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Study Protocol
Revised

Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial

[version 2; peer review: 1 approved, 1 approved with reservations]
PUBLISHED 19 Mar 2024
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OPEN PEER REVIEW
REVIEWER STATUS

This article is included in the Datta Meghe Institute of Higher Education and Research collection.

Abstract

Vitamin D, traditionally linked to bone metabolism, plays pleotropic roles in cellular regulation. In critically ill children, Vitamin D deficiency is associated with adverse outcomes, motivating our open-label Randomized Control Trial. Our aim is to assess short-term outcomes in Vitamin D-deficient critically ill children following a single high oral dose. Conducted at a central Indian tertiary care hospital with a sample size of 100, participants aged 1 month to 18 years will be randomized. Group A receives standard treatment with customary cholecalciferol dosing, while Group B receives standard treatment with a single high oral/nasogastric tube dose (10,000 IU/kg to 400,000 IU) of Vitamin D. Outcomes include PICU stay duration, mechanical ventilation period, occurrences of Ventilator-Associated Pneumonia and Central Line-Associated Blood Stream Infection, instances of Acute Kidney Injury, presence of Multiorgan dysfunction, maximum Vasoactive-Inotrope Score, and mortality rates. Results and interpretation will be guided by study observations.

Trial registration: CTRI/2022/10/046556.

Keywords

Vitamin D, Steroid hormone, Critically ill children, study protocol, Intensive care

Revised Amendments from Version 1

1. Abstract Revision:
The abstract has been meticulously rewritten for conciseness, with improved clarity regarding sample size and methodology. This modification aims to enhance the reader's understanding of the study at a glance.
 
2. Introduction Edits:
Subtle syntax and grammatical changes have been implemented in the introduction section to improve overall readability and coherence.
 
3. Methodology Adjustment:
As our study protocol allowed for flexibility, a significant alteration has been made in the methodology. The control group, initially devoid of vitamin D supplementation, will now receive regular doses. This adjustment ensures sufficient vitamin D levels without compromising the study's integrity, as the correction in serum vitamin D levels will occur over an extended period compared to the higher doses administered to other groups.
 
4. Statistical Analysis Modification:
The statistical analysis approach has been updated from ANOVA and Scheffé's test to a more suitable method, providing a robust and justified analysis of the data.
 
5. Discussion Refinement:
The discussion section has undergone refinement to present the findings in a more succinct and coherent manner, fostering a clearer understanding of the implications and contributions of our study.
 
We believe that these changes strengthen the overall quality and clarity of our manuscript.

See the authors' detailed response to the review by Dayre McNally
See the authors' detailed response to the review by Tushar Jagzape

Introduction

Vitamin D is a fat-soluble vitamin and is classically considered to play a major role in bone metabolism and maintaining calcium and phosphorus equilibrium.1 With progressing research, other roles of Vitamin D are surfacing. This has been driven by the presence of Vitamin D receptors for cholecalciferol on most body tissues.2 The pleotropic functions of Vitamin D include regulation of expression of genes in many organs like immune cells, brain, colon and kidneys which are of importance in critically ill children. These added functions of Vitamin D regulate cell proliferation, differentiation, apoptosis, and angiogenesis.3 The non-skeletal actions of vitamin D closely resemble those of steroid hormones. Consequently, Vitamin D is regarded as more akin to a steroid hormone rather than merely a vitamin.4 The majority of Vitamin D requirement is fulfilled by exposure to sunlight and lesser amount is obtained through diet. Despite sufficient sunlight in India, prevalence of Vitamin D deficiency is accounted to be 50% of critically ill children.5 In critically ill children, Vitamin D deficiency is associated with poor outcome in form of increased PICU stay, increased duration of mechanical ventilation, higher rate of Ventilator Associated Pneumonias, increased incidence of sepsis, higher intensive care scores (Pediatric Logistic Organ Dysfunction Logistic- 2 and Pediatric Sequential Organ Failure Assessment) and increased incidence of end organ dysfunction.5 10

There have been many studies conducted to determine the outcome of critically ill Vitamin D deficient children but there is a sparse data about the outcome of these children after supplementation of Vitamin D therefore we wish to take up this study. There are multiple dosing regimens and routes of administration of Vitamin D. In most of the studies, cholecalciferol was used from 200 to 540,000 IU in oral or intramuscular injection form either in single or multiple doses. The daily supplementation of Vitamin D takes months to replenish the body stores but there is a need of its rapid optimization in critically children if we desire its immunomodulatory function.11 A systematic review and meta-analysis led by McNally et al. scrutinized over one hundred interventional trials. The findings suggested that administering Vitamin D at a dosage ranging from 10,000 IU/kg to a maximum of 400,000 IU is not linked to adverse effects, anticipating an elevation of Vitamin D levels into the high normal range within 2-3 days.12 Consequently, we will adopt this specific dosing regimen in our study, where we aim to conduct an open-label Randomized Control Trial to investigate the short-term outcomes of Vitamin D-deficient critically ill children after the supplementation of a single high dose of oral Vitamin D.

Objectives

The primary objective of this study is to assess the short-term outcome of Vitamin D deficient critically ill children after supplementation of single high dose oral Vitamin D. Secondly, to determine the prevalence of Vitamin D deficiency in critically ill children in Central India.

Methods

Research questions

  • 1. Can supplementation of single dose Vitamin D orally, improve the short term outcome in critically ill children?

  • 2. What is the prevalence of Vitamin-D deficiency in critically ill children in Central India.

Study design

This will be an open-label randomized control trial. This study will be conducted at Acharya Vinoba Bhave Rural Hospital, a 1525 bedded tertiary care hospital located at Sawangi (Meghe), Wardha, Maharashtra in the duration of three years with total sample size of 100. The Insititutional Ethics Committee clearance has been obtained with reference number DMIMS (DU)/IEC/2022/207. This open label randomized control trial is also registered on the National Clinical Trial registration portal with reference number - CTRI/2022/10/046556.

Inclusion criteria

Children aged 1 month to 18 years, admitted in the Pediatric Intensive care unit with Serum 25 Hydroxy Vitamin D (25 OH Vitamin D) level less than 20 ng/dL will be included in this study.

Exclusion criteria

The following will be excluded from the study.

  • 1. All the cases of Rickets (already diagnosed or diagnosed on this admission)

  • 2. Patients admitted in the PICU for monitoring purpose like post operative cases, for performance of a procedure like lumbar puncture, bone marrow aspiration etc.

  • 3. Patients with abdominal pathology.

  • 4. Patients requiring Intensive Care Unit stay less than 24 hours.

Participants, Intervention, Comparison, Outcome (PICOs) - The information for Participants, Intervention, Comparison, Outcome (PICOs) is provided below.

Participants:

  • Children aged 1 month to 18 years admitted to the Pediatric Intensive Care Unit with Serum Vitamin D levels below 20 ng/dL.

Intervention:

  • Administering a single high dose of Vitamin D orally or via nasogastric tube, ranging from 10,000 IU/kg to a maximum of 400,000 IU.

Comparison:

  • Standard dosing that we follow in our institute of Vitamin D, with 400 IU for children below 1 year and 800 IU for those above 1 year.

Outcomes:

Primary Short-Term Outcomes:

  • - Pediatric Intensive Care Unit stay duration

  • - Mechanical ventilation duration

  • - Incidence of Hospital-acquired infections (e.g., Ventilator-Associated Pneumonia, Central Line-Associated Blood Stream Infection)

  • - Mortality

Secondary Outcomes:

  • - Multiorgan dysfunction

  • - Maximum Vasoactive-Inotrope Score

Tertiary Outcomes:

  • - Acute Kidney Injury assessment.

All the children admitted in the PICU will be screened using exclusion/inclusion criteria. After excluding those children, the Serum 25 Hydroxy Vitamin D level of the study group will be measured in the hospital laboratory. Children with serum Vitamin D level less than 20 ng/dL will be included in the study. Participants in the study will be randomly assigned using computer-generated allocation to either Group A, which will receive the standard treatment protocol along with the customary dosing of cholecalciferol (400 IU for children below 1 year and 800 IU for those above 1 year) in accordance with our institute’s practice, or Group B, which will undergo the standard treatment protocol along with a single oral or nasogastric tube administration of cholecalciferol at a dosage of 10,000 IU/kg, up to a maximum of 400,000 IU.

Participants will be formally enrolled following the acquisition of informed written parental consent, and for children aged 7 years and above who are not under mechanical ventilation, assent will also be sought. Randomization will be carried out using the WINPEPI software, and the patients will be allocated as case number and randomized. All the children will be divided equally between the control group (Group A) and the experimental or research group (Group B).

Nutritional status assessment in both the groups will be done as per WHO criteria in which wasting is defined as weight for height (gender specific) to be less than -2 standard deviation on the growth chart and stunting is defined as height for age (gender specific) to be less than -2 standard deviation on the growth chart.13 Baseline blood investigations, including a Complete Blood Count, Liver Function Test, Kidney Function Test, Serum Lactate levels, coagulation profile, and inflammatory markers such as C-Reactive Protein, Serum Ferritin, and Lactic Dehydrogenase, will be conducted on both groups of critically ill children. These assessments will occur on Day 0, which corresponds to the day of admission, and on Day 3, precisely 72 hours after admission, for both groups—before and after the administration of Vitamin D in Group B. The multiorgan dysfunction will be assessed by Pediatric Logistic Organ Dysfunction Logistic-2 (PELOD-2) scoring system on day 0 and day 3.

The magnitude of requirement of ionotropic support will be assessed by Vasoactive-Ionotropic Score,14 the maximum score will be considered for comparison in both the groups. Acute Kidney Injury will be defined based on Urine Output and serum creatinine level as per Pediatric RIFLE criteria.15

The outcome of both the groups in form of number of days of Paediatric Intensive Care Unit stay, duration of mechanical ventilation, occurrence of Hospital acquired infection like Ventilator Associated Pneumonia and Central Line Associated Blood Stream Infection, Acute Kidney Injury, Multiorgan dysfunction, maximum Vasoactive-Inotrope Score and mortality will be noted and compared in both the groups. End of the study will be considered at the day of discharge from the hospital or mortality of the patient. Results and interpretation will be determined on the basis of the obtained observation. The methodology is been depicted in a flowchart in Figure 1.

dc5eba80-f3e4-47aa-8faf-a911a32aca3a_figure1.gif

Figure 1. Flowchart depicting the methodology of the proposed study.

Statistical analysis

Data analysis for this open-label randomized control trial will utilize STATA 12 software, while Microsoft Excel 2007 will be employed for generating graphs. The statistical analysis plan encompasses a thorough evaluation of baseline characteristics, primary and secondary outcomes, nutritional status, blood investigations, and severity scores. Descriptive statistics will succinctly summarize baseline characteristics, and comparative analyses will employ suitable statistical tests for assessing differences between Group A (standard dosing) and Group B (single high-dose supplementation). Time-to-event analysis will scrutinize PICU stay duration and mortality, and subgroup analyses may delve into variations based on relevant factors. Addressing missing data will follow specified methods, with statistical software such as R or SAS being utilized. Hypothesis testing will adhere to a significance level of 0.05, and ethical considerations will uphold unbiased reporting. The detailed plan delineates transparent methodologies for data analysis, providing a sturdy framework for interpretation.

Study status

The recruitment of the children began on 01 April 2023. As of publication, 16 patients have been included and randomized into Group A and Group B.

Discussion

In the realm of literature, the well-established benefits of Vitamin D as a fat-soluble vitamin in calcium and bone metabolism are widely recognized. However, its pleiotropic functions and steroid hormone-like actions remain relatively lesser known. Recent research studies are shedding light on these less-explored facets of Vitamin D. Notably, Vitamin D exhibits immunomodulatory functions by regulating cellular proliferation, differentiation, apoptosis, and angiogenesis, which can hold significant implications for critically ill children.

Numerous studies have investigated the outcomes of critically ill children with Vitamin D deficiency, yet the impact of Vitamin D supplementation on these children is less explored. In an interventional study conducted by Yung Wang et al.,16 a supplementation of 150,000 IU of Vitamin D in septic children deficient in Vitamin D resulted in improved outcomes. El Gendy et al.,17 in an observational study, identified an association between lower 25(OH) D levels and sepsis in Vitamin D-deficient children, emphasizing the prevalence of Vitamin D deficiency in critically ill children with sepsis.

Labib et al.18 further contributed to the discourse by conducting a double-blinded placebo-controlled randomized control trial, focusing on the outcome of Vitamin D supplementation in deficient children with pneumonia. However, these studies categorized their participants based on specific ailments. In contrast, our study aims to encompass all Vitamin D-deficient critically ill children, regardless of their specific illnesses, addressing a notable research gap.

The primary objective of our study is to determine the outcomes in Vitamin D-deficient critically ill children following supplementation. Given the widespread availability, good tolerability, and cost-effectiveness of Vitamin D supplements, incorporating them into our Pediatric Intensive Care unit protocol could potentially offer a novel avenue to enhance the short-term outcomes of these children.

Ethics approval and consent to participate

The institutional ethics committee has granted the permission to conduct the study with reference number - DMIMS (DU)/IEC/2022/207. Consent will be obtained from all the participants in the local language while enrolling them in the study.

Data availability

No data are associated with this article.

Comments on this article Comments (1)

Version 2
VERSION 2 PUBLISHED 19 Mar 2024
Revised
Version 1
VERSION 1 PUBLISHED 29 Aug 2023
Discussion is closed on this version, please comment on the latest version above.
  • Reader Comment 30 Nov 2023
    DINESH HINGE, PEDIATRICS, JAWAHRLAL NEHARU MEDICAL COLLEGE,SAWANGI MEGHE ,WARDHA, WARDHA, India
    30 Nov 2023
    Reader Comment
    Very useful and interesting
    Competing Interests: No competing interests were disclosed.
  • Discussion is closed on this version, please comment on the latest version above.
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Vagha K, Lohiya S, Vagha J et al. Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Research 2024, 12:1047 (https://doi.org/10.12688/f1000research.138765.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
VERSION 2
PUBLISHED 19 Mar 2024
Revised
Views
2
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Reviewer Report 16 Apr 2024
Tushar Jagzape, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Raipur, Chhattisgarh, India 
Approved
VIEWS 2
The revision made are satisfactory and addresses the major concern which was raised previously. 
The following one more modification should be done in the study protocol, so that the results are not biased and the patient in control group ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Jagzape T. Reviewer Report For: Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Research 2024, 12:1047 (https://doi.org/10.5256/f1000research.163598.r257336)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Views
4
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Reviewer Report 02 Apr 2024
Dayre McNally, University of Ottawa, Ottawa, Canada 
Approved with Reservations
VIEWS 4
Thanks for resending. 

I have a few suggestions for this article and study:

1. I suggest the authors indicate what outcome is their primary outcome. As of now they have a list of "primary" ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
McNally D. Reviewer Report For: Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Research 2024, 12:1047 (https://doi.org/10.5256/f1000research.163598.r257337)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 1
VERSION 1
PUBLISHED 29 Aug 2023
Views
10
Cite
Reviewer Report 05 Oct 2023
Dayre McNally, University of Ottawa, Ottawa, Canada 
Approved with Reservations
VIEWS 10
This study will add value to the field. Congrats to the team for identifying this question and seeking to help provide an answer. 

However, there  are aspects of the report that warrant clarification. See comments below. In ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
McNally D. Reviewer Report For: Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Research 2024, 12:1047 (https://doi.org/10.5256/f1000research.151991.r205666)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 04 Apr 2024
    Keta Vagha, Pediatrics, Jawaharlal Nehru Medical College, Wardha, 442001, India
    04 Apr 2024
    Author Response
    I wish to express my sincere gratitude for your thoughtful review of the manuscript. Rest assured, I highly value your insights, and I am committed to incorporating all of your ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 04 Apr 2024
    Keta Vagha, Pediatrics, Jawaharlal Nehru Medical College, Wardha, 442001, India
    04 Apr 2024
    Author Response
    I wish to express my sincere gratitude for your thoughtful review of the manuscript. Rest assured, I highly value your insights, and I am committed to incorporating all of your ... Continue reading
Views
17
Cite
Reviewer Report 20 Sep 2023
Tushar Jagzape, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Raipur, Chhattisgarh, India 
Not Approved
VIEWS 17
The researchers are doing a randomized controlled trial (open label) to study the effect of single high dose of vitamin D in vitamin D deficient children admitted to the Pediatric intensive care unit. 
Following are my observations: 
    ... Continue reading
    CITE
    CITE
    HOW TO CITE THIS REPORT
    Jagzape T. Reviewer Report For: Study protocol for supplementation of single high dose Vitamin D in deficient critically ill children and assessment of their short-term outcome: An open label randomized control trial [version 2; peer review: 1 approved, 1 approved with reservations]. F1000Research 2024, 12:1047 (https://doi.org/10.5256/f1000research.151991.r202369)
    NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
    • Author Response 04 Apr 2024
      Keta Vagha, Pediatrics, Jawaharlal Nehru Medical College, Wardha, 442001, India
      04 Apr 2024
      Author Response
      I would like to express my sincere appreciation for your thoughtful review of the manuscript. I would like to address a few misunderstandings regarding the drafting of the manuscript:

      ... Continue reading
    COMMENTS ON THIS REPORT
    • Author Response 04 Apr 2024
      Keta Vagha, Pediatrics, Jawaharlal Nehru Medical College, Wardha, 442001, India
      04 Apr 2024
      Author Response
      I would like to express my sincere appreciation for your thoughtful review of the manuscript. I would like to address a few misunderstandings regarding the drafting of the manuscript:

      ... Continue reading

    Comments on this article Comments (1)

    Version 2
    VERSION 2 PUBLISHED 19 Mar 2024
    Revised
    Version 1
    VERSION 1 PUBLISHED 29 Aug 2023
    Discussion is closed on this version, please comment on the latest version above.
    • Reader Comment 30 Nov 2023
      DINESH HINGE, PEDIATRICS, JAWAHRLAL NEHARU MEDICAL COLLEGE,SAWANGI MEGHE ,WARDHA, WARDHA, India
      30 Nov 2023
      Reader Comment
      Very useful and interesting
      Competing Interests: No competing interests were disclosed.
    • Discussion is closed on this version, please comment on the latest version above.
    Alongside their report, reviewers assign a status to the article:
    Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
    Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
    Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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