Development

 

Enteral Feeding Intolerance (EFI) is a serious unmet medical need affecting between 30% and 40% of critically ill patients fed by the enteral route. EFI develops as a result of impaired gastrointestinal motility and results in the inability to provide prescribed nutrition.  While impairment of GI motility is a common functional problem seen in many medical settings, inadequate provision of nutrition in an ICU population is correlated with significant loss of skeletal muscle and with poorer outcomes, including increased mortality. No drugs are approved for EFI.  Ulimorelin (LP101), a ghrelin agonist currently in development by Lyric, might offer important effects on both GI motility and muscle mass that could benefit EFI patients. This Prokinetic PlusTM approach combines potential prokinetic and muscle effects. Ulimorelin is currently under study in PROMOTE, an international Phase 2 clinical trial for the treatment of EFI in critically ill patients.

 

Enteral Feeding

Enteral tube feeding is used to deliver enteral nutrition (EN) to the stomach or small intestine via a feeding tube. Tube feeding employs nutritionally complete, commercially manufactured enteral formulas for patients who are comatose or unable to ingest normally. The aim of tube feeding is to improve or maintain nutritional status during illness and metabolic stress. The predominant route of tube feeding is nasogastric, but orogastric and percutaneous routes may also be utilized (Martindale, 2009; Marik, 2003; Reintam Blaser, 2013).

Enteral nutrition has been associated with improved protein turnover, improved wound healing, reduced septic complications, decreased bacterial translocation across intestinal mucosa, and reduced catabolic response to injury (Zaloga, 1999; Heyland, 1993). Enteral feeding is recommended over parenteral nutrition as the first choice for nutrition support in critically ill patients (Kreymann, 2006; Singer, 2009; McClave, 2016). The value of EN over TPN (total parenteral nutrition) is supported by superior outcomes in clinical trials (Gramlich, 2004) and by mechanistic data delineating its physiologic effects and benefits to the critically ill patient, including maintenance of gut integrity, production of secretory IgA from lymphatic tissues at epithelial surfaces, and improved intestinal absorptive capacity (McClave, 2009a; McClave, 2014). Nutrition and critical care society guidelines in Europe and North America recommend that EN be started as soon as is safely possible following admission to the ICU in order to achieve benefits and minimize the development of the protein-calorie deficit that frequently occurs during critical illness (Kreymann, 2006; Dhaliwal, 2014; McClave, 2016).

Numerous studies and meta-analyses indicate that EN reduces infection, hospital length of stay, and mortality (Heyland, 2003; Doig, 2009; Lewis, 2009).  Among the various components of a nutritional formula, which typically includes calories, carbohydrate, protein, fat, antioxidants, and micronutrients, intake of protein is most highly correlated with more favorable ICU outcomes. Across studies, administration of either 1.2 g/kg (Weijs, 2012; Allingstrup, 2012), or, 80% or more of the protein prescription per day (Alberda, 2009; Nicolo, 2016; Compher, 2017), has been associated with better retention of non-fat mass and skeletal muscle mass, as well as reduction in hospital mortality, time to discharge alive and 6-month mortality (Looijaard, 2017). Long-term physical recovery and quality of life in ICU survivors are impaired in patients with enteral nutritional deficits during the ICU admission (Wei, 2015).

 

Enteral Feeding Intolerance (EFI)

Acute gastric motor dysfunction developing in critically ill, enterally tube fed patients prevents prescribed enteral feeding from being adequately tolerated. This condition is known as Enteral Feeding Intolerance (Nguyen, 2007a; Chapman, 2011). Patients with EFI have profound abnormalities of gastric emptying. Instigating factors include head injury, abdominal surgery, sepsis, recumbent position, drugs (narcotics or catecholamines), electrolyte abnormalities (hyperglycaemia), surgery, shock, circulating cytokines, and mechanical ventilation (Ritz, 2000; Dive, 1994; Kao, 1998; Dive, 2000; Zaloga, 2000). To fulfil the definition of EFI, the impairment of gastric emptying must be functional and mechanical obstruction must be absent. While EFI is of diverse etiologies, EFI patients exhibit similar pathophysiologic abnormalities and follow similar paths of hospital outcomes, including higher mortality and longer hospital stay (Gungabissoon, 2015).

Critically ill patients are highly dependent on adequate nutrition to preserve nutritional status and develop EFI at a time when such nutrition is needed most (Gungabissoon, 2015; Heyland, 2003; Doig, 2009); these patients are severely catabolic and lose as much as 17% of their non-fat mass and as much as 22% of their skeletal muscle mass over a 10-day ICU stay (Puthucheary, 2013; Ishibashi, 1998).

EFI is defined both in society guidelines and in more recent clinical trials as the measurement of a gastric residual volume (GRV) of 500 mL or greater in a nasogastrically, orogastrically, or percutaneous gastrically tube-fed patient in the absence of mechanical obstruction (Montejo, 2010; McClave, 2016; Kirby, 1995; Frost, 1997; McClave, 1992; Reintam Blaser, 2014; Gungabissoon, 2015; Elke, 2014). GRV is determined by measuring the residual contents of the stomach during enteral tube feeding. Elevated GRV has prognostic value and has been shown to correlate with higher incidences of aspiration and pneumonia (Mentec, 2001), longer duration of mechanical ventilation, increased length of ICU stay, and higher 60‑day mortality (Reintam Blaser, 2014; Gungabissoon, 2015; Elke, 2014).

EFI in the critically ill is a serious unmet medical need (Reintam Blaser, 2014; Gungabissoon, 2015). No safe and effective therapies are available or approved to treat the condition. Prokinetic agents like metoclopramide, erythromycin, and ex-US, domperidone, are prescribed off-label because they stimulate gastric emptying in other medical conditions (Heyland, 2003; McClave, 2009b); however, studies do not support their effectiveness in this use. These older drugs are associated with central nervous system side effects, QT interval prolongation, ventricular arrhythmias, sudden cardiac death, and microbial resistance (Van de Meer, 2014; Heyland, 2003; EMA position paper for metoclopramide, 2013; EMA position paper on domperidone, 2014). The European Medicines Agency recommends restriction on the use of metoclopramide (European Medicines Agency, 2013) while the Canadian Critical Care Clinical Practice Guidelines recommends that erythromycin not be used at all in EFI due to potential emergence of resistant microbial strains and superinfection (Heyland, 2003). An EMA panel recommended limiting the use of domperidone. Cisapride, formerly used off label to treat EFI, has been withdrawn in most countries, or, the labelling revised substantially, due to QT prolongation and serious cardiac arrhythmias (EMA Opinion Following an Article 31 Referral, 2002; WHO Pharmaceuticals: Restrictions in Use and Availability, 2001).

Direct feeding into the small intestine has been explored as an alternative to gastric feeding in EFI but evidence for the effectiveness of this feeding method is lacking in this patient population. Randomized, controlled studies with small bowel feeding tubes show no difference in the rates of EFI-related complications, including aspiration and ventilated-associated pneumonias, compared with patients fed intragastrically (Deane, 2013).

EFI is highly prevalent. An observational study of 1888 ICU patients revealed that approximately 30% of critically ill patients were intolerant of enteral feedings (Gungabissoon, 2014).

 

Ghrelin Agonism for EFI

Ghrelin is a peptide secreted from the stomach during fasting (Wren, 2001; Kojima, 1999). Fasting plasma ghrelin concentrations are reduced in critical illness (Nematy, 2007), and low ghrelin concentrations have been correlated with intolerance to enteral feedings and increased ICU mortality (Deane, 2010a; Crona, 2012). Ghrelin has been termed the “feeding hormone” (Pradham, 2013) because it stimulates appetite and gastric emptying and augments muscle mass (Levin, 2006; Camilleri, 2009). The effects of ghrelin on gastric emptying appear to be mediated by vagal stimulation (Avau, 2013) while the effects on muscle mass are mediated indirectly via stimulation of growth hormone (GH) secretion, and its downstream effector molecule insulin-like growth factor-1 (Kojima, 1999; Takaya, 2000; Gullett, 2010), and directly, via effects on muscle (Reano, 2014; Cappellari, 2016). Ghrelin also has anti-inflammatory properties that may lower insulin and GH resistance in muscle and decrease catabolism (Jacob, 2010).

 

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