Clinical trial NCT00512122: Impact of Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients
Official title: Impact of Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Critical Illness
Starvation
Keywords: early parenteral nutrition
critical illness
respiratory failure
kidney failure
hepatic failure
muscle strength
rehabilitation
overfeeding
Reduced Oral Intake
Lead sponsor: KU Leuven
Sponsor class: OTHER
Collaborators: name: Fund for Scientific Research, Flanders, Belgium
name: Baxter Healthcare Corporation
First posted: 2007-08-07
Enrollment: 4640
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In critically ill patients, a strategy aimed at an early delivery of full caloric support, with a combination of Enteral Nutrition (EN) and Parenteral Nutrition (PN) (in conditions preventing hyperglycemia and overfeeding), results in shorter ICU and hospital stay and less morbidity as compared to a strategy using only EN.

Detailed description: Written informed consent will be obtained from the patient or the closest family member or legal guardian. The family member or the patient can withdraw from the trial, at any time, without impact on his treatment or penalty. The investigators confirm that this study concerns a condition that directly threatens patient health and that the adult patient not able to give consent suffers from the condition. The experiment is essential to confirm the results from earlier research in patients who could consent or from other research methods.

On admission patients will be randomly assigned to receive EN combined with early PN or only EN. At ICU admission, consecutive patients will be randomly assigned to one of these two treatment groups using blinded envelopes, stratified according to primary diagnostic category on admission. Upon addition of the new study site, the numbered en sealed envelopes for randomization stratified according to primary diagnostic category on admission were replaced by an identical digital system allowing central randomization.

As initial nutritional support, patients randomised to the 'EN combined with early PN' group will receive glucose 20% at 40 ml/hr. EN will be initiated in the evening of the second ICU hospitalisation day, PN will be started the morning of the third ICU hospitalisation day. The amount of PN to be given on any particular day will be the difference between calculated caloric needs and the calories delivered by EN the previous 24 hours. When EN covers 80% of calculated caloric needs PN will be stopped. When the patient is able to eat, the parenteral regimen will be reduced and eventually stopped. Whenever oral (+ enteral) intake is below 50% of calculated caloric needs, the PN will be (re)-started.

As initial nutritional support, patients randomised to the 'EN only' group will receive glucose 5% at 40 ml/hr. EN will be initiated on the evening of the second ICU day. From the morning of the third ICU hospitalisation day on, the amount of glucose 5% to be given will be the same as the volume of PN the patient theoretically would require to receive 100% of presumed caloric needs based on the amount of EN delivered the previous 24 hours. When the patient is able to eat, the parenteral regimen (glucose 5%) will be reduced to 50% and eventually stopped. Whenever oral (+ enteral) intake is below 50% of calculated caloric needs, the PN (glucose 5%) will be (re)-started. If these patients would need to stay for more than seven days on the ICU and enteral feeding of at least 80% of the calculated calories is not possible, they will be switched to EN and PN on day eight.

Common strategy for attempting early enteral nutrition in both study arms:

EN will be initiated on the evening of the second ICU day, unless patients are able to eat. The increase of enteral feeding volume and the adaptation of the regimen to pathological conditions will be according to protocol. Trace elements, minerals and vitamins will be administered daily intravenously (IV) to all patients from the day of admission onwards. IV substitution will be stopped in patients receiving at least 1500 ml of EN. All patients will be treated following the intensive insulin therapy schedule - targeting a blood glucose level of 80 - 110 mg/dl - from admission until discharge or oral feeding.

Patients will be weaned from the ventilator according to a standard protocol. End-of-care decisions in patients for whom further intensive care is considered to be futile will be taken in consensus by a group of two senior ICU physicians and the referring specialist, all blinded to study treatment allocation.

In a subgroup of patients, pathways of inflammation and metabolism and the endocrinological impact of the intervention will be studied in blood samples and in snap-frozen in vivo biopsies of muscle and adipose tissue. Blood and tissue samples from healthy volunteers will serve as references for these exploratory studies. In some patients, radiological evolution of regional muscle and adipose tissue volumes will be evaluated.

Eligibility criteria: Inclusion Criteria:

1. Patients admitted to any of the five intensive care units
2. Older than 18 years
3. Nutritional risk screening score (NRS) higher or equal to three upon ICU admission

Exclusion Criteria:

1. Patients with a do not resuscitate (DNR) code or moribund at the time of ICU admission
2. Patients already enrolled in another trial
3. Patients transferred from another intensive care unit with an established nutritional therapy
4. Patients suffering from ketoacidotic or hyperosmolar coma on admission
5. Patients with a body mass index (BMI) below 17 kg/m\^2
6. Short bowel syndrome
7. Patients known to be pregnant or nursing
8. Patients on mechanical ventilation at home
9. NRS score lower than three
10. Patient readmitted to ICU after randomization to the EPaNIC trial.
11. Patient not critically ill on admission. (No clinical indication for central intravenous catheter or patient ready for oral nutrition on admission.)

Primary outcomes:
measure: Length of stay in ICU and length of stay in the hospital.
timeFrame: 2 years
Secondary outcomes:
measure: Death (hospital and ICU mortality and 90 days mortality)
timeFrame: 10 years
measure: Days to weaning from mechanical ventilation
timeFrame: 2 years
measure: The need for renal replacement therapies
timeFrame: 2 years
measure: The presence or absence of new kidney injury during intensive care
timeFrame: 2 years
measure: Days of vasopressor or inotropic support
timeFrame: 2 years
measure: The presence or absence of signs of ICU liver disease: hyperbilirubinemia (defined as bilirubin level > 3 mg/dl), presence of liversteatosis, sludge…
timeFrame: 2 years
measure: The need for tracheotomy
timeFrame: 2 years
measure: The presence or absence of hyper-inflammation within five days after ICU admission
timeFrame: 2 years
measure: Blood lipid profiles and albumin on days one, five, ten, and fifteen after admission
timeFrame: 2 years
measure: The presence or absence of bacteraemia, ventilator-associated pneumonia and of wound infections
timeFrame: 2 years
measure: Episodes of hypoglycaemic events (defined as glycemia less than 40 mg/dl)
timeFrame: 2 years
measure: Amount and type of calories delivered
timeFrame: 2 years
measure: Muscle strength: among others: MRCss, Maximum Inspiratory Pressure in patients staying more than 7 days in ICU and a subset staying < 7 days, as well as in individuals who have never stayed in ICU. Presence of electrophysiological signs of CIP/CIM.
timeFrame: 10 years
measure: Rehabilitation/functionality: among others: six minute walking distance and activities of daily life at hospital discharge and at follow-up moments. SF 36 questionnaire at several follow-up moments and in individuals who have never stayed in ICU.
timeFrame: 10 years
Other outcomes:
Locations:
city: Hasselt
country: Belgium
facility: Surgical Intensive Care Unit Regional Hospital Jessa
city: Leuven
country: Belgium
facility: Medical Intensive Care Unit
city: Leuven
country: Belgium
facility: Surgical Intensive Care Unit, Catholic University Leuven University Hospitals
Study officials:
affiliation: Director of the Department of Intensive Care Medicine Catholic Univeresity Leuven
name: Greet Van den Berghe, MD Ph D
role: STUDY_DIRECTOR
affiliation: Department of Intensive Care Medicine Catholic University Leuven
name: Michaël P Casaer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Medicine Catholic University Leuven
name: Alexander P Wilmer, MD Ph D
role: PRINCIPAL_INVESTIGATOR
affiliation: Surgical Intensive Care Unit Regional Hospital Jessa
name: Jasperina Dubois, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67. doi: 10.1056/NEJMoa011300.
citation: Van Dyck L, Guiza F, Derese I, Pauwels L, Casaer MP, Hermans G, Wouters PJ, Van den Berghe G, Vanhorebeek I. DNA methylation alterations in muscle of critically ill patients. J Cachexia Sarcopenia Muscle. 2022 Jun;13(3):1731-1740. doi: 10.1002/jcsm.12970. Epub 2022 Mar 11.
citation: Vanhorebeek I, Derese I, Gunst J, Wouters PJ, Hermans G, Van den Berghe G. Persisting neuroendocrine abnormalities and their association with physical impairment 5 years after critical illness. Crit Care. 2021 Dec 16;25(1):430. doi: 10.1186/s13054-021-03858-1.
citation: Ingels C, Langouche L, Dubois J, Derese I, Vander Perre S, Wouters PJ, Gunst J, Casaer M, Guiza F, Vanhorebeek I, Van den Berghe G. C-reactive protein rise in response to macronutrient deficit early in critical illness: sign of inflammation or mediator of infection prevention and recovery. Intensive Care Med. 2022 Jan;48(1):25-35. doi: 10.1007/s00134-021-06565-1. Epub 2021 Nov 24.
citation: Van Aerde N, Meersseman P, Debaveye Y, Wilmer A, Gunst J, Casaer MP, Wauters J, Wouters PJ, Gosselink R, Van den Berghe G, Hermans G. Five-year outcome of respiratory muscle weakness at intensive care unit discharge: secondary analysis of a prospective cohort study. Thorax. 2021 Jun;76(6):561-567. doi: 10.1136/thoraxjnl-2020-216720. Epub 2021 Mar 12.
citation: Van Dyck L, Gunst J, Casaer MP, Peeters B, Derese I, Wouters PJ, de Zegher F, Vanhorebeek I, Van den Berghe G. The clinical potential of GDF15 as a "ready-to-feed indicator" for critically ill adults. Crit Care. 2020 Sep 14;24(1):557. doi: 10.1186/s13054-020-03254-1.
citation: Van Aerde N, Meersseman P, Debaveye Y, Wilmer A, Gunst J, Casaer MP, Bruyninckx F, Wouters PJ, Gosselink R, Van den Berghe G, Hermans G. Five-year impact of ICU-acquired neuromuscular complications: a prospective, observational study. Intensive Care Med. 2020 Jun;46(6):1184-1193. doi: 10.1007/s00134-020-05927-5. Epub 2020 Jan 22.
citation: Hermans G, Van Aerde N, Meersseman P, Van Mechelen H, Debaveye Y, Wilmer A, Gunst J, Casaer MP, Dubois J, Wouters P, Gosselink R, Van den Berghe G. Five-year mortality and morbidity impact of prolonged versus brief ICU stay: a propensity score matched cohort study. Thorax. 2019 Nov;74(11):1037-1045. doi: 10.1136/thoraxjnl-2018-213020. Epub 2019 Sep 3.
citation: Van Dyck L, Derese I, Vander Perre S, Wouters PJ, Casaer MP, Hermans G, Van den Berghe G, Vanhorebeek I. The GH Axis in Relation to Accepting an Early Macronutrient Deficit and Outcome of Critically Ill Patients. J Clin Endocrinol Metab. 2019 Nov 1;104(11):5507-5518. doi: 10.1210/jc.2019-00842.
citation: Thiessen SE, Derde S, Derese I, Dufour T, Vega CA, Langouche L, Goossens C, Peersman N, Vermeersch P, Vander Perre S, Holst JJ, Wouters PJ, Vanhorebeek I, Van den Berghe G. Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition. Am J Respir Crit Care Med. 2017 Nov 1;196(9):1131-1143. doi: 10.1164/rccm.201702-0354OC.
citation: Flechet M, Guiza F, Schetz M, Wouters P, Vanhorebeek I, Derese I, Gunst J, Spriet I, Casaer M, Van den Berghe G, Meyfroidt G. AKIpredictor, an online prognostic calculator for acute kidney injury in adult critically ill patients: development, validation and comparison to serum neutrophil gelatinase-associated lipocalin. Intensive Care Med. 2017 Jun;43(6):764-773. doi: 10.1007/s00134-017-4678-3. Epub 2017 Jan 27.
citation: Hermans G, Van Mechelen H, Bruyninckx F, Vanhullebusch T, Clerckx B, Meersseman P, Debaveye Y, Casaer MP, Wilmer A, Wouters PJ, Vanhorebeek I, Gosselink R, Van den Berghe G. Predictive value for weakness and 1-year mortality of screening electrophysiology tests in the ICU. Intensive Care Med. 2015 Dec;41(12):2138-48. doi: 10.1007/s00134-015-3979-7. Epub 2015 Aug 13.
citation: Hermans G, Van Mechelen H, Clerckx B, Vanhullebusch T, Mesotten D, Wilmer A, Casaer MP, Meersseman P, Debaveye Y, Van Cromphaut S, Wouters PJ, Gosselink R, Van den Berghe G. Acute outcomes and 1-year mortality of intensive care unit-acquired weakness. A cohort study and propensity-matched analysis. Am J Respir Crit Care Med. 2014 Aug 15;190(4):410-20. doi: 10.1164/rccm.201312-2257OC.
citation: Hermans G, Casaer MP, Clerckx B, Guiza F, Vanhullebusch T, Derde S, Meersseman P, Derese I, Mesotten D, Wouters PJ, Van Cromphaut S, Debaveye Y, Gosselink R, Gunst J, Wilmer A, Van den Berghe G, Vanhorebeek I. Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet Respir Med. 2013 Oct;1(8):621-629. doi: 10.1016/S2213-2600(13)70183-8. Epub 2013 Sep 10.
citation: Boonen E, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE, Vanwijngaerden YM, Spriet I, Wouters PJ, Vander Perre S, Langouche L, Vanhorebeek I, Walker BR, Van den Berghe G. Reduced cortisol metabolism during critical illness. N Engl J Med. 2013 Apr 18;368(16):1477-88. doi: 10.1056/NEJMoa1214969. Epub 2013 Mar 19.
citation: Langouche L, Vander Perre S, Marques M, Boelen A, Wouters PJ, Casaer MP, Van den Berghe G. Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. J Clin Endocrinol Metab. 2013 Mar;98(3):1006-13. doi: 10.1210/jc.2012-2809. Epub 2013 Jan 24.
citation: Casaer MP, Wilmer A, Hermans G, Wouters PJ, Mesotten D, Van den Berghe G. Role of disease and macronutrient dose in the randomized controlled EPaNIC trial: a post hoc analysis. Am J Respir Crit Care Med. 2013 Feb 1;187(3):247-55. doi: 10.1164/rccm.201206-0999OC. Epub 2012 Nov 29.
citation: Vanderheyden S, Casaer MP, Kesteloot K, Simoens S, De Rijdt T, Peers G, Wouters PJ, Coenegrachts J, Grieten T, Polders K, Maes A, Wilmer A, Dubois J, Van den Berghe G, Mesotten D. Early versus late parenteral nutrition in ICU patients: cost analysis of the EPaNIC trial. Crit Care. 2012 May 25;16(3):R96. doi: 10.1186/cc11361.
citation: Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011 Aug 11;365(6):506-17. doi: 10.1056/NEJMoa1102662. Epub 2011 Jun 29.
citation: Casaer MP, Hermans G, Wilmer A, Van den Berghe G. Impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients (EPaNIC trial): a study protocol and statistical analysis plan for a randomized controlled trial. Trials. 2011 Jan 24;12:21. doi: 10.1186/1745-6215-12-21.