Tag Archives: fish oil

New lipid emulsions — lacking data to support usage

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According to a systematic review of the literature regarding ω-3 (n-3FA) fatty acid lipid emulsions, there is a “lack of sufficient high-quality data to support the use of parenteral n-3FA lipid emulsions in children” (JPEN 2013; 37: 44-55). Thanks to Kipp Ellsworth for this reference.

The authors of this study researched 4 databases up to March 2011 and extracted relevant studies.  Five randomized controlled trials and 3 high-quality prospective cohort studies were included.  The strength of evidence was “consistently low or very low across all lipid emulsion comparisons and outcomes.”

Specific criticisms:

  • Few studies examined important outcomes like length of hospital stay or intensive care stay.
  • There was lack of data on growth, cognitive development or potential long-term effects/harms.
  • All of the studies in children varied considerably with regard to the dosing regimens, duration of administration, and duration of followup.
  • The studies were small with sample sizes ranging from 28-91 patients.
  • The 5 RCTs had unclear risk of bias due to inadequate blinding of participants and study personnel.
  • All of the RCTs were funded by the manufacturer.
  • While some biochemical outcomes improved, no difference in mortality has been identified.  A biochemical response is a poor measure of effectiveness.  In fact, several studies have shown deterioration in liver histology and fibrosis despite improved biochemical measures in infants on Omegaven.
  • For Omegaven (fish oil) treatment, all studies used a historical control group.  In these studies, typically the Omegaven dose was half the dose of Intralipid used in the control group.

This article (in its Table 1) identifies the constituents in the commercial available lipid products which include Intralipid, Clinoleic, Liposyn II, Omegaven, SMOFLipid, and Lipoplus.  Intralipid which is widely used is devoid of substantial arachidonic acid (ARA) and docosahexaenoic adic (DHA).  This is particularly important in premature infants as noted in recent blogs:

Omegaven, in particular, and SMOFLipid, to a lesser degree, have much more AA and DHA.  As such, both of these emulsions have the potential improve vision and cognitive outcome in premature infants.

Related blog posts:

PNAC, PNALD, and IFAC

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Intravenous lipids may cause parenteral nutrition associated cholestasis (PNAC), parenteral nutrition associated liver disease (PNALD), or intestinal failure associated cholestasis (IFAC) (J Pediatr 2012; 160: 421-7 & editorial 361-2).  PNAC refers to cholestasis due to parenteral nutrition and PNALD refers to PNAC that has progressed to liver dysfunction or permanent liver injury.

In a previous blog (Four advances for intestinal failure), one of the advances for intestinal failure that was noted was the reduction of lipid infusions with parenteral nutrition which reduces IFAC.  This study adds additional information to this area.  In this prospective study, 31 patients were enrolled in a reduced IV fat emulsion group and compared with a matched historical control group.  The reduced fat group received 1gm/kg of a standard soybean-based lipid emulsion (liposyn 20%) twice weekly.  Patients were eligible if they received PN for >2 weeks and had a direct bilirubin >2.5 mg/dL.

Outcomes:

  • Total bilirubins dropped 0.73 mg/dL each week in the reduced fat group; in the control group, the bilirubin increased 0.29 mg/dL each week
  • Growth was similar in both groups
  • Essential fatty acid deficiency (biochemical not clinical features) was identified in 13 of 31 infants among the restricted IV fat emulsion group.

Essential fatty acid deficiency was defined as having a triene: tetraene ratio >0.05 (mild), >0.2 (moderate) or >0.4 (severe).

Limitations:

  • Historical control group & small study population
  • Fat-restricted group received enteral antibiotics which may have helped reduce cholestasis
  • Majority of patients with relatively short duration of TPN: 18 of 31 for less than one month

The reasons why lipids may contribute to PNAC/PNALD/IFAC include the presence of phytosterols.  This in turn may damage hepatocytes via the farnesoid X receptor.  One other aspect of the study was that the fat-restricted cohort had a higher mortality.  This was thought to be related to the cohort being sicker rather than to any nutritional effect.  Specific causes of death included respiratory failure in a patient with an abdominal wall defect, chylothorax/sepsis in a patient with a congenital diaphragmatic hernia, and cardiopulmonary failure in a patient with pulmonary hypoplasia.

The article does throw into question whether the use of a fish oil lipid preparation is needed to improve cholestasis.  In studies supporting fish oil preparations, a confounder was that the total lipid administered was reduced to 1 gm/kg/day in comparison to soybean lipids which were administered at 2-3 gm/kg/day.  This study suggests that reducing the total amount of lipid infusion is the more important factor.

The accompanying editorial makes a couple of useful points:

  • Increasing enteral feeds (>50%) is as effective as using less intravenous lipids
  • Use of standard lipids at 1gm/kg/day decreased IFAC from 15% to 4% in their intestinal failure patient population
  • Drastic reductions in lipids lead to essential fatty acid deficiency and should be avoided.
  • Use of Omegaven has not been shown to prevent liver fibrosis even with resolution of cholestasis; similarly, these studies do not inform fully on the long-term liver effects of reducing standard lipids
  • Neurologic followup will be important
  • Explains “Morton’s fork.”  John Morton was a 16th century Archbishop who wanted to increase taxes on people who were living lavishly.  In addition, he wanted to increase taxes on those living modestly (must be hiding wealth).

Additional references:

  • -NEJM 2010; 362: 181.  Letter to editor describes use of fish oil in (n=125) Boston pediatric patients.
  • -JPGN 2009; 48: 209. n=12. SBS.  9/12 improved with Omegaven. 3 had transplant (L-ITx). No controls.
  • -Pediatrics 2008; 121: e678-86. n=18.  Use of fish oil improved cholestasis compared to historical controls.
  • -Pediatrics 2006; 118: e197-e201.  Reversal of TPN-AC c IV omega-3 fatty acids (fish oil-derived) instead of intralipids

Four advances for intestinal failure

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Several advances in the management of intestinal failure have the potential to improve the outlook for our intestinal failure (IF) (aka Short Bowel Syndrome) patients (JPEN 2012; 36: 36S-42S).

Although IF patients already have improving survival with rates of 80-95% over followup ranging from 1-5 years, many still do not survive, primarily due to bacterial infections or chronic liver disease.  Ongoing research has made some promising steps in the management of these pediatric patients.  This article focuses on four of these steps.

1. Citrulline monitoring

  • Major source of citrulline is enterocyte production.  Citrulline is an amino acid not encoded in human genetic code; it is present in some proteins as a product of posttranslational modification.
  • Watermelon is one of few dietary sources.
  • Useful biomarker for bowel length/absorption –independent of inflammatory markers
  • Levels >15-20 μmol/L indicate good likelihood of achieving enteral autonomy
  • Levels <12μmol/L indicate a very low likelihood of achieving enteral autonomy

2. Teduglutide therapy

  • Analog of glucagon-like peptide 2 (GLP-2) but harder to degrade (longer half-life)
  • Preliminary studies in adults indicate improvement in absorption and villous histology after subcutaneous administration for three weeks.  Improvements reverse when drug is discontinued.
  • Since GLP-2 is produced by colon & increased in IF (if colon present), unclear whether exogenous administration will be as beneficial in patients with residual colon

3. Lipid minimization &/or fish oil lipids

  • Cholestasis increases in patients receiving more than 1 g/kg/day of intralipids (soy based).
  • Fish oil (Omegaven) has shown benefit in lowering cholestasis in numerous case reports.  This may be due the high content of anti-inflammatory ω-3 fatty acids.
  • Another preparation SMOFLipid is a mixed formulation and may be safer than pure fish oil; randomized controlled studies of both of these lipid formulations are underway.
  • Fish oil has not been shown to improve histology
  • Parenteral nutrition associated liver disease (PNALD) may improve with lowering lipids & may not need omegaven

4. Ethanol locks

  • May be beneficial in treating and preventing central line infections.  In both situations, in small studies, ethanol locks lowered incidence of recurrent infections.
  • Six studies involving 75 patients (66 pediatric patients) lowered infection rates from approximately 10 per 1000 catheter days to 2 per 1000 catheter days.
  • Ethanol concentrations were mostly 70% in these studies, though 25% has been used.
  • Dwell times ranged from 2-14 hours.
  • Randomized studies are in progress.
  • Fewer infections should reduce the likelihood of death from sepsis and death due to loss of venous access.

Additional references:

  • -NEJM 2010; 362: 181.  Letter to editor describes use of fish oil in (n=125) Boston pediatric patients.
  • -JPGN 2009; 48: 209. n=12. SBS.9/12 improved with omegaven. 3 had transplant (L-ITx). No controls.
  • -NEJM 2009; 361: 998. Intestinal Rx.  Review claims ~90% 1yr survival. 47% 5yr, 61% 3yr (expecting to go higher)
  • -JPGN 2009; 48: 334. Isolated liver w SBS feasible IF 50cm small bowel remaining or 30cm w ICV, 50% enteral nutrition >4 weeks with good growth, no dysmotility.
  • -Pediatrics 2008; 121: e678. n=18. use of fish oil improved cholestasis compared to historical controls.
  • -Gastroenterology 2008; 135: 61, 303. Survival of ITx (vs. HAL).  In many conditions, better off from survival standpoint without Tx. Tx if failure of TPN (severe liver dz/thrombosis of >/= 2 central veins, multiple bouts of sepsis/frequent dehydration), high risk of death, severe short bowel (<10cm in infants and <20cm in adults), pseudoobstruction, unwillingness to accept long-term tpn. 93% of TPN patients who did not have TPN-complications had 93% survival rate.  Thus, TPN is first line Rx as survival and quality of life often better.
  • -Pediatrics 2006; 118: e197-e201.  Reversal of TPN-AC c IV omega-3 fatty acids (fish oil-derived) instead of intralipids
  • -Liver Transplantation 2006; 12: 1062, 1040. Liver transplant alone reasonable to consider in some SBS patients who tolerate >50% enteral therapy and are less than 2 years old.
  • -Gastroenterology 2006; 130. Supp 1. Summary of NIH workshop on intestinal failure. TX Indications: Liver disease, thrombosis of major veins, recurrent catheter-related sepsis, frequent severe dehydration/electrolyte imbalance.
  • -JPGN 2005; 41: 47A (pg507). Poor prognosis: <40cm, needing >40kcal/kg PN, increased bili (>150 μmol/L)
  • -J Pediatr 2005; 146: 542. Serum citrulline > 19 μ/L associated with bowel adaptation/weaning off HAL.
  • -J Pediatr 2004; 145: 157-163. Survival of SBS with as little as 15
  • -Arch Pediatr Adolesc Med 2006; 160: 104953.  Use of ethanol lock (70%, 08-1.4mL for 12-24hrs, then withdraw). n=51.  High success rate in salvaging line
  • -J Pediatr 2001; 139: 27-33. Review of 30 pts. 3 of 30 pts with bowel length 40cm or less able to wean PN.
  • -Gastroenterology 2001; 120: 806-815. Glucagon-like peptide 2 improves nutrient absorption marginally.