill. When 12 eligible trials were statistically aggregated, we did not find statistically significant effects. However, the magnitude of the potential treatment effect, in terms of a reduction in mortality (relative risk reduction 17%) and reduction in ICU LOS (more than 2 days less), if realized, would be consistent with a large and clinically and economically important difference. The lack of statistical precision is likely due to the small number of studies and the small sample size of each study. Given the heterogeneous population of ICU patients included in this systematic review (sepsis, severe sepsis/septic shock, surgery, trauma, burns, and SIRS), the conclusions of our systematic review could be applied to a broad group of ICU patients. However, given the heterogeneity of alternative LEs, we explored several subgroups to evaluate if the treatment effect was different across different commercial preparations. There are no head-to-head comparisons of these different alternative LEs strategies. Indirectly, by examining the risk ratios of the different alternatives, there does not appear to be any difference in the treatment effects. Therefore, we are unable to define the best ω-6 sparing strategy in the critically ill as available evidence on the differential effects of LEs in ICU patients remains limited after our meta-analysis.

The anti-inflammatory properties of EPA and DHA have been described and exhaustively studied in different experimental and clinical studies [66,67]. Two RCTs included in our systematic review found a significant reduction of the proinflammatory cytokine interleukin 6 and an increase in the HLA-DR expression. However, we were unable to demonstrate any significant effect with FO based LEs rich in EPA and DHA. Recently, two meta-analyses on parenteral FO have been published. Pradelli et al [68] demonstrated that parenteral FO enriched LE were associated with a statistically and clinically significant reduction in infections (P= 0.002) and the LOS, both in the ICU (P= 0.005) and in hospital (P= 0.0005) [68]. Nonetheless, these results cannot be compared with our findings because our meta-analysis included only RCTs evaluating clinical outcomes in the critically ill and excluded RCTs performed in non ICU surgical patients.

More recently, Palmer et al [69] concluded that parenteral FO does not improve mortality, infectious complications, and ICU LOS in comparison with standard PN. These results are similar to our findings. However, we found a tendency toward a reduction in mechanical ventilation days. We believe that this difference was largely due to the difference in the papers included in the different reviews. In fact, Palmer et al [69] have included two papers published by Wang et al in 2008 [28] and 2009 [63]. However, we have decided to include the study published in 2009 [63] and exclude the previous study because it did not include ICU patients and did not report on relevant clinical outcomes. In addition, we excluded two unpublished studies by Liderman et al [70] and Ignatenko et al [71], as both are published as abstracts and we have not had any response from the investigators, which was needed to complete our data abstraction form.

The strength of our meta-analysis includes the fact that we used several methods to reduce bias (comprehensive literature search, duplicate data abstraction, specific criteria for searching and analysis) and have focused on clinically important primary outcomes for ICU patients. The major limitation of our meta-analysis was the small number of trials included which resulted in statistical imprecision. Furthermore, the presence of heterogeneity, both clinical and statistical, weakens any inferences we can make from these data.

In spite of these limitations, we have demonstrated that alternative oil-based LEs in the critically ill could be able to reduce overall mortality, shorten ventilation days and ICU LOS. Further research is warranted and should define the best mixture of lipids, target patient population, best timing, and duration of therapy to optimize the effects on underlying systemic inflammation, immune status, and metabolic processes while at the same time achieving an acceptable safety and tolerance profile.

Appendix 1

“omega-6 sparing”, “omega-6 reducing”, “alternative fat emulsions”, “fish oil lipid emulsions”, “omega-3”, “omega 9”, “olive oil lipid emulsions”, “medium chain triglycerides (MCT) lipid emulsions”, “randomized,” “blind,” “clinical trial,” “nutritional support”, “parenteral nutrition”, “lipid emulsions”, “critical illness” and “critically ill”.

Appendix 2: Methodological Quality Assessment

We scored the methodological quality of individual trials considering the following key features of high-quality studies: a) extent to which randomization was concealed, b) blinding, c) analysis was based on the intention-to-treat (ITT) principle, d) comparability of groups at baseline, e) extent of follow-up, f) description of treatment protocol and co-interventions, and g) definition of clinical outcomes. Each individual study was scored from 0 to 14.