• Canadian Critical Care Trials Group
    The Canadian Critical Care Trials Group (CCCTG) is a highly collegial group that is dedicated to the pursuit of excellence and advancement of critical care research in Canada.
  • Canadian Critical Care Trials Group
    The CCCTG has are more than 30 research programs underway and over 100 peer-reviewed publications to its credit, with direct impact on clinical practice in critical care.
  • Canadian Critical Care Trials Group
    The Canadian Critical Care Trials Group (CCCTG) is a national organization of more than 300 individuals with research interests in the management of the critically ill patient.
  • Canadian Critical Care Trials Group
    Endorsement by the CCCTG communicates our full commitment to ensure that the work is undertaken in a rigorous and ethical manner, and communicated in a timely and effective way.
Programs

Principal Investigator(s)

Dayre McNally

Coordinator(s)

Katie O’Hearn

Status

Completed

VITdAL-PICU - Rapid normalization of vitamin D in critically ill children

Rapid normalization of vitamin D in critically ill children: a phase II dose evaluation randomized controlled trial (VITdAL-PICU pilot)

Population and problem: Critical illness occurs in tens of thousands of children each year in North America. In addition to death, these children are at risk for significant suffering, prolonged periods of rehabilitation and chronic illness. Roles for vitamin D in calcium homeostasis, cardiovascular and respiratory health, inflammation, innate immunity, and neuromuscular function have led to the recent hypothesis that deficiency might represent a modifiable risk factor for outcomes in critical illness. Multiple adult and pediatric studies have reported high vitamin D deficiency rates, and associations between lower vitamin D levels and organ dysfunction, health resource utilization, and mortality. For example, our multicentre study of critically ill Canadian children determined that 70% were vitamin D deficient and lower levels were associated with a 2-fold higher odds of heart dysfunction, ventilatory support, and ICU duration1. Optimization of vitamin D status in PICU patients could represent a simple, inexpensive and safe means of improving outcomes and reducing spending.

Knowledge gaps to address problem: Before these new findings can be translated into clinical practice a number of knowledge gaps should be addressed:
1. No interventional studies have established that prevention and/or rapid repletion of vitamin D improves outcomes in any PICU population. A single phase III study on critically ill adults2, suggested a reduction in mortality with a 540000 IU enteral load.
2. Attempts to perform large outcome based RCTs in any PICU population would be premature as no dosing regimens that safely prevent and/or replete vitamin D status have been identified.
3. Although clinical trial data from healthy children clearly demonstrate that age-based daily and loading therapy regimens are safe, extrapolation of these findings to critically ill children may not be appropriate. 

Description of project(s):
The essential next step is the completion of a pilot dose evaluation RCT to determine whether repeated weight based enteral loads of vitamin D, will rapidly and safely normalize vitamin D levels in critically ill children

Methodology and progress to date: To properly develop the protocol for rapid normalization of vitamin D in critically ill children we completed a systematic review and meta-analysis of all high dose pediatric clinical trials3. Based upon our analysis of 100 clinical trials we determined that 10000 IU/kg (maximum 400000 IU) was the most appropriate regimen to evaluate in a pilot RCT. Recruitment was initiated in January 2016 and completed in August 2017. A total of 67 patients were randomized across 4 international centres.

Significance/Knowledge Translation: Information obtained from the proposed studies (25OHD levels achieved, adverse events, and recruitment) will be used to determine the suitability of the protocol for a phase III trials. We will share our new knowledge with both the Canadian Critical Care community through the CCCTG, and ICU researchers worldwide to determine how to proceed with one or more multicenter phase III studies. Despite representing pilot studies, given the absence of other data, the results will be of immediate value to physicians caring for children with CHD and critical illness.

References:
  1. McNally JD, Amrein K, O’Hearn K, Fergusson D, Geier P, Henderson M, Khamessan A, Lawson M, McIntyre L, Redpath S, Weiler H, Menon K. “Study Protocol for a Phase II Dose Evaluation Randomized Controlled Trial of Cholecalciferol in Critically Ill Children with Vitamin D Deficiency (VITDAL-PICU). Pilot and Feasibility Studies. 2017; 3: 70. Doi: 101186/s40814-017-0214-z (PMID: 29234503).
  2. McNally JD, Nama N, O’Hearn K, Sampson M, Amrein K, Iliriani K, McIntyre L, Fergusson D, Menon K. “Vitamin D deficiency in critically ill children: A systematic review and meta-analysis”. Critical Care. 2017; 21(1):287. Doi 10.1186/s13054-017-1875-y (PMID: 29169388).
  3. McNally JD, Iliriani K, Pojsupap S, Sampson M, O’Hearn K, McIntyre L, Fergusson D, Menon K. “Rapid normalization of vitamin D levels: A meta-analysis”. Pediatrics. 2015; 135(1): e152-e166. (PMID: 25511115) *Impact Factor: 5.5
  4. McNally JD, Menon K, Chakraborty P, Fisher L, Williams KA, Al-Dirbashi OY, Girolamo T, Maharajh G, Doherty DR. "Impact of Anesthesia and Surgery for Congenital Heart Disease on the Vitamin D Status of Infants and Children: A Prospective Longitudinal Study" Anesthesiology. 2013; 14(5):462-6. (PMID: 23470437) *Impact Factor: 5.2
  5. McNally JD, Doherty DR , Lawson ML , Al-Dirbashi OY , Chakraborty P , Ramsay T , Menon K, "The relationship between vitamin d status and adrenal insufficiency in critically ill children", JCEM, 2013; 98(5):E877-81. (PMID: 23547046) *Impact Factor: 6.2.
  6. McNally JD, Menon K, Chakraborty P, Fisher L, Williams KA, Al-Dirbashi OY, Doherty DR, “The association of vitamin D status  with pediatric critical illness”, Pediatrics. 2012; 130(3)429-36. (PMID: 22869837) *Impact Factor: 5.5

Co-Investigators

Kusum Menon, Dean Fergusson, Lauralyn McIntyre, Patricia Fontela (Montreal), Anna Gunz (London), Karin Amrein (Austria), Margaret Lawson, Pavel Geier, Stephanie Redpath, Raul Bustos (Chile), Katie O’Hearn

Participating Centers

Children’s Hospital of Eastern Ontario (Ottawa, Canada)
London Health Sciences Centre (London, Canada)
Medical University of Graz (Graz, Austria)
Hospital Guillermo Grant Benavente (Concepcion, Chile)