Can enhanced recovery programmes be further improved by the addition of omega three fatty acids?
The term “enhanced recovery programme (ERP)” means applying defined protocols to augment the recovery of patients following surgery. Inflammation is body’s response to insults such as infection, injury and surgical procedures. Inflammatory mediators whose function is initially protective may cause undesirable consequences, if the response is unnecessarily prolonged. The principle effects of ERP result from the reduction of the profound stress which results following major surgical procedures.
A Pubmed literature search was undertaken using the keywords enhanced recovery, surgery and omega-3. The primary endpoint was whether the addition of omega-3 to ERP improved morbidity and mortality.
Nine randomised trials examining the effect of omega-3 enriched diets following surgery were analysed. Inclusion of omega-3 helps in maintaining a positive nitrogen balance, overcome immune dysfunction, lower the incidence of post-operative infections with the consequence of reduced morbidity and mortality.
The provision of early or continuous nutrition is one of the cornerstones of an ERP. A theoretically ideal regimen would provide an energy substrate and protein and contain a component which would limit inappropriate inflammation. The beneficial role of omega-3 results from a number of effects which limit the inflammatory response, principally by influencing the production of eicosanoids and modulating cytokines. They also enhance cell-mediated immunity and preserve immune function better than standard dietary formulations. Although ERPs have already produced significant progress, there is sufficient evidence to suggest that the provision of omega-3 fatty acids may result in further improvements.
KeywordsEnhanced recovery programmeOmega-3 fatty acidsSurgery
Enhanced recovery programmes for surgical patients
Fast track perioperative care also known as enhanced recovery (enhanced recovery programmes; ERP) means applying defined protocols that augment the recovery of patients following surgical procedures by reducing the resulting profound stress. Traditionally, perioperative management of patients following surgery involved fasting from midnight and keeping them nil by mouth until the clinical resolution of the ileus that was felt to be an inevitable consequence of any medium to large surgical procedure, particularly if the peritoneal cavity was opened. As a result of this “inevitable” ileus, it was believed that complications (aspiration of gastric contents and disruption of anastomoses) would occur if feeding was commenced too early [1–3]. The rationale behind this concept was the occurrence of complications due to aspiration of gastric contents in the early 1900 and the belief that the response was physiological and necessary to allow a sufficient rest period for recovery . This surgical dogma persisted essentially unchanged until the late 20th century when it was subsequently realised that the body develops a catabolic state following surgery due to the stress and increased metabolic demands associated with the physiological insult. This leads to protein-energy malnutrition which impairs immunological responses and wound healing and increases morbidity [5, 6].
Main components of ERP
Counselling of patient in pre-operative clinic
No bowel prep
Pre-operative carbohydrate loading
Use of short acting anaesthetic agents
Use of mid-thoracic epidural anaesthesia/analgesia
Avoidance of hypothermia
No nasogastric tubes
Avoid fluid overload
Prevention of nausea and vomiting
Use short incisions if possible
Prevention of nausea and vomiting
Use of non-opiate analgesics
Early removal of urinary catheters
Early enteral nutrition
Inflammation and omega-3 fatty acids
Inflammation is body’s response to insults such as infection, injury and surgical procedures. It is characterised by the five classical cardinal signs; redness (rubor), increased heat (calor), swelling (tumour), pain (dolour) and loss of function (functio laesa). It results from the increased movement of plasma and leucocytes (especially granulocytes) from the systemic circulation into the injured tissues. This is followed by a cascade of events involving complement, clotting cascades and the immune system. The primary aim of this response is to protect the host from the insulting agent but unfortunately (and not uncommonly) hyper or inappropriate inflammation can occur. This is the basis of a number of acute and chronic diseases such as asthma, rheumatoid arthritis, cardiovascular diseases, Alzheimer’s disease, cancer and inflammatory bowel disease [11, 12].
Hyper-inflammation can occur as part of body’s response to the surgical stress and attention has turned towards those products which could potentially address both the nutritional status and this inappropriate inflammation. These immunomodulatory dietary products rather than just being a source of energy provide nutritional agents which have specific well-defined effects and are particularly effective in producing modifications which help protect the immune system and modulate the production and effect of inflammatory mediators.
Nine trials have reported the use of diets enriched with omega-3, arginine and ribonucleic acid as part of post-operative nutrition and compared them to standard enteral diets. These trials have demonstrated a number of benefits including the prevention of weight loss, maintenance of a positive nitrogen balance and abrogation of immune dysfunction [13–21]. The treated group also had lower rates of infective complications which consequently reduced post-operative morbidity and mortality. The provision of omega-3 appeared to produce this effect by preventing early post-operative impairment of the host defence mechanisms, controlling the overwhelming inflammatory reaction and modulating the metabolic response by favoring the synthesis of constitutive proteins instead of acute-phase proteins. The overall result was reduction of the hospital stay due to the significantly reduced complication rates and a more rapid recovery from the surgical insult.
Gianotti et al.  divided their patients into two groups where one group received standard enteral nutrition post-operatively and the second group received a nutrition formulation supplemented with arginine, omega-3 and ribonucleic acid. Treatment was administered preoperatively for 7 days and continued for the same period following surgery. The most impressive results were seen in the perioperative nutrition group with a reduction of the post-operative morbidity and mortality. The reasons for the improved results in this group were probably the incorporation of omega-3 fatty acids into the inflammatory cells with a consequent reduced production of pro-inflammatory cytokines. Similar findings were noted in the study by Braga et al.  that discussed the effect of these supplements on “the immunometabolic host response and outcome” and suggested that these changes resulted from the modulation of cytokine production and enhanced cell-mediated immunity. These changes clearly have the potential to impact significantly on the cost of surgical procedures and the reduction in the need for health care resources (saved as a result of the reduced morbidity) are likely to far outweigh the additional costs incurred by the use of the nutritional supplements. While these studies demonstrate that the pre-operative phase of a surgical procedure is as important nutritionally as the post-operative phase the additional nutrition used in these studies is a combination of omega-3, arginine and nucleotides and their beneficial effects cannot be ascribed to a single component.
Mechanisms of action of omega-3
The beneficial effects of omega-3 fatty acids (the metabolic products of dietary omega-3 lipids) were highlighted when over an 8 year period, the epidemiological studies of Dyerberg et al.  in Greenland Eskimos clearly demonstrated their anti-thrombotic effect and the consequent protective role in heart disease. Omega-3 fish oils include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Humans cannot synthesise these to any significant extent and obtain them from cold water fish that themselves derive them from consumed plankton and algae (where they are synthesised). The active ingredients, DHA and EPA have been extensively studied in the clinical as well as the epidemiological setting. The cell membranes of all cells are composed of phospholipids and the polyunsaturated fatty acid components, omega-3 and omega-6 fatty acids (defined by the first carbon atom with a double bond counted from the omega [methyl] end) are metabolised to produce a bewildering array of products. These include virtually all the molecules included in the inflammatory cascade which result from a competitive metabolism of the omega-3 and omega-6 components by the cyclo-oxygenase (COX) and 5-lipoxygenase (LOX) pathways. The competitive nature of these metabolic pathways means that the relative proportions of the omega-3 and omega-6 fatty acids determine which products are produced. Principle amongst these are the eicosanoids (the term is derived from the Greek eicosanoids meaning 20 and referring to the number of carbon atoms) and although they can be derived from either the omega-3 or omega-6 fatty acids, those derived from the omega-6 series are strongly pro-inflammatory whereas those from the omega-3 series are much less so or even anti-inflammatory. The resulting eicosanoids comprise four groups; the prostaglandins, prostacyclins, leukotrienes and thromboxanes (named from the tissue in which they are first described). They are very powerful “local hormones” acting only at the site of production. As a consequence, any adjustment of the diet which affects the ratio of omega-3 and omega-6 fatty acids in the cell wall has the potential to significantly influence the type of eicosanoids which are produced and it is this effect which is able to modulate the cells of the immune system. The aim of omega-3 supplementation is thus to reduce the amount of substrate available for the synthesis of harmful inflammatory mediators by competing with arachidonic acid for metabolism via COX and LOX. They also inhibit the release of arachidonic acid from phospholipids by phospholipase A2 meaning that less is available for metabolism. The overall result is the formation of a number of inflammatory mediators with a different structure to those derived from arachidonic acid which are biologically less potent and include the 3-series prostaglandins and thromboxanes and 5-series leukotrienes [23, 24]. It was shown by Lee et al.  and later in1993 by Sperling et al.  that there was a 40–70% reduction in LTB4 and 5-hydroxyeicosatetraenoic acid production by neutrophils and monocytes following dietary enrichment with EPA and DHA. There were similar findings by Stenson et al.  and Hawthorne et al.  in patients with ulcerative colitis whose diets were enriched with fish oil over a prolonged period.
Products derived from the metabolism of omega-3 significantly decrease the generation of inflammatory cytokines such as TNF-α, IL-1, IL-6 and IL-8 [29–31]. Animal models have shown that omega-3 also suppresses inflammatory gene expression especially for TNF-α, IL-6 and IL-1ß as this gene expression is regulated by eicosanoids derived from arachidonic acid. In addition, it is also now known that some of this effect is due to a direct effect of omega-3 on intracellular signalling pathways which leads to activation of one or more transcription factors particularly nuclear factor kappa-ß .
The body also responds to stress by producing a temporary state of immunosuppression and it was traditionally believed that this immunosuppression follows the initial hyper-inflammation. It is however now recognised (and has been demonstrated by a number of groups) that they can co-exist. Immunosuppression is characterised by failure of antigen presentation and impairment of the T-helper lymphocyte type-1 response and both these responses are responsible for the production of cytokines [33–35]. This was examined in a study by Lin et al.  that randomised rats undergoing gastrectomy to receive TPN with either 50% soybean emulsion and 50% fish oil emulsion or soybean emulsion alone (the control group). Their results suggested that omega-3 administration promoted lymphocyte T-helper 1 cytokine production, enhanced peritoneal macrophage activity and reduced leucocyte adhesion molecule expression. These findings supported the concept of an improved immune function following supplementation with omega-3 which did not appear to be at the expense of any immunosuppression. The administration of the omega-3 appears to protect or enhance cell-mediated immunity with no deleterious effects.
The main contributors to the patient’s length of stay in hospital following surgery are analgesic requirements, ileus, immobility and nutritional support. The aim of ERP is to target these factors by reducing the catabolic response, immune dysfunction and insulin resistance, thus helping the patient recover as quickly as possible. It has been shown in a number of trials that malnutrition is an important risk factor for post-operative morbidity and mortality and also that providing early post-operative nutrition is an important part of any ERP. With the advent of fish oil emulsions which allow supplementation to be given enterally or parenterally, there is now the potential to address issues of nutritional support and the reduction of inappropriate or excessive inflammation contemporaneously. Studies to date certainly suggest a clinical benefit from omega-3 enriched diets in patients following surgery. Omega-3 fatty acids abrogate some undesirable aspects of the inflammatory response by influencing the production of eicosanoids (prostaglandins, prostacyclins, thromboxanes and leukotrienes) and modulating cytokines (interleukins, lymphokines, tumour necrosis factor and interferons). They also enhance cell-mediated immunity and as a consequence preserve immune function, by protecting against the immunosuppressive effect of surgery better than standard formulations [37–39].
A number of trials performed in the last decade have examined the role of ERP but the approach is frequently misunderstood. It is often believed that fast track programmes are protocols which are specifically aimed at early patient discharge following surgical procedures. This is certainly a consequence of the improved care and will generally facilitate early discharge, but the real aim is to help the patient to recover from the stress of the surgical procedure as smoothly, rapidly and completely as possible.
For an ERP to be successful, it requires a well-informed team of surgeons, anaesthetists, dieticians, physiotherapist, social worker and nursing staff . It is the combination of all of these elements of the protocol that is important for its effective implementation. Based on all the available data, a consensus has been presented by The European Society of Clinical Nutrition and Metabolism (ESPEN) on the management of patients undergoing such programmes . This protocol refers to patients undergoing major gastrointestinal surgery and organ transplantation. Nevertheless, the advent of immunomodulatory protocols and specifically those incorporating omega-3 fatty acids is an exciting development which offers the opportunity to address two of the most problematic perioperative issues at the same time. Review of available literature raises a number of questions such as the best route to administer the omega-3 fatty acids. Parenteral and enteral formulas are now available which increases the flexibility and they could potentially be given by different routes at different stages of the procedure and subsequent recovery. If omega-3 fatty acids are given parenterally, at present the ideal timing and amounts are not known. If given pre-operatively, there are issues relating to the additional cost which will have to be addressed and examined in the context of improved recovery. Oral preparations are less expensive and easier to administer but compliance is known to be poor and it would be essential to demonstrate that adequate and therapeutic levels were achieved (sufficiently rapidly with appropriate adjustments of cell membrane omega-3 to omega-6 ratios). Finally, apart from epidemiological evidence from countries where the normal consumption of fish oil is high there is no data concerning the potential benefit of the prolonged use of omega-3 post-operatively, specifically whether oral supplementation would be beneficial in the post-hospital phase?
The use of immunomodulation is an exciting area and potentially allows several post-operative issues to be addressed by a single inexpensive, safe and widely available (enterally and parenterally) product. A number of areas require study before clear guidelines can be produced, but fish oil and particularly the omega-3 fatty acids EPA and DHA are likely to be used increasingly in a number of perioperative situations.
Conflict of interest