Nutritional Therapy of ARDS with Borage Seed Oil Supplements

Summary and Abstract Article by Michael J. Murray, M.D., Ph.D.
reprinted with permission - November 1999

Mayo Clinic and Foundation
200 First Street, S.W.
Rochester, MN 55905

KEY PERSONNEL

Our primary focus is to demonstrate that certain dietary oils, fed to patients with acute lung injury (ALI), will significantly improve outcome by attenuating the effects of cytokines on cardiopulmonary and immune function.  Acute respiratory distress syndrome (ARDS), the worst form of ALI, is a common complication of a number of disease processes (several hundred thousand cases annually in the U.S.) and is associated with a high mortality rate (50-60%).  A number of therapeutic modalities (artificial lungs, extracorporeal circulatory techniques, nitric oxide, ventilator-management strategies) have been tried without success.  We have had experience with all of these modalities, but have been most impressed by the benefits we have seen with using a specialized enteral formula that contains increased amounts of fat, comprised primarily of polyunsaturated long-chain w-3 and w-6 fatty acids (FA), and antioxidants.  In a prospective, randomized, controlled trial in which 146 patients were studied, there was a 36% reduction in mortality in the group receiving this experimental diet (p < 0.08).  We have evidence from animal work that the benefits of this diet are not from the high fat content nor the antioxidants, but from the oils (borage seed and fish) included in the diet.  Our objective is to demonstrate that patients with ARDS, independent of whether they are fed parenterally or enterally, have decreased mortality if their nutritional needs are supplemented enterally with a combination of borage seed and fish oils.  Our specific aims are to demonstrate that these dietary supplements attenuate the physiologic sequelae of ARDS, leading to an improvement in outcome:  decreased pulmonary alveolar macrophage (PAM) count, decreased hypoxia, increased ventilator-free days, and decreased mortality.  A secondary aim is to determine the effects of the experimental diet on FA composition (increased dihomogammalinolenic acid [DGLA]) of plasma and of phospholipids in platelets and PAMs.  The third aim is to demonstrate that these diets modulate eicosanoid profiles measured in patients’ plasma, urine, and bronchoalveolar lavage fluid.  The goal is to demonstrate that increased levels of DGLA lead to increased levels of monoenoic eicosanoids—the biochemical basis for why these diets likely improve outcome.  We hypothesize that increased DGLA levels and altered eicosanoid profiles correlate with PAM function and with improvements in oxygenation, and increase survival.

Nutritional Therapy of ARDS with Borage Seed Oil Supplements

Michael J. Murray, M.D., Ph.D.

Introduction

             Feeding borage seed oil, which contains an increased amount of gammalinolenic acid (GLA), an 18-carbon -6 polyunsaturated fatty acid (PUFA) (C18:36), and fish oil, which contains eicosapentaenoic acid (EPA), a 20-carbon -3 PUFA (C20:53), to patients with acute respiratory distress syndrome (ARDS) may modify the type of 20 carbon-chain PUFA stored in membrane phospholipids (PL), precursors to a group of cytokines (eicosanoids) associated with ARDS and its outcome.  The GLA is elongated to dihomogammalinolenic acid ([DGLA] C20:36), which is not desaturated because of the inhibitory effects of EPA on -5 desaturase.  DGLA, arachidonic acid ([AA] C20:46), and EPA are precursors of eicosanoids (prostaglandins and thromboxanes [Tx] of the mono-, di-, and trienoic series, respectively), cytokines that have important vascular and immune functions.  Increasing the amount of DGLA in cell membranes, in turn, may alter the type and amount of eicosanoids released by these “cells” (e.g., increased prostaglandin E₁ [PGE₁]), resulting in pulmonary vasodilation with a decrease in the pulmonary shunt and an improvement in oxygenation in patients with ARDS.  In conjunction with an alteration in pulmonary alveolar macrophage (PAM) number and function, these physiologic benefits may lead to an improvement in the high mortality rate associated with ARDS.

             We have previously demonstrated that animals and patients fed a diet enriched with borage seed oil and fish oil have an improvement in the pathophysiology associated with ARDS.  In these experiments, the ingestion of GLA, contained in the borage seed oil, led to increased amounts of DGLA, the precursor of AA.  We speculate that DGLA was not dehydrogenated to AA, as would normally occur, because of an inhibitory effect of EPA (contained in the fish oil) on -5 desaturase.  The DGLA, though it was not desaturated to AA, may have served as a precursor to PGE₁, a known pulmonary vasodilator. 

 In the multicenter trial in which we participated, patients with ARDS were fed a diet supplemented with these unique oils and showed dramatic improvements in oxygenation, bronchoalveolar lavage (BAL) fluid leukocyte count, and ventilator-free days (Appendix A).  The enteral product had 55% of calories from fat—borage seed oil and fish oil, along with antioxidants. 

Methods

             The mortality rate from ARDS continues to be approximately 60%.  We have observed in our clinical practice that of the approximately 150 patients a year who meet criteria for ARDS, 20% (about 30 patients/year) are managed with nitric oxide (NO) and increasingly with ventilation in the prone position.  In the thoracic and vascular surgical intensive care unit (ICU), when patients with ARDS have been so critically ill as to warrant NO therapy and ventilation in the prone position, patients had their diets supplemented with borage seed oil and fish oil.

 Results

             We have been impressed in that of the 7 patients so treated, 5 survived for a mortality rate of 28% (Table 1) compared to patients similarly treated but who did not receive the nutritional supplement (Table 2).  Even that number is misleading because one of the patients who survived the initial experience with ARDS and was weaned from the ventilator developed septic shock and died on day 28.  Likewise, a second patient died not from the sequelae per se of ARDS, but from an unplanned endotracheal tube extubation. 

 Discussion

             These results (Table 1) confirm the PRCT in which we participated.  Unfortunately, as commented previously, there were several deficiencies of that study.  Many patients with lung carcinoma were excluded, and steroids were not administered during the study.  Given the poor outcome of patients with lung carcinoma undergoing surgical procedures, we thought it unreasonable to exclude these patients.  Furthermore, corticosteroids are currently used in clinical practice in the U.S. during the fibroproliferative phase of ARDS.  We thought it inappropriate to design a study that did not reflect current clinical practice.  Additional problems arose because of the differences between centers when patients were enrolled; at some centers, patients were enrolled within 24 hours of developing ARDS, and at other centers, one to two weeks elapsed before patients were enrolled.  Furthermore, there were differences even within our own center:  comparing the results of the Ross-sponsored study to our NO study, despite the similarity of many of the entry criteria, patients who were enrolled in the NO study, based on APACHE III scoring systems were much sicker than those patients who were enrolled in the Ross laboratory study (PaO₂/FIO₂ ratios in the NO study were < 100, and in the Ross-sponsored study, PaO₂/FIO₂ ratios were on average approximately 175).  Furthermore, in the Ross-sponsored study, there were no differences found in mortality between groups.  Also, there was no attempt to examine the mechanism of how these diets work.  For example, though neutrophil counts decreased in the BAL of patients receiving Oxepa®, there was no assessment of neutrophil function performed.  What does it mean when neutrophil counts decrease in BAL?  Presumably, it is a manifestation of a decreased inflammatory response, but without knowing the effects of the diets on leukocyte function, this is speculation.  In our opinion, further studies were and are warranted.

Table 1.  Patients with ARDS who Received Borage Seed Oil and Fish Oil

Table 2.  Patients with ARDS who Received Nitric Oxide*

*This table includes the 7 patients who received borage seed oil and fish oil supplemented diets.  Summaries:  Gender:  64% male, 36% female.  Race:  4% Middle Eastern, 7% Hispanic, 89% White.  **Excludes patients who received borage seed and fish oils. † not available