Tag Archives: PNAC

Double-Blind Randomized SMOFLipid Study

Posted on by

A recent double-blind randomized study (A Repa et al. J Pediatr 2018; 194: 87-93) compared a mixed lipid emulsion (SMOFlipid) to a soybean-oil lipid in 223 extremely low birth weight infants. Median time on parenteral nutrition was ~23 days.

Key findings:

  • The primary outcome of parenteral nutrition associated cholestasis (PNAC) was NOT significantly different in the two groups: 10.1% for SMOF and 15.9% for control group (P=.20).
  • No other outcome measures were affected, including ROP, BPD and growth.

The authors note that even the control group had less cholestasis than previous cohorts and indicated that the use of probiotics and possibly more aggressive enteral feeds were at work.

My take (borrowed in part from authors): These results “cannot be generalized to infants with substantially longer time on PN.” However, this study shows that SMOFlipid alone will not prevent cholestasis, which is well-known to be multifactorial.

Sandy Springs

Enteral Fish Oil and Intestinal Adaptation in Premature Infants

Posted on by

A provocative article (J Pediatr 2014; 165: 274-9) examines supplementation of enteral fat/fish oil in premature infants as a mechanism to reduce parenteral nutrition associated cholestasis (PNAC).  While the study’s limitations will prevent any dramatic conclusions, the article and associated editorial (pgs 226-27) do make several useful points.

Before discussing the limitations, the design of the study:

Infants were block randomized (block size of 8) into either a control group or treatment group.  While both groups received conventional PN, the treatment group received supplemental enteral fat as microlipid and fish oil after tolerating enteral feeds at 20 mL/kg/d.  Microlipid was started at 1 g/kg/d and advanced up to 2.5 g/kg/d; coinciding with microlipid increases, parenteral intralipid was decreased.  Fish oil was started at 0.2 g every 12 hours and was advanced to a maximum of 0.5 g every 6 hours.  The two fish oil products were Major Fish Oil 500 (Major Pharmaceuticals) and Rugby Sea Omega 50 (Rugby Laboratories).

The limitations include the following:

  • Small cohort of 18 patients in each arm
  • Due to the smell of fish oil, the study could not truly be blinded which introduces potential bias
  • Only 7 of the 36 patients could be considered to have short bowel syndrome as most of the infants had small amounts of intestine resected
  • Advancement of enteral feedings were halted if stoma output reached 20 mL/kg/d.  The editorialists note that 40 mL/kg/d would be more typical.  Thus, in both the treatment group and the control group, there was significant opportunity to reduce PN by more aggressive enteral nutrition advancement.

With these limitations in mind, there authors were able to show that supplemental fat (with fish oil) was associated with less parenteral intravenous lipid, and reduced conjugated bilirubin prior to anastomosis.  However, there was no significant difference in PN duration.  Growth parameters were similar prior to anastomosis, but improved in the treatment group after anastomosis.

In the editorial, it is noted that “enteral feeding with a high-fat diet has been demonstrated to enhance structural features of resection-associated adaptation, the underlying mechanisms for this phenomenon are still presently unknown.”

Take-home message: Enteral fat/fish oil supplementation helped decrease parenteral intravenous lipids in this study.  More broadly, advancing enteral nutrition by accepting higher ostomy outputs is likely the best strategy to avoid PNAC and other PN-associated complications.

Related blog posts:

 

Biliary Atresia More Common in Preterm Infants

Posted on by

During my fellowship, one of the faculty presented an abstract indicating that 4 out of 40 preterm infants with cholestasis had significant underlying liver disease in addition to parenteral nutrition associated cholestasis (PNAC).  One of these patients had biliary atresia.  The obvious point was not to assume that the cholestasis was due to the usual suspects found with premature infants.

A recent study indicates that biliary atresia (BA) in Taiwan is more common in preterm infants than in term infants (J Pediatr 2013; 163: 100-3).  The authors identified 197 cases (166 term infants) of BA between 2004-2010. This retrospective study used a nationwide screening for BA (the national stool card registry center database) along with reports from surgeons of the Taiwan Biliary Atresia Study Group.

Results:

  • Annual incidence of BA per 10,000 live births was 1.43 and 2.37 for term and preterm infants respectively.
  • Kasai operation before 60 days occurred in 68.7% of term and 44.4% of preterm infants.  Mean age of Kasai was 52.9 days for term infants and 71.8 for preterm infants.
  • Major congenital anomalies along with BA were more common among preterm (18.5%) than term (4.1%).
  • Mean onset of clay-colored stools among preterm infants was 33.6 days compared with 29.6 for term infants.
  • Stool cards had good sensitivity in detecting BA in both preterm and term infants: 96.3% and 92.8% respectively.
  • Jaundice-free at 3 months following Kasai was 62% of term infants and 37% of preterm infants.
  • 18-month survival with native liver was 72.7% in term infants and 50% in preterm infants.

While the authors point out several studies that have shown prematurity is an independent risk factor associated with BA, nevertheless this idea is counter to conventional wisdom that BA patients are typically well-appearing term infants at the time of diagnosis.  The authors also note that despite delayed diagnosis in preterm infants, this was not correlated with an impact on jaundice-free status 3 months following surgery.  This finding, in particular, should be cautiously interpreted as there were only 27 infants in the preterm group.

Related blog posts:

Foil PNALD with FOLE?

Posted on by

As noted on previous blog entries (see below), there has been significant enthusiasm for fish oil based lipid emulsion (FOLE) despite a lack of data showing superiority compared with standard soy-based lipid emulsions at similar dosing.  More data for FOLE helping infants with cholestasis are available (J Pediatr 2013; 162: 793-8).

Design: Single center, prospective observational study of 57 infants with parenteral nutrition-associated liver disease (PNALD) which  took place between 2007-2011.  All infants were between 2 weeks and 6 months of age at enrollment.  At enrollment, FOLE (Omegaven) at a dose of 1 g/kg/d was infused over 24 hrs.  FOLE which is not FDA-approved is available on a compassionate use protocol.

Infant characteristics: Median gestational age: 28 weeks. 47 of 57 were long-term survivors.  The median time at initiation of FOLE was 39.3 weeks post-menstrual age.

Results:

  • Median conjugated bilirubin at initiation of FOLE therapy was 7.5 mg/dL.
  • Resolution of cholestasis occurred at a median of 35 days (range 7-129) after starting FOLE.  Longer times for resolution were noted in those with higher initial bilirubin.
  • Time to resolution was inversely proportional to gestational age at birth (p=0.02) and directly to time to receive 100% calories enterally (p=0.03)

The authors note that none of the infants who died had liver failure; most deaths were due to multi-organ failure and sepsis.

In the discussion, the authors state “the most significant finding from this study is the effectiveness of FOLE in resolving cholestasis irrespective of the initial serum bilirubin values.”  I take issue with this statement primarily because the design of the study does not allow such attribution.  Without a randomized trial comparing FOLE to standard intralipids, this statement overstates any conclusion that can be drawn from this study.  Given the fact that resolution was correlated with advancement of enteral feedings, it is plausible that a similar result would occur with standard intralipids.

The authors make a number of other speculations about the potential superiority of FOLE over standard soy-based lipid emulsions, but concede that “our study was not adequately equipped to address” the association of reduced intralipid with improvement in cholestasis.  Despite this concession, the authors boldly proclaim in the concluding paragraph: “while awaiting the more general availability of FOLE, infants at high risk should be identified early and referred to centers that provide the option of FOLE…in which families are fully informed of both the potential benefits and limited current data.”

A recent media report also promotes the effectiveness of FOLE: http://nbcnews.to/11vbL2E 

Related blog posts:

TPN cycling

Posted on by

A randomized prospective study of early parenteral nutrition cycling was not helpful in reducing parenteral nutrition associated cholestasis (PNAC): J Pediatr 2012; 161: 229-33.

This study enrolled preterm infants <1250 g in the first five postnatal days to either cycled (n=34) or continuous parenteral nutrition (n=36).  Cholestasis was defined as direct bilirubin >2 mg/dL. The study indicated that intralipid 20% was administered in all patients over 18 hours; the exact amount is not clear, though in the cycled group, patients received 3 g/kg/day on postnatal day 3.9 ± 2.6.  All patients received dextrose over 24 hours; only the amino acid (TrophAmine) infusion varied: 20 hours compared with 24 hours.

  • PNAC in each group was nearly identical, 32% vs 31% as were bilirubin and transaminase values.
  • While the study was randomized, the cycled group did have more frequent late-onset sepsis 22 (65%) compared with 14 (39%) which reached statistical significance.
  • In addition, a trend towards more frequent non-surgical NEC in cyclical group was noted as well: 6 (18%) compared with 3 (8%).
  • PNAC was associated with days until full enteral nutrition/duration of parenteral nutrition and bronchopulmonary dysplasia.

The higher incidence of late-onset sepsis could have occurred randomly and affected the results; alternatively, the higher rate could reflect an increased risk of sepsis due to doubling the frequency of central line access.

This study was  only powered to detect a 25% difference between the groups; the authors estimate that a study with 290 patients would be needed in each group to identify a reduction of 10% in the incidence of PNAC.  As such, this study leaves open the possibility that cycled parenteral nutrition may be helpful in a smaller percentage, particularly if efforts are made to eliminate central line infections.  More promising efforts to minimized PNAC are noted in previous blog entries:

PNAC, PNALD, and IFAC

Optimizing lipids to minimize cholestasis

More on PNAC

Four advances for intestinal failure

Optimizing lipids to minimize cholestasis

Posted on by

As discussed in previous blog entries (PNAC, PNALD, and IFAC, More on PNAC, Four advances for intestinal failure), the right amount of lipid and the type of lipid both can contribute to parenteral nutrition associated cholestasis (PNAC).  More information about SMOFlipid which is a complex mixed-type lipid emulsion derived from soybean, coconut, olive, and fish oils is available (JPGN 2012; 54: 797-802).  SMOF contains 30% soybean oil, 30% MCT, 25% monounsaturated fatty acids, and 15% fish oil.

This study had a retrospective cohort comparison design & examined serum bilirubin over 6 months in children with PN-associated cholestasis (PNAC).  In one cohort, 8 patients received the SMOFlipid and the other 9 patients continued on Intralipid (IL).

The SMOF cohort was receiving 81% of caloric needs as PN at entry whereas the IL cohort was receiving 92%.  Six months later, SMOF cohort was receiving 68% of caloric needs as PN compared with 50% for IL cohort.  Nevertheless, the SMOF group had improved cholestasis with a median bilirubin drop of 99 μmol/L compared with an increase of 79 μmol/L among IL patients.  Overall, 5 of 8 children in the SMOF group had resolution of jaundice compared with 2 of 9 in the IL group.

While the authors state that SMOF may have important properties to prevent PNALD, the study has limited ability to draw any firm conclusions.

The authors state that no other treatment innovations were introduced; however, the authors overlook the large discrepancy in lipid volume administered.  The IL group was receiving much more lipid both before and during study.  Prior to entry of study, the IL group was receiving about 3.1 g/kg/day whereas the SMOF group about 2 g/kg/day; the SMOF group continued initially at the same lipid dosing with the new formulation.  This is one of the problems with historical controls.  While the authors might believe that the cholestasis improved because of the lipid content, the key factor may in fact be the amount of lipid given.

In the same issue (JPGN 2012; 54: 803-11), specific plant sterols (PS) were elevated among neonates with intestinal failure-associated liver disease (IFALD).  This study looked at 28 neonates and 11 children from Finland who required PN for more than 28 days.  Specific markedly-elevated PS included stigmasterol, sitosterol, avenasterol and campesterol (Table 4 in study).  Some of these PS in the neonates were more than 20-fold higher than healthy controls.

More on PNAC

Posted on by

In a previous blog entry (PNAC, PNALD, and IFAC), reduction in intralipids was shown to improve parenteral nutrition associated cholestasis (PNAC).  This change in the use of parenteral nutrition (PN) and others are emphasized in a review article by the American Pediatric Surgical Association (J Ped Surg 2012; 47: 225-40).

This review tries to provide evidence-based guidelines for PNAC with ratings of the evidence for each of their recommendations.

A summary of their findings is given in Figure 1 of the article.  Key points:

  • PN duration is a significant predictor for cholestasis
  • NEC & sepsis both play a role in the development of PNAC
  • Insufficient data to determine if antibiotics used to decrease bacterial translocation/hepatocyte damage may be beneficial
  • Fat emulsion restriction may reduce PNAC without detriment to growth
  • Fish-oil based lipid emulsions are safe and effective for PNAC.  “Despite the promise of Omegaven…the literature is insufficient to provide a recommendation higher than grade C.”  (Grade C= “possibly effective, ineffective, or harmful;” requires at least 2 convincing class III studies [class III studies generally are non-randomized non-blinded studies]).  Information to obtain Omegaven:

http://www.oley.org/documents/How_Physicians_Can_Obtain_Omegaven.pdf
http://www.oley.org/lifeline/PN_Liver_Disease.html

  • Strong evidence that higher initial protein load does not increase the risk of PNAC
  • Strong evidence that trophic feeds are beneficial to reduce PNAC
  • Weak/conflicting evidence that there is any benefit of Aminosyn over Trophamine
  • Weak evidence to support the routine removal of copper or manganese from PN as a prophylactic strategy to prevent PNAC
  • Weak evidence to support prophylactic cycling of PN to reduce PNAC.  There are also concerns about the development of hypoglycemia in preterm infants off of PN
  • Use of CCK is not recommended
  • Oral bile acids may result in improvement
  • Erythromycin may promote motility and facilitate enteral feeds, thereby reducing PNAC

PNAC, PNALD, and IFAC

Posted on by

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