Forte for Perioperative Nutritional Support in the Perioperative Period

Introduction

The preoperative assessment of both sarcopenia, malnutrition, and high arginase states is increasingly recognized as important adjunct in risk reduction for patients undergoing major gastrointestinal (GI) surgery in enhanced recovery programs (ERP). At least 10 metaanalyses regarding the assessment of immunonutrition have been published, however, virtually all of the data is from a period of time to adoption for ERP’s. This gap is highlighted by the metaanalysis peformed by Hegazi which assessed 8 randomized controlled trials (RCTs) of preoperative immunonutrition (IN) vs. standard enteral therapy were identified and 9 RCTs of IN vs. no supplements. The authors concluded that there is no advantage of IN over standard protein supplementation.

Similarly, comparing two recent studies demonstrates the same conundrum regarding the benefits of supplement components within an ERP:

  1. Moya et al- randomized patients into receiving no supplement versus IN and reported a reduction in surgical site infection in the absence of a mechanical/antibiotic bowel prep.
  2. Huber et al randomized elective major GI surgery between IN or isocaloric isonitrogenous nutrition (ICN) given for 5 days preoperatively within an ERAS pathway which demonstrated no improvement in outcomes.

These data are further complicated by recent data suggesting that glutamine and omega 3 fatty acids are either associated with increased risk or no benefit in many stressed patient populations. Therefore, there remains a significant gap in the appropriate supplement components based on modern assessment of nutritionally at risk surgical patients and the impact of a better formulation on functional outcomes.

Modern Assessment of Nutritionally at Risk Surgical Patients

The current evidence-based investigations capable of assessing this at risk surgical patients include:

  • CT measured sarcopenia scores
  • Ultrasound assessment of rectus femoris size
  • Nutritional metabolic scores (Prognostic Nutritional Index and Glasgow Prognostic Score)
  • Assessement of systemic arginine bioavailability (systemic methylarginines, ornithine:citrulline ratio, and proline:citrulline ratio).

These data are easily and economically efficient means of assessing preoperative nutritional and immunologic impairment of major surgical patients. Clinicians should strongly consider routine application of some of these strategies within their ERP. The PNI has consistently demonstrated efficacy in highlighting patients with poor short and long term outcomes, especially with oncologic surgery.

Surgical Stress Impact on Arg/ADMA and use of L-Citrulline Versus Enteral Arginine and Glutamine

The surgical stress response also induces a decrease in arginine (Arg) bioavailability and an increase in asymmetric dimethyl arginine which is an natural inhibitor of arginine associated nitric oxide function. The net result is a lowering of the Arg/ADMA ratio in the early postoperative period and is associated with increased SSI rates, cardiovascular complications, and acute kidney injury.

A reduced arg/ADMA ratio has been demonstrated to correlate with poor outcomes in a variety of settings of physiologic stress including cardiac and non-cardiac surgery, acute coronary syndrome, stroke, and sepsis. Echeloef et al recently confirmed the negative impact of perioperative reduction in arginine bioavailability on endothelial dysfunction in colectomy.

Acute and chronic elevations in serum glucose also work to lower this ratio. LCitrulline has recently and consistently been demonstrated to safely and effectively restore systemic arginine levels and reduce ADMA in a variety of clinical scenarios. L-Citrulline is virtually 100% absorbed by the intestine and subsequently, virtually 100% is converted to arginine for systemic utilization. Conversely, surgical stress increases the function of constituitively active hepatic arginase which degrades a significant component of enterally administered arginine, rendering it inactive.

Similarly, the principal potential benefit of enteral glutamine appears to be related to enterocyte conversion to citrulline which is absorbed and converted to arginine. Therefore, it is simply more efficient to provide the superior biologic precursor, L-Citrulline, to enhance the systemic arginine/ADMA ratio as well as the ornithine:citrulline ratio, and proline:citrulline ratios. The higher degree of bioavalibility of systemic arginine is also important because of its ultimate conversion to ornithine and then proline which supports wound healing via collagen formation. Higher doses of arginine are required to support similar systemic levels but

Negative Impact of High Carbohydrate to Protein Ratios in Sarcopenic States

It appears that moderate-to-large servings of protein or amino acids increases muscle protein synthesis similarly in both young and elderly, especially in ranges of 10 and 20g per servings of essential amino acids. However, Volpi et al demonstrated that co-ingestion of protein and relatively large amounts of simple carbohydrate markedly diminishes the benefit of protein supplementation in sarcopenic elderly patients.

As a result of this research, we have significantly reduced the amount of carbohydrates and provided those calories in the form of a complex carbohydrate (maltodextrin). In addition, Forte is enriched with whey protein isolate to supply the more beneficial branch chain amino acid leucine to further enhance the impact of protein supplementation on muscle protein synthesis. Vitamin K2 has also demonstrated an adjunctive role with respect to muscle protein synthesis in sarcopenic patients and this is included at a level associated with improved protein utilization.

Vitamin K2 has demonstrated efficacy in improving cardiac output even with short term supplementation.

Summary

The table below demonstrates the differences between Forte and the typically recommended Impact AR. We believe the reduction in simple carbohydrates and the use of complex carbohydrate is superior. Complex carbohydrates appear efficient in inducing insulin sensitivity. Reliance upon whey protein provides a robust branch chain amino acid, especially leucine. Substitution of Citrulline for arginine and the additional supplementation with vitamin D and K2 offer an excellent, evidence-based option for the preoperative care of the nutritionally-at-risk surgical population.

Forte Supporting Research Chart

Selected References

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