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

• ClinicalTrials.gov Identifier: NCT03587870
• Recruitment Status: Recruiting
• First Posted: July 16, 2018
• Last Update Posted: June 6, 2023
• Sponsor: University Hospital, Basel, Switzerland
• Information provided by (Responsible Party): University Hospital, Basel, Switzerland

Tracking Information

• First Submitted Date: June 4, 2018
• First Posted Date: July 16, 2018
• Last Update Posted Date: June 6, 2023
• Actual Study Start Date: March 25, 2019
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 26, 2019)

Daily protein target quantity [ Time Frame: During ICU stay for the duration of 7 days after study inclusion ]

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).

Original Primary Outcome Measures (submitted: July 3, 2018)

Daily protein target quantity [ Time Frame: During ICU stay for the duration of 7 days after study inclusion ]

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 BW protein in the control group, to 1.5 g/kg BW protein in the experimental group).

Current Secondary Outcome Measures (submitted: July 3, 2018)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Protein Delivery in Intermittent and Continuous Enteral Nutrition in ICU Patients
• Official Title: 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

Brief Summary

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.

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
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

A prospective, randomised controlled pilot study in critical ill patients with a protein-rich formula

Masking: None (Open Label)
Primary Purpose: Prevention

• Condition: Muscle Wasting in Critically Ill

Intervention

Other: Enteral nutrition with Fresubin Intensive

Comparison of intermittent (experimental) vs continuous (standard, active comparator) enteral nutrition on muscle wasting in critically ill patients

Study Arms

• Experimental: Bolus enteral nutrition with Fresubin Intensive
  Bolus nutrition over 30-40 minutes every 4 hours with Fresubin Intensive
  Intervention: Other: Enteral nutrition with Fresubin Intensive
• Active Comparator: Continuous enteral nutrition with Fresubin Intensive
  Continuous nutrition over 20 hours per day with Fresubin Intensive (standard)
  Intervention: Other: Enteral nutrition with Fresubin Intensive

• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 3, 2018): 68
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 31, 2024
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Alexa Hollinger, MD; +41786747130; alexa.hollinger@usb.ch

Contact: Désirée Yeginsoy, MD; +41774261353; desi.y@bluewin.ch

• Listed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT03587870
• Other Study ID Numbers: EKNZ 2018-00259
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: University Hospital, Basel, Switzerland
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital, Basel, Switzerland
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: University Hospital, Basel, Switzerland
• Verification Date: June 2023