Parenteral Fish Oil (FO) in Gastrointestinal Surgery: A Review of the Literature

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Parenteral fish oil (FO) in Gastrointestinal Surgery:

A Review of the Literature

Introduction

Intravenous lipid emulsions (IVFEs), which are a dense form of energy in parenteral nutrition (PN) and provide essential fatty acids (FA), have evolved over time. Original IVFE formulations were made from 100% soybean oil (SO), with newer formulations made from alternative lipids, such as medium-chain triglycerides (MCTs), olive oils (OOs), and fish oils (FO). Lipids consist of triglycerides and each triglyceride differs in its FA, phytosterol and α-tocopherol content (Table 1). Thus the different manufactured IVFE have different proportions of ω-3:ω-6 FAs (Table 2). For example, FO is rich in ω-3 FA, which is highly bioactive compared with MCT and OO (Vanek et al., 2012). Clinically, ω-3 FAs are relatively less proinflammatory and are considered to have anti-inflammatory effects compared to ω-6 FAs (Vanek et al., 2012). Therefore patients are thought to have better clinical outcomes when using fish oil containing IVFEs (FO-IVFE) as it reduces the intake of the potentially proinflammatory ω-6 FA, linoleic acid, which comprises more than 50% of the FA profile in SO (Vanek et al., 2012; Raman et al., 2017).

Table 1.  Oils in IVFEs (Fell et al., 2015)

Lipid Component

Soybean

Safflower

Olive

Fish

Coconut

 

FA composition (%)

Linoleic Acid (ω-6)

50

77

4

1-3

2

Arachidonic Acid (ω-6)

Alpha Linoleic Acid (ω-3)

10

1.3-5.2

Eicosapentaenoic acid (ω-3)

5.4–13.9

Docosahexaenoic acid (ω-3)

5.4–26.8

Oleic acid (ω-9)

25

15

85

16–20

6

Medium chain triglycerides (MCT)

65

Saturated fatty acids (SFA)

15

8

11

10–20

27

Phytosterols (mg/100 mg oil)

300

450

200

Trace

70

α-Tocopherol (mg/100 mg oil)

6.4-7.5

34

10–37

45–70

Table 2. Comparison between commercially available IVFE

(adapted from Vanek et al., 2012; Leguina-Ruzzi and Ortiz, 2018; Abbasoglu et al., 2019)

 

IVFE

Year, Manufacturer

ω-6: ω-3

Soybean

MCT

Olive Oil

Fish Oil

α- tocopherol

ClinOleic

1990, Baxter

9:1

20%

0

80%

0

32 mg/L

Intralipid

1961, Fresenius Kabi

7:1

100%

0

0

0

38 mg/L

Lipofundin

1984, B. Braun

7:1

50%

50%

0

0

85  mg/L

SMOFlipid

Late 1990, Fresenius

2.5:1

30%

30%

25%

15%

200 mg/L

Omegaven

Late 1990, Fresenius

1:8

0

0

0

100%

150–296

There has been increasing interest in the use of FO-IVFE (SMOFlipid and Omegaven). For example, the 2017 ESPEN nutrition and surgery guidelines provide Grade B evidence that “postoperative parenteral nutrition including omega-3-fatty acids should be considered” (Weimann et al., 2017). However, there are conflicting reports in meta-analysis and systematic reviews whether there are clinical benefits to FO-IVFE. A recent systematic review by Abbasoglu et al. (2019) stated that there is very little high quality evidence of the beneficial effect of FO-IVFE over standard formulations. On the other hand, other meta-analysis have reported significant clinical benefits for surgical patients including reduced infections, length of stay and mortality (Pradelli et al., 2012; Li et al., 2014; Bae et al., 2017). However not all these meta-analysis are reliable. Abbasoglu et al. (2019) reported how the Pradelli et al. (2012) meta-analysis only imputed up to 50% of standard deviations by the original trial but did not correct for possible type 1 errors. Other meta-analysis have reported no clinical benefits (Tian et al., 2013; Chen et al., 2014).

This review was undertaken as the dietetic service in Imperial College Healthcare (ICH) trust wanted to review which patient groups should receive SMOFlipid.  Currently the upper gastro-intestinal (UGI) patient population, who are based in St. Marys Hospital, are the only patient group to receive this FO-IVFE. As this service moved hospital site to where SMOFlipid it is not currently used, the dietetic team was requested to review if other patient groups should also receive it. The author works in pancreatic cancer and resection, therefore this review originally aimed to investigate the current published evidence in the use of FO-IVFE in this patient group. An initial search highlighted the limited studies on the use of FO-IVFE in pancreatic surgery. Thus, the search was expanded to include gastrointestinal surgery.  Therefore, the aim of the study was to address the question: Do FO-IVFE improve outcomes for patients undergoing gastrointestinal surgery?

Methods

A literature search was conducted of medline and embase databases. The keywords “ω-3 fatty acid” OR “fish oil” OR “EPA” OR “DHA”) AND (“cancer” OR “malignancy” OR “carcinoma” OR “neoplasms”) AND “parenteral nutrition” were used. See Appendix A for the search undertaken.  A manual search was also undertaken from reference lists. Papers were included if they were produced after 2000, published in English and met the following criteria:

  1. Study design: randomised controlled trials (RCT), systematic review or meta-analysis;
  2. Participants: gastrointestinal surgical patients;
  3. Intervention:  FO-IVFE compared with SO/MCT/OO containing IVFE;
  4. Outcomes:

    1. clinical effectiveness: length of hospital stay (LOS), infectious complications, mortality
    2. safety: liver parameters, inflammatory markers, immune markers.

Papers were excluded if the intervention group received other immunonutrition and contained participants that had included other surgeries than gastrointestinal surgery.

Results

A systematic search revealed 15 number of studies. Two studies were excluded as they contained other surgeries than GI surgery (Tsekos et al., 2004; Mertes et al., 2006). Another study was excluded as it contained the immunonutrient glutamine (Klek et al., 2005). The author did consider including this study as there was a subgroup that received only FO+SO however on critical analysis of the paper the study was not deemed high enough quality. This was because the total amount of IVFE delivered to the patient was not reported, there were several dropouts due to infectious complications and mortality but this was not included in Klek’s analysis and the study had a risk of bias as it was unclear whether there was selection bias with no details on random sequence generation, blinding and allocation concealment.  Thus, a total of 11 RCT and 1 meta-analysis were included in this review (Table 3).

Study Design of RCT

Seven RCT had <50 participants, three had 50-100 participants and only one had >100 participants (Jiang et al., 2010). The duration of intervention was between 5-7 days. No studies conducted long term follow up. Seven studies were on gastrointestinal cancers, two contained both gastric and pancreatic carcinomas, one specifically focused on pancreaticoduodenectomy (Zhu et al., 2013) and one study did not state the type of GI surgery undertaken (Grimm et al., 2006). Regarding risk of bias, six studies were double blinded but methods of blinding outcome assessments were not clearly stated in most publications. Allocation concealment was reported in most studies. Two studies did not state whether trace-elements and vitamins were provided (Grimm et al., 2006; Makay et al., 2011) whereas the other studies all provided patients with trace-elements and vitamins as part of the PN regime. Most studies were isocaloric and isonitrogenous. See Table 3.

The interventions in the RCTS were either SMOFlipid in three studies or FO admixtures in eight studies (Omegaven replacing a proportion of the control) and the control groups also differed with SO, SO+ MCT and SO+OO (Table 3). The FO admixtures ranged from FO 0.2 + SO 0.8 g/kg (Heller et al., 2004), FO 0.2 + SO 1.0 g/kg (Jiang et al., 2010; Zhu et al., 2012), FO 16% of 0.7-1 g/kg SO/OO (Badía-Tahull et al., 2010), 10% FO of 1.1 g/kg SO (Zhu et al., 2013), 10% FO up to 0.2 g/kg SO (Wei et al., 2014), FO 0.2 + SO 0.6 g/kg (Liang et al., 2008; Makay et al., 2011).  SMOFlipid was provided in varying quantities ranging from 1.5 g/kg (Grimm et al., 2006), 1.0-2.0 g/kg (Ma et al., 2012) and 250 ml vs. MCT (Wu et al., 2014) of SMOFlipid.  SMOFlipid and Omegaven+SO also contain higher amounts of α-tocopherol compared with controls (Table 2).

Clinical effectiveness

Nine studies reported LOS. Five showed no statistical difference and four showed a statistically reduced LOS for the FO-IVFE intervention (Grimm et al., 2006; Jiang et al., 2010; Zhu et al., 2012, 2013).  

Eight studies reported rates of infectious complications with only three of these studies reporting statistically lower rates with the intervention (Badía-Tahull et al., 2010; Zhu et al., 2013; Wei et al., 2014). However, the Zhu paper gave no details of what was measured for this outcome and the Wei study only showed significantly lower combined incidences (1/26 vs. 6/20) but individual complications did not show statistical differences.

Regarding mortality, five studies reported no significant differences between groups. The end point of mortality was not specified in one of these studies (Makay et al., 2011).  Most RCT do recognise that due to the small patient numbers mortality is underpowered to be detected (Liang et al., 2008).

Laboratory parameters

Four papers assessed liver parameters including alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin. Only two papers showed a statistically lower ALT and AST level (Heller et al., 2004; Zhu et al., 2013).

Surgery-related injury results in the release of proinflammatory cytokines, such as IL-6 and TNF-α. Four studies evaluated these inflammatory markers with three showing a significant decrease in the production of systemic IL-6 and TNF-α (Liang et al., 2008; Zhu et al., 2012; Wei et al., 2014) with FO-IVFE.

Four trials evaluated the effect of ω-3 FA on immune function including CD4+ and CD8+ expression and the CD4+/CD8+ ratio, three of these studies showed a statistically lower CD4+/CD8+ ratio (Liang et al., 2008; Jiang et al., 2010; Zhu et al., 2012).  

Other outcomes

Two studies investigated total costs of FO intervention and no significant difference in cost between FO-containing PN and SO-based PN (Jiang et al., 2010; Zhu et al., 2012).

Discussion

The results highlight how there are inconsistent reports whether FO-IVFE provides a significant improvement in any of outcomes assessed. Inflammatory markers and immune response were the most likely outcome to show a statistical benefit (75% of studies), but LOS, infectious complications, and mortality are all inconclusive (44%, 37.5%, 0% statistical benefit in studies respectively). This is different from the meta-analysis on 457 gastrointestinal surgical patients conducted  by Bai et al. (2018) which showed statistical benefit for FO-IVFE with regards LOS (2.29 days CI: 3.64-0.93), infectious complications and an increased CD4+/CD8+ ratio. This may be due to the RCTs included in this review have small participants numbers and by combining individual studies into a meta-analysis it increases their analytical power.

However, is a meta-analysis of these studies appropriate and reliable? It can be seen that the interventions and controls were slightly different in all the RCTs with regards total FO provision, different concentrations of α-tocopherol and different controls (SO vs. SO+MCT vs.SO+OO). Therefore the studies themselves are likely not directly comparable. OO and MCT emulsions are thought to provide an immunoneutral option (Cury-Boaventura et al., 2008) and a recent meta-analysis reported that the effect of MCT-based IVFEs compared to FO-containing IVFEs in reducing infectious morbidity was not statistically significant (Bae et al., 2017). Abbasoglu et al. (2019) also discussed whether combining RCTs is correct and undertook a qualitative literature review as opposed to meta-analysis as most studies were considered low quality and had considerable heterogeneity.

In addition, there may be the confounding influence of α-tocopherol in the interventions. SO-based IVFEs, containing a limited amount of α-tocopherol can lead to a depletion of antioxidant defences overtime (Becvarova et al., 2005). Therefore it could be the combined effect of the low content of ω-6 in addition to the high α-tocopherol content of FO-IVFE which contribute to an improvement in stress on the body (Badía-Tahull et al., 2010)  and not just FO alone.

Surgical procedures can result in an inflammatory response, and it is thought a lower  ω-6: ω-3 ratio is associated with a reduced production of proinflammatory cytokines and improves immune function (Calder, 2007). In the authors opinion in most studies there was a trend, even if not significant, towards improved inflammation and immune markers with FO-IVFE. However whether this provides overall clinical benefit was not confirmed. 

As discussed in the introduction, the ESPEN surgical guidelines provide Grade B evidence for the consideration of omega-3 FA in PN. The working group felt that they could not give stronger support due to the methodological problems of individual studies such as lack of homogenous criteria in definitions of outcomes (e.g. LOS, infectious complications). This review confirms this view with all the 11 RCT included have heterogeneous methods and definitions of outcomes.

Conclusion

The author cannot definitively state from this literature review whether there is an overall clinical benefit for FO-IVFE over standard IVFE. Nevertheless, when RCTs are combined into meta-analysis they do show a trend towards statistically significant improved outcomes, especially improvements in inflammatory markers and immune function.  These meta-analysis need to be interpreted with caution as they may not be reliable due to lack of rigor behind included studies.

More RCTs on gastrointestinal cancer with FO-interventions specifically evaluating what duration  and dose is best (optimal ω-3: ω-6 ratio), with homogenous methodologies and larger sample sizes are needed before a clear benefit for the use of FO-IVFE can be strongly recommended for the gastrointestinal patients in ICH.

Table 3a. Characteristics of included studies

Reference

 Study Design

Participants (number in intervention/control)

Intervention vs. Comparator

Outcome

Length of Study

SMOF Lipid Intervention

(Grimm et al., 2006)

Double-blind, RCT 2 centres

n=33 (19/14) well-nourished patients postoperative days following major abdominal surgery.

SMOFlipid 20% vs. SO (Lipovenoes MCT 20%).

1.5 g lipids/kg BW/day

Clinical effectiveness: LOS 


Laboratory Outcomes: alpha-T, Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA),

 Leukotriene B4 (LTB4), LTB5, LTB ratio

5 days

(Ma et al., 2012)

Prospective, double-blind RCT

n=40 (20/20) following elective digestive surgery

SMOFlipid 20% vs. SO (Lipovenoes MCT 20%).

1‐2 g lipids/kg BW/day.

Clinical Effectiveness: adverse events.
Laboratory Outcomes: CD4, CD8, CD4/CD8. IL-6 and TNF-α

5 days

(Wu et al., 2014)

Prospective RCT 

n = 40 (20/20) following gastric adenocarcinoma(n=30) and gastrointestinal stromal tumour (n=5)

SMOFLipid 20%vs. SO (Lipovenoes MCT 20%)
250ml of each lipid per day.

Clinical effectiveness: LOS and major infectious complications

Laboratory markers: Triglyceride. IL-6, IL-10, CRP, TNF-α, and TGF-β1

5 days

Fish Oil Admixtures

(Heller et al., 2004)

Prospective, double-blind RCT

n=44 (24/20) following elective surgery for carcinoma of the gastrointestinal tract or the pancreas

FO (Omegaven) + SO (FO 0.2 + SO 08 g/kg BW) vs. SO (Lipovenoes MCT 10% 1.0 g lipid/kg BW)

Clinical effectiveness: LOS and weight loss, infectious complication.
Laboratory parameters: liver and pancreatic enzymes (ALT, AST, bilirubin, LDH, lipase). IL-6 and IL-10.

 5 days

(Liang et al., 2008)

Prospective, double-blind RCT

n=42 (21/21) following colorectal cancer resection

FO + SO (Omegaven up to 0.2g/kg + Intralipid) vs. SO (Intralipid 0.8g/kg).

Clinical Effectiveness: LOS, Infection, Mortality


Laboratory Parameters: IL-6, TNF-α, CD3+, CD4+, and CD8+ lymphocytes

7 days

(Jiang et al., 2010)

Double-blind RCT, multicentre

n=206 (100/103) gastrointestinal or colonic cancer

 SO & FO (0.2 g/kg/d Omegaven + 1.0 g/kg/d Intralipid  (ω-3/ ω-6 fatty acid ratio 1:3))  vs. SO (1.2 g/kg/d  Intralipid)

Clinical effectiveness: LOS, number of postoperative infectious complications and occurrence of SIRS, mortality

Laboratory parameters: The CD4/CD8 ratio , serum IL- 6  and TNF-α

7 days

(Badía-Tahull et al., 2010)

Prospective, double-blind RCT

n=27 (14/13) elective gastrointestinal tract major surgery (n=12 gastric adenocarcinoma, n=10 pancreatic ductal adenocarcinoma, n=3 oesophageal adenocarcinoma, n=4 colectomy/practical resection of small intestine)

Omegaven 16% w/w + SO/OO vs. SO/OO (Clinoleic)

0·7–1 g lipid /kg per day

Clinical effectiveness: Mortality, sepsis, infectious complications, LOS.


Laboratory parameters: ALT, CRP, bilirubin, Cr.

5 days

(Makay et al., 2011)

RCT

n = 26 (14/12) following major gastric surgery

FO&SO (Omegaven, 0.2 g/kg/d; Lipovenoes 10%, 0.6 g/kg/d vs. SO  (Lipovenoes 10%, 0.8 g/kg/d)

Clinical effectiveness: LOS, mortality, infectious complications


Laboratory parameters: ALT, AST, lactate levels

5 days

(Zhu et al., 2012)

Prospective, double-blind RCT

n=57 (29/28) following radical colectomy for colorectal cancer

Omegaven + SO (0.2 g/kg/d fish oil + 1.0 g/kg/d soybean oil) vs.  SO(Intralipid 1.2g/kg/d)

Clinical effectiveness: Infectious complications, duration of SIRS, LOS, total medical costs.


Laboratory parameters: CD4, CD8, CD4/CD8. IL-6 and TNF-α

7 days

(Zhu et al., 2013)

RCT

n=76 (38/38) following pancreaticoduodenectomy (PD).

Omegaven 10% 2 mL/kg/d + SO (Lipofundin) with early EN support (n=38) vs. SO (Lipofundin) combined with early EN support (control group, 38 patients).

Provided at 1.1g/kg/day.

Clinical effectiveness: Infectious complications, LOS, mortality
Any complication 30 days after hospital discharge.


Laboratory parameters: ALT, AST, bilirubin, LDH.

5 days

(Wei et al., 2014)

Prospective, RCT

n=52 (26/20) following surgery of gastric tumours

FO + SO (10% Omegaven up to 0.2 g/kg, (ω-3/(ω-6 ratio was 1:4)) + vs. SO (Intralipid) (n=26)

Clinical Effectiveness:  infectious complications.


Laboratory Parameters:  CD3, CD4, CD8, CD4/CD8, IL-6, TNF- α, IL-1B, nutritional parameters

6 days

Meta-analysis

(Bai et al., 2018)

7 included RCT

n = 457 following postoperative gastrointestinal cancer patients receiving ≥3 days of PN in a hospital

Intervention: FO-IVFE. Dose: up to 0.02g/kg FO. Comparator:  SO, SO/MCT

Outcome measures:  immune indices, infectious complications, LOS.

5-7
days

ALT: Alanine transaminase; AST: Aspartate transaminase; CD: cluster of differentiation; FO: Fish oil; IL: Interleukin; LDH: lactate dehydrogenase; LOS: length of hospital stay; SIRS: systemic inflammatory response; SO: soybean oil; TGF: transforming growth factor; TNF: tumour necrosis factor

Table 3b: Results and critique of included studies

Reference

Results

Strengths

Limitations

SMOF Lipid Intervention

(Grimm et al., 2006)

Clinical Effectiveness A reduced length of hospital stay with SMOFlipid vs. SO (13.4 ± 2.0 vs. 20.4 ± 10.0 days, p < 0.05).

Laboratory Outcomes:

SMOFlipid group significant increase in total n-3 FA, EPA, and DHA and significant decrease in total n-6 FA, LA, and AA.


Significant increase in the ratio of n-3/n-6 SMOFlipid
 

Leukocyte generation of LTB5 was significantly increased in SMOFlipid group

Isocalorific, isonitrogenous regimen

Unclear whether there was random sequence generation/allocation concealment.
No details on the division of type of surgery patients had in each group.

Large CI within LOS for comparator group
No sample size/power calculation completed
Did not state whether vitamins and minerals were provided
Small patient population

(Ma et al., 2012)

Metabolic parameters, laboratory parameters, proinflammatory cytokine levels, adverse events, and clinical outcomes did not differ between the 2 groups, with the exception that postoperative low‐density lipoprotein levels decreased significantly in the composite IVFE group (93.2 ± 24.3 vs. 110.5 ± 26.4 mg/dL, P = .038)

Isocalorific, isonitrogenous and vitamins and minerals provided.

IVFE dosed at 1-2 g/kg which is a big range.
Small patient population

(Wu et al., 2014)

Clinical Effectiveness: No statistical difference in LOS  (FO 17.45 ± 4.80 d, SO 19.62 ± 5.59 d, P = .19),
mortality and occurrence of infectious complications.

Laboratory Parameters: Inflammation parameters (IL-6, IL-10, CRP, TNF-α, and TGF-β1) were not different between groups.

The increment of triglyceride on day 6 from baseline was significantly lower in SMOFlipid group than in Lipovenoes MCT/LCT group.

Isocalorific, isonitrogenous and vitamins and minerals provided.


Power calculation provided.


Computer derived block randomisation system


Used both ITT analysis and per protocol population analysis

Small patient group


No information on blinding/allocation concealment

Fish Oil Admixtures

(Heller et al., 2004)

Clinical Effectiveness: No difference in ICU or hospital LOS and complication rates. However subgroup analysis: exclusive analysis of patients at risk for sepsis after gastrectomies and Whipple procedures (n = 19) revealed a shorter ICU stay after FO ( p < 0.01).

Patients at risk of sepsis (IL-6/IL-10 ratio >8), a tendency for a shorter ICU stay was observed (p < 0.065) after FO supplementation.
 

Laboratory Parameters: FO significantly reduced liver and pancreatic function tests: AST [0.8 ± 0.1 vs. 0.5 ± 0.1 mmol/), ALT [0.9 ± 0.1 vs. 0.6 ± 0.1 mmol/], bilirubin (16.1 ± 5.3 vs. 6.9 ± 0.6 mmol/l), LDH (7.7 ± 0.4 vs. 6.7 ± 0.4 mmol/L) and lipase (0.6 ± 0.1 vs. 0.4 ± 0.1 mol/L).


Absence of weight loss with FO (SO 1.1 +- 2.2kg).

Patients randomised using computerised system.

Participants and investigators adequately blinded

Power calculation completed
Isocalorific, isonitrogenous and vitamins and minerals provided.

Meta-analysis completed by other authors report they could not get an original data set.

Outcomes underpowered

Small patient population

(Liang et al., 2008)

Clinical effectiveness was lower but not significantly between groups (LOS, infection, mortality).

Laboratory Parameters: Serum IL-6 levels were significantly lower in the FO group than in the reference group (-44.43 ± 30.53 vs -8.39 ± 69.08, P = 0.039).
 

Ratios of CD4+/CD8+ were significantly increased in the FO group (0.92 ± 0.62 vs 0.25 ± 1.22, P = 0.035).
 

TNF-α similar between groups

Isocalorific, isonitrogenous and vitamins and minerals provided.


Computerised randomisation system


Patients and investigators blinded
 

All patients accounted for at the end of the study


Homogenous population (Colorectal cancer)

Small patient population

(Badía-Tahull et al., 2010)

Clinical effectiveness: Rates of infection lower in FO group (FO 3 [23.1%] vs, SO/OO 11 [78.6%] , P = .007)
 

Other finding was similar between groups: LOS (FO 15 d, SO/OO 16 d, p = NS), sepsis (FO 1 [7.7%], SO/OO 5 [35.7%], P = NS), mortality (FO 1 [7.7%] SO/OO 2 [14.3%] P = NS).

Laboratory Parameters: CRP, prealbumin, WBC, and other safety parameters were similar for both groups

Power calculation completed and study was sufficiently powered.


Computerised randomisation system


Investigators and participants blinded


Isocalorific, isonitrogenous and vitamins and minerals provided.

Small patient population


Difficult to compare with other studies as it is an olive oil-based control

(Jiang et al., 2010)

Clinical Effectiveness:

Rates of infection lower in FO group but not statistically different (FO 4 participants, SO 12  participants, P = .066),
Rates of SIRS significantly decreased from 13 of 103 to 4 of 100 (P = .039) in the FO group
LOS significantly lower in FO group (FO 15 ± 5 d, SO= 17 ± 8 d, P = .041).

Laboratory Parameters:
Inflammatory markers similar between groups: IL-6
(median change from day 0 to day 8: FO−20.05 pg/mL, SO=−16.7 pg/mL, p = .184),

TNF-α (median change from day 0 to day 8: FO−0.19 pg/mL, SO 0.00 pg/L, p = .107)

CD4/CD8 was lower (P = 0·021).

Total postoperative medical costs were comparable but not significant  in the two groups

Isocalorific, isonitrogenous and vitamins and minerals provided.


Sample size calculated and study was sufficiently powered


Investigators and participants blinded

Insufficient allocation concealment


Did not use ITT analysis

(Makay et al., 2011)

Clinical effectiveness: There were no statistically significant differences between the groups complications, or length of hospital stay or mortality.

Laboratory Parameters: No lower serum lactate levels nor lower rates of complications between groups.
There were no statistically significant differences between the groups in other biochemical parameters.

Computerised randomisation


Investigators blinded


Both regimens were isonitrogenous and isocaloric.


Appropriate statistical tests used to assess main outcomes


Power calculation completed, and study was sufficiently powered.

No details whether vitamins and minerals were added to the PN.


Endpoint for mortality outcome not specified


Small patient population

(Zhu et al., 2012)

Clinical Effectiveness:

Infectious complications were similar between groups (FO 4 [14%], SO 8 [29%], P = NS)
Duration of SIRS was shorter in FO group (FO 12 ± 4 d, SO 15 ± 6 d, P < .05)
LOS was shortened  (FO 12 ± 4 d, SO 15 ± 6 d, P <.05).

Laboratory Parameters:
Inflammatory markers were lower in FO group: IL-6 (FO 18.2 ± 7.6 pg/mL, SO 23.7 ± 8.2 pg/mL, P < .05), TNF-α (FO 5.7 ± 2.8 pg/mL, SO 7.8 ± 3.2 pg/mL, P < .05); CD4+/CD8+ was lower in FO group (FO 1.3 ± 0.8, SO 0.9 ± 1.4, P < .05)

Computerised randomisation system.

Blinded participants.


Isocalorific, isonitrogenous and vitamins and minerals provided.

Investigator providing PN not blinded.


Small patient population

(Zhu et al., 2013)

Clinical Effectiveness:

The ratio of infectious complications in the PUFA group was significantly decreased (57.9% vs 36.8%).
The postoperative hospital stay was decreased 15.3 ± 4.3 vs. 13.5 ± 3.8a (P < .05)

No hospital mortality

Laboratory Parameters:

Significant difference was seen in the extent of decrease in ALT, AST, and LDH in the PUFA group (P < .05).
 

Isocalorific, isonitrogenous and vitamins and minerals provided.


Computerised randomisation system

No power/sample size calculation


Unclear whether patients/investigators were blinded.


Confounding factor: patients provided EN


No data was provided for the mortality outcome

Wei et al 2014

Clinical Effectiveness:
Combined incidences of complications in the control group was significantly higher than that of the intervention group (1/26 vs 6/20). However each complication individually did not show statistical differences.

Laboratory Parameters:

No statistical differences in immunologic indicators (CD3, CD4, CD8, CD4/CD8)
The differences in WBC (7.42 ± 2.79 and 5.95 ± 1.46), IL-1β (302.32 ± 37.61 vs 332.61 ± 35.34), IL-6 (14.35 ± 45.95 vs 48.25 ± 67.49) and TNF-α (12.05 ± 60.31 vs 53.56 ± 75.23) between the 2 groups post-surgery were statistically significant (P < 0.05).

Isocalorific, isonitrogenous and vitamins and minerals provided.


Clear outcomes and results matching outcomes

Six patients were excluded from the control group because of incomplete data (did not use Intention-to-treat analysis)


No information on blinding or randomisation


Small patient population and no power calculation.

Meta-analysis

Bae et al 2018

FO-containing vs. non-FO-containing ILEs:
Clinical Effectiveness
Infectious complications was significantly different between the intervention and control groups (odds ratio: 0.36; 95% confidence interval: 0.18, 0.74, p<0.05)
 

Hospital LOS significantly shorter in intervention group (weighted mean difference: −2.29, 95% confidence interval: −3.64, −0.93; p<0.05)

Laboratory Parameters: Increased the level of CD4+ and CD4+/CD8+ ratio.

Two reviewers independently performed selection and analysis of studies


Used Jadad scale and graded for quality of analysis


Used random-effects model for meta-analysis

English language only studies.


Included RCT were single-centre trials with small sample sizes


Some data was transformed from SEMs into SDs by using a formula

ALT: Alanine transaminase; AST: Aspartate transaminase; CD: cluster of differentiation; FO: Fish oil; IL: Interleukin; LDH: lactate dehydrogenase; LOS: length of hospital stay; SIRS: systemic inflammatory response; SO: soybean oil; TGF: transforming growth factor; TNF: tumour necrosis factor

References

         ABBASOGLU, O., HARDY, G., MANZANARES, W., PONTES-ARRUDA, A., 2019. Fish Oil–Containing Lipid Emulsions in Adult Parenteral Nutrition: A Review of the Evidence. Journal of Parenteral and Enteral Nutrition. vol. 43(4), pp. 458–470.

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