Complete Shielding of Multivitamins to Reduce Toxic Peroxides in the Parenteral Nutrition: A Pilot Study (C-SMART-PN)

Complete Shielding of Multivitamins to Reduce Toxic Peroxides in the Parenteral Nutrition: A Pilot Study (C SMART-PN, Pilot)

The purpose of this study is to examine if a new and simple method involving complete photo-protection of multivitamins only (since sampling through infusion) will result in a significant reduction of peroxide contamination of parenteral nutrition compared to standard method of parenteral nutrition preparation and infusion in extremely preterm infants.

Study Overview

• Status: Completed
• Conditions: Pathologic Processes; Lung Diseases; Infant, Premature, Diseases; Bronchopulmonary Dysplasia; Infant, Newborn, Disease; Parenteral Nutrition; Respiratory Tract Disease
• Intervention / Treatment: Other: Photo-protection; Other: Standard Care

Detailed Description

Hypothesis and Objectives:

The investigators propose, in this pilot study, a new and simple method involving complete photo-protection of multivitamins (MV) only (since sampling through infusion) and they hypothesize that this method will be readily applicable and will result in a significant reduction of peroxide contamination of parenteral nutrition (PN) compared to standard care of PN preparation and infusion method.

In Vitro Results Using This Proposed Photo-Protection Method:

This method has reduced the quantity of infused peroxides (as equivalent H2O2). When adding the generated peroxides over 5 hours (5 samples: at times 0, 30 minutes, 1, 3 and 5 hours), the total peroxides were 1270± 47 micromolar (μM) without photo-protection vs. 710±16 μM with this method, leading to 45% reduction of peroxides (data presented as a poster presentation in the Pediatric academic societies meeting , 2018, Poster number 2874.625). This reduction is comparable to the previously reported in vitro data for the whole PN complete photo-protection that reported 50% reduction of peroxides.

Specific objective of this pilot study:

To examine if this new and simple method will be feasible in clinical practice and will result in a significant reduction of urinary peroxide concentration when compared to standard PN compounding and infusion technique.

Innovation:

The investigators' team's long experience in this field permitted the identification of the interaction between light and MV (specifically riboflavin) that leads to doubling the amount of peroxides contaminating the PN. The complexity of complete photo-protection encountered by the team to conduct small uni-center studies and the incapacity to introduce the complete photo-protection in daily clinical practice led the team to create this simple intervention that will address the problem at its origin in a practical way. All trials, including complete PN photo-protection, faced the complexity of keeping MV away from light while needing to prepare the PN admixture under the light of a sterile hood. Added to this was the complexity of completely covering the PN bag while compounding the admixture. Light exposure may also occur during the transportation of the PN from the hospital pharmacy to the neonatal unit (even with special attention to the bottom of the bag and the area around the tubing being well covered).

The proposed intervention will eliminate all these complex procedures by directly sampling the MV in a photo-protected syringe, transporting it in this syringe, and directly infusing the MV into the photo-protected intravenous lines through its infusion into the patient.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Montréal, Canada
    • University of Montreal, Sainte-Justine Hospital
  • Quebec
    • Montréal, Quebec, Canada, H3T 1C5
      • CHU Sainte-Justine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 minute to 2 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Infants < 28 weeks of gestational age
• Obtaining parental consent before the start of the first PN prescribed by the attending physician

Exclusion Criteria:

• Significant congenital malformations
• Infant is currently enrolled in another trial -unless approval of trial research team-
• Parent inability to comprehend and consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MV Photo-protection; Includes infants in whom the new procedure of MV separation and photo-protection will be applied. This arm will be stratified to male and female 1:1	Other: Photo-protection; The MV solution is delivered from producing companies in amber vials. The MV will be sampled by the pharmacy technician in a syringe that is photo-protected with a white label indicating the subject study name, protocol number and the infusion rate. The MV will be transported to the unit in the same photo-protected syringe. In the neonatal unit, this syringe will be installed in the pump and connected to photo-protected extension duration.
Placebo Comparator: Standard of care; Includes infants in whom the standard method of preparation and infusion of PN will be applied. This arm will be stratified to male and female 1:1	Other: Standard Care; This group will receive the standard practice of PN compounding in the pharmacy followed by infusion in standard infusion kit available in Sainte-Justine's Hospital.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in urine peroxides concentration	From each urine sample, an aliquot (0.2 ml) will be used for creatinin measurement whereas another (0.5 ml) will be used for peroxide determination using the ferrous oxidation/xylenol orange technique. H2O2 will serve for the standard curve. The results will be expressed as μmol equ H2O2/mg creatinine.	Baseline, 48 hours post-parenteral nutrition and on day 7 of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary ascorbylperoxide (AscOOH)	Urine AscOOH concentration will be determined using Mass spectrometry.	On day 7 of life
Whole blood glutathione redox potential	Whole blood levels of glutathione (GSH) and glutathione disulfide (GSSG) will be measured by capillary electrophoresis as previously described by the investigators' team, using 0.5 ml of blood. The whole blood redox potential (mV) will be calculated, using the Nernst equation.	On day 7 of life
Whole blood glutathione redox potential	Whole blood levels of glutathione (GSH) and glutathione disulfide (GSSG) will be measured by capillary electrophoresis as previously described by our team, using 0.5 ml of blood. The whole blood redox potential (mV) will be calculated, using the Nernst equation.	At 36 weeks Post-Menstrual Age
Serum inflammatory cytokines: Interleukin 1 alpha (IL-1alpha) and beta (IL-1beta), Interleukin 6 (IL-6), Interleukin 8 (IL-8), Interleukin (IL-10), Tumor Necrosis Factor alpha (TNF-alpha), Vascular Endothelial Growth Factor (VEGF)	Multiplex assay (Luminex R&D systems), using 0.1 ml of blood	On day 7 of life
Serum inflammatory cytokines: IL-1alpha, IL-1beta, IL-6, IL-8, IL-10, TNF-alpha, VEGF	Multiplex assay (Luminex R&D systems), using 0.1 ml of blood	At 36 weeks Post-Menstrual Age
Clinical outcome - Incidence of Bronchopulmonary dysplasia (BPD) and BPD severity (Mild, moderate, sever)	According to the National Institute of Child Health and Human Development (NICHD) criteria (Jobe Alan H.,2001)	At 36 weeks Post-Menstrual Age
Clinical outcome - Mortality rate	Death before 36 weeks post menstrual age	At 36 weeks Post-Menstrual Age
Clinical outcome - length of mechanical ventilation (invasive, non-invasive)	Total number of days on mechanical ventilation (both invasive and non invasive respiratory support)	From birth to discharge home, an average of 4 months
Clinical outcome - length of supplemental oxygen (in days)	Total number of days on Nasal cannula O2 supplements	From birth to discharge home, an average of 4 months
Clinical outcome - Incidence and stage of necrotizing enterocolitis (According to Bell's classification)	Necrotizing enterocolitis stages as defind by Bell stage II or higher. The incidence in the two arms will be reported and compared	From birth to discharge home, an average of 4 months
Clinical outcome - Incidence and grade of intraventricular hemorrhage (IVH), according to Papille criteria	Any intraventricular hemorrhage (IVH), IVH grade III and IV in each arm will be reported and compared.	From birth to discharge home, an average of 4 months
Clinical outcome - Incidence of significant liver cholestasis (defined as two or more consecutive conjugated bilirubin values ≥ 34 μmol/L)	Cholestasis is defined as two or more consecutive conjugated bilirubin values ≥ 34 μmol/L. The incidence of cholestasis in each arm will be reported and compared.	From birth to discharge home, an average of 4 months
Clinical outcome - Incidence and stage of Retinopathy Of Prematurity (ROP) (highest stage)	The incidence of ROP stage II and higher as defined by the National Eye Institute will be reported and compared.	From birth to discharge home, an average of 4 months
Clinical outcome - Incidence of significant Patent Ductus Arteriosus (PDA)	PDA requiring medical or surgical treatment according to the treating neonatologist will be reported and compared.	From birth to discharge home, an average of 4 months
Clinical outcome - infant anthropometry: weight	Weight in grams	At 36 weeks Post-Menstrual Age
Clinical outcome - infant anthropometry: length	Length in centimeters	At 36 weeks Post-Menstrual Age
Clinical outcome - infant anthropometry: head circumference	Head circumference in centimeters	At 36 weeks Post-Menstrual Age
Clinical outcome - length of hospital stay (in days)	Total number of days till discharge home	From birth to discharge home, an average of 4 months

Collaborators and Investigators

• Sponsor: St. Justine's Hospital
• Investigators: Principal Investigator: Ibrahim Mohamed, M.D.,Ph.D., Sainte-Justine Research center, Sainte-Justine hospital, University of Montreal

Publications and helpful links

General Publications

• Thibeault DW. The precarious antioxidant defenses of the preterm infant. Am J Perinatol. 2000;17(4):167-81. doi: 10.1055/s-2000-9422.
• Mohamed I, Elremaly W, Rouleau T, Lavoie JC. Oxygen and parenteral nutrition two main oxidants for extremely preterm infants: 'It all adds up'. J Neonatal Perinatal Med. 2015;8(3):189-97. doi: 10.3233/NPM-15814091.
• Saugstad OD. Oxygen and oxidative stress in bronchopulmonary dysplasia. J Perinat Med. 2010 Nov;38(6):571-7. doi: 10.1515/jpm.2010.108. Epub 2010 Aug 31.
• Laborie S, Lavoie JC, Pineault M, Chessex P. Contribution of multivitamins, air, and light in the generation of peroxides in adult and neonatal parenteral nutrition solutions. Ann Pharmacother. 2000 Apr;34(4):440-5. doi: 10.1345/aph.19182.
• Laborie S, Lavoie JC, Chessex P. Increased urinary peroxides in newborn infants receiving parenteral nutrition exposed to light. J Pediatr. 2000 May;136(5):628-32. doi: 10.1067/mpd.2000.105131.
• Bassiouny MR, Almarsafawy H, Abdel-Hady H, Nasef N, Hammad TA, Aly H. A randomized controlled trial on parenteral nutrition, oxidative stress, and chronic lung diseases in preterm infants. J Pediatr Gastroenterol Nutr. 2009 Mar;48(3):363-9. doi: 10.1097/mpg.0b013e31818c8623.
• Mohamed I, Elremaly W, Rouleau T, Lavoie JC. Ascorbylperoxide Contaminating Parenteral Nutrition Is Associated With Bronchopulmonary Dysplasia or Death in Extremely Preterm Infants. JPEN J Parenter Enteral Nutr. 2017 Aug;41(6):1023-1029. doi: 10.1177/0148607116643704. Epub 2016 Apr 1.
• Elremaly W, Mohamed I, Mialet-Marty T, Rouleau T, Lavoie JC. Ascorbylperoxide from parenteral nutrition induces an increase of redox potential of glutathione and loss of alveoli in newborn guinea pig lungs. Redox Biol. 2014 May 20;2:725-31. doi: 10.1016/j.redox.2014.05.002. eCollection 2014.
• Lavoie JC, Rouleau T, Chessex P. Interaction between ascorbate and light-exposed riboflavin induces lung remodeling. J Pharmacol Exp Ther. 2004 Nov;311(2):634-9. doi: 10.1124/jpet.104.070755. Epub 2004 Jul 13.
• Chessex P, Harrison A, Khashu M, Lavoie JC. In preterm neonates, is the risk of developing bronchopulmonary dysplasia influenced by the failure to protect total parenteral nutrition from exposure to ambient light? J Pediatr. 2007 Aug;151(2):213-4. doi: 10.1016/j.jpeds.2007.04.029.
• Chessex P, Laborie S, Nasef N, Masse B, Lavoie JC. Shielding Parenteral Nutrition From Light Improves Survival Rate in Premature Infants. JPEN J Parenter Enteral Nutr. 2017 Mar;41(3):378-383. doi: 10.1177/0148607115606407. Epub 2016 Sep 30.

Study record dates

Study Major Dates

• Study Start (Actual): November 23, 2020
• Primary Completion (Actual): October 27, 2021
• Study Completion (Actual): January 17, 2022

Study Registration Dates

• First Submitted: January 8, 2020
• First Submitted That Met QC Criteria: January 15, 2020
• First Posted (Actual): January 21, 2020

Study Record Updates

• Last Update Posted (Actual): October 31, 2022
• Last Update Submitted That Met QC Criteria: October 27, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Oxidative Stress; Photo-protection of Multivitamins; Ascorbyl peroxide; Urine peroxides
• Additional Relevant MeSH Terms: Lung Injury; Ventilator-Induced Lung Injury; Lung Diseases; Infant, Premature, Diseases; Bronchopulmonary Dysplasia; Respiratory Tract Diseases; Infant, Newborn, Diseases; Pathologic Processes
• Other Study ID Numbers: 2020-2713

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The authors will do every efforts to make the study protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR) and analytic code available to other researcher (either by protocol publication before the study of as supplemental material with the final publication).
• IPD Sharing Time Frame: Within 6 months of collecting all data and for a maximum of 2 years
• IPD Sharing Access Criteria: Anonymized information will be available for research and academic purposes.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

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