Protein Delivery in Intermittent and Continuous Enteral Nutrition in ICU Patients (ProBoNo)

Protein Delivery in Intermittent and Continuous Enteral Nutrition in ICU Patients A Prospective, Randomised Controlled Pilot Study in Critical Ill Patients With a Protein-rich Formula

Acute skeletal muscle wasting in ICU patients is associated with functional impairment and with increased risk of death. Of what we know today, physical disability can persist up to 5 years. Adequate nutrition is the basis for an optimal recovery for ICU patients and for prevention of muscle wasting. Today, continuous feeding is still the standard enteral nutrition form for patients in the ICU to limit the incidence of aspiration. A study of Serpa et al. and Georgia et al. compared the continuous feeding versus a bolus nutrition with a feeding time of 30 - 60 minutes every 4 hours. They showed no statistical differences in complications between both groups.

ProBoNo is a prospective, randomized, controlled pilot study of critically ill patients with a protein- rich formula to explore the impact of continuous or intermittent bolus nutrition on muscle breakdown in ICU patients. The investigators would like to recruit 68 patients during the first 24 hours after surgical intensive care unit admission. Prior beginning of nutrition administration, and on the 7th day thereafter the investigators will perform a muscle biopsy and an ultrasound from the vastus lateralis muscle in both groups.

The primary outcome is the time from 6.00 am of the following day after admission until the patient reaches his daily protein's target quantity. Secondary outcomes include the diameter and densitiy of the hamstrings assessed by ultrasound and histology, the process of gastric residual volume, number of diarrhoea events and laboratory findings like glucose, urea and insulin like growth factor (IGF)-1, all compared between the two time points.

Intermittent feeding is not only more natural and could help to limit the muscle wasting in ICU patients, it is also easier to handle for the ICU caring medical team. A trial from Georgia et al. in 2007 compared continuous to intermittent enteral nutrition. They found that the intermittently fed patients reached their nutrition goal faster than those being continuously nourished. This might in part be explained by feeding interruptions in the continuous feeding regimen. Presumably, preoperative holding of tube feedings in the continuous nutrition group most commonly caused interruptions. Thus, independently from prevention of muscle breakdown, a bolus nutrition would be more attractive.

Study Overview

• Status: Recruiting
• Conditions: Muscle Wasting in Critically Ill
• Intervention / Treatment: Other: Enteral nutrition with Fresubin Intensive

Detailed Description

The relevance of early continuous or intermittent enteral feeding of critically ill patients has been discussed controversially in the last years. Today, continuous feeding is still the standard for enteral nutrition in the ICU. The continuous nutrition can prevent abdominal intolerance like vomiting, diarrhoea and aspiration. Pulmonary aspiration is the most dramatic consequence of enteral nutrition and can be limited by a continuous feeding as shown by a study in 2003. However, nutrition was started with a bolus of 125ml as baseline by force of gravity over 15 minutes. Compared to the continuous nutrition, this is considered much volume in a short time. Naturally, risk of gastric intolerance in this scenario is very high.

In other studies, a similar amount of nutrition was given over a longer period of time (30 - 60 minutes) every 4 hours. In each cohort (continuous and bolus), only one case of pulmonary aspiration or tube obstruction was detected. After this study, other trials with a similar result followed. In 2007 a trial of Georgia et al. showed no statistical differences in complications regarding tube feeding, no differences of diarrhoea, emesis or pneumonias between continuous and bolus nutrition. The feeding time for bolus nutrition is also a critical influential factor. When an intermittent feeding is given over a longer period of time (20-40 minutes), the incidence of nausea and vomiting has not increased.

Intermittent feeding is not only a good alternative to continuous feeding, but also more natural, as long-term intake of nutrition over 20 hours is not common in any mammal. The alimentary tract and metabolic pathways of humans seem designed for intermittent ingestion of essential nutrients reduced to a few times a day. Different hormones of the endocrine cells affect complex roles of gastrointestinal motility, gall bladder contraction and nutrient absorption. The level of these hormones depends on the amount of nutrient ingestion. This response of the hormones is almost completely abolished in continuous feeding. But in intermittent nutrition, hormones like incretin, glucose-dependent insulinotropic polypeptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) boost the level of insulin and the resulting carbohydrate load and therefore influence the muscle protein synthesis and breakdown.

In healthy individuals, the anabolic effects of feeding occur due to an increase on the synthetic rate of muscle protein synthesis of approximately 300% with a simultaneous 50% decrease in the rate of protein breakdown. Two studies of 2009 and 2011 compared the intermittent bolus and continuous feeding and the effect of protein synthesis in skeletal muscle in neonatal pigs. They analysed the fractional rates of protein synthesis in muscle samples of continuous and intermittent bolus feeding groups. They could show that although both groups, continuous and intermittent bolus feeding, stimulate muscle protein synthesis, but in the bolus-fed, in the fractional rates of protein synthesis called K's was greater after a meal.

An ongoing study wants to show the effect of bolus vs. continuous feeding in ICU patients related to muscle wasting by measurements of ultrasound and blood samples. In this trial, the investigators would like to have a similar approach but with different measurements. Using ultrasound and muscle biopsies, the investigators aim to determine whether intermittent enteral feeding could preserve muscle mass better or more than standard continuous enteral feeding in the critically ill patients. In addition, the investigators would like to assess if intermittent bolus feeding optimizes protein intake in the first 7 days of critical illness since the intermittent route is less affected by interruptions following treatment and diagnostic procedures.

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alexa Hollinger, MD; Phone Number: +41786747130; Email: alexa.hollinger@usb.ch
• Study Contact Backup: Name: Désirée Yeginsoy, MD; Phone Number: +41774261353; Email: desi.y@bluewin.ch

Study Locations

• Switzerland
  • Basel-Stadt
    • Basel, Basel-Stadt, Switzerland, 4031
      • Recruiting
      • University Hospital Basel, operative ICU
      • Contact: Alexa Hollinger, Dr. MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Informed Consent as documented by signature
• Adult patients (age 18 years or older)
• Expected ICU stay of five days or longer
• Expected enteral feeding during at least five days

Exclusion Criteria:

• Pregnancy or breast feeding (women of childbearing age are tested for high beta-human chorionic gonadotropin (hCG) in urine or serum upon ICU admission)
• Clinically significant chronic or acute kidney insufficiency with a glomerular filtration rate (GFR) <15.
• BMI ≤ 18 and ≥ 35.
• Intestinal perforation, peritonitis, intestinal fistula, necrosis or other contraindication to enteral diet
• Death or discharge before 48 hours of observation
• Noradrenaline ≥ 0.5 µg/kg bodyweight /min
• Inherited and chronic skeletal muscle disease (e.g. Morbus Duchenne or other motoneuron disease)
• Paralysis (e.g. hemiplegia, tetraplegia and paraplegia)
• Immunosuppression
• Haematologic malignancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bolus enteral nutrition with Fresubin Intensive; Bolus nutrition over 30-40 minutes every 4 hours with Fresubin Intensive	Other: Enteral nutrition with Fresubin Intensive; Comparison of intermittent (experimental) vs continuous (standard, active comparator) enteral nutrition on muscle wasting in critically ill patients
Active Comparator: Continuous enteral nutrition with Fresubin Intensive; Continuous nutrition over 20 hours per day with Fresubin Intensive (standard)	Other: Enteral nutrition with Fresubin Intensive; Comparison of intermittent (experimental) vs continuous (standard, active comparator) enteral nutrition on muscle wasting in critically ill patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily protein target quantity	Is the time from 6.00 am of the following day after admission until the patient reaches his daily protein target quantity (1.2 g/ kg Biologische Wertigkeit (BW)/ biological value protein in the control group, to 1.5 g/kg BW protein in the experimental group).	During ICU stay for the duration of 7 days after study inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diameter of the hamstrings	Diameter of the hamstrings assessed by ultrasound and histology	During ICU stay, exactly 7 days after study inclusion
Gastric residual content	Amount of gastric residual volume (ml)	Every day during ICU stay for the duration of 7 days after study inclusion
Diarrhoea	Number of diarrhoea events	Every day during ICU stay for the duration of 7 days after study inclusion
Glucose (mmol/l) measurement	Laboratory parameters relevant to assess under enteral Nutrition (Glucose (mmol/l))	Every day during ICU stay for the duration of 7 days after study inclusion
BUN (mg/dl) measurement	Laboratory parameters relevant to assess under enteral Nutrition (BUN (mg/dl))	Every day during ICU stay for the duration of 7 days after study inclusion
IGF-1 (mmol/l) measurement	Laboratory parameters relevant to assess under enteral Nutrition (IGF-1 (mmol/l))	Every day during ICU stay for the duration of 7 days after study inclusion

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Alexa Hollinger, MD, University Hospital Basel, Basel Switzerland

Publications and helpful links

General Publications

• Reinhold S, Yeginsoy D, Hollinger A, Todorov A, Tintignac L, Sinnreich M, Kiss C, Gebhard CE, Kovacs B, Gysi B, Imwinkelried L, Siegemund M. Protein delivery in intermittent and continuous enteral nutrition with a protein-rich formula in critically ill patients-a protocol for the prospective randomized controlled proof-of-concept Protein Bolus Nutrition (Pro BoNo) study. Trials. 2020 Aug 25;21(1):740. doi: 10.1186/s13063-020-04635-1.

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2019
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): March 31, 2024

Study Registration Dates

• First Submitted: June 4, 2018
• First Submitted That Met QC Criteria: July 3, 2018
• First Posted (Actual): July 16, 2018

Study Record Updates

• Last Update Posted (Actual): June 6, 2023
• Last Update Submitted That Met QC Criteria: June 5, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: intensive care unit; muscle wasting; intermittent enteral nutrition; continuous enteral nutrition
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Nervous System Diseases; Neurologic Manifestations; Disease Attributes; Nutrition Disorders; Body Weight; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Body Weight Changes; Atrophy; Weight Loss; Thinness; Muscular Atrophy; Critical Illness; Wasting Syndrome; Cachexia
• Other Study ID Numbers: EKNZ 2018-00259

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No