Vitamin A supplementation for cystic fibrosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine if vitamin A supplementation in children and adults with CF:
(1) reduces the frequency of vitamin A deficiency disorders;
(2) improves general and respiratory health;
(3) increases the frequency of vitamin A toxicity.
Background
Cystic fibrosis (CF) is a genetic disorder that affects multiple organs. Pancreatic insufficiency affects up to 90% of people with CF. Fat malabsorption occurs and pancreatic enzyme replacement is required to prevent steatorhoea and malnutrition (Dodge 2006). Fat soluble vitamins (A, D, E and K) are co‐absorbed with fat and thus deficiency of these vitamins may occur (Dodge 2006). Some CF centres routinely administer these vitamins as supplements from the neonatal period, whilst others administer them only later in life or when deficiencies are detected clinically or on routine monitoring. While deficiencies may occur from the disease process of CF and insufficient supplementation, vitamin toxicity may also occur from excess supplementation. Both deficiency and excess of these vitamins may lead to specific medical problems (Dodge 2006; Sethuraman 2006).
Vitamin A is an essential nutrient for epithelial cell maintenance and repair in the respiratory, urinary and intestinal tract, immune response, and bone growth (DAA 2006). Dietary vitamin A (retinol or retinol esters) is found in liver, beef, eggs, fish, the fat of dairy products and vitamin A fortified margarine. Beta‐ and alpha‐carotene can act as precursors for the synthesis of vitamin A. The dietary carotenoid (beta‐carotene) is found in red, orange, yellow and leafy green vegetables (e.g. carrots, sweet potato, silverbeet) and red and orange fruit (e.g. mangos, oranges).
Vitamin A deficiency can be defined as serum retinol (SROL) concentration less than 0.70 µmol/L (less than 20 µg/dl) (West 2003). However, SROL levels may be influenced by albumin and retinol binding protein (RBP) as well as acute illnesses with infection and inflammation (Napoli 1996; Stephensen 1994). SROL levels should be measured during clinical stability (DAA 2006).
The major consequence of vitamin A deficiency is ocular with abnormal dark adaptation (night blindness), conjunctival and corneal xerosis which can lead to blindness (DAA 2006; West 2003). Another consequence of vitamin A deficiency is the skin condition phrynoderma (a form of follicular hyperkeratosis associated with some micronutrient deficiencies). Vitamin A deficiency has also been linked to impaired mechanisms of host resistance to infection, poor growth and increased mortality in a study of mothers and children (West 2003).
Supplementation of these vitamins to excessive levels may cause harm to the respiratory and skeletal systems (osteoporosis and fractures) (Penniston 2006) in children with and without CF (Graham‐Maar 2006; Sethuraman 2006). The approach of addressing the possibility of the development deficiency of these fat soluble vitamins is variable among CF centres. Thus a systematic review on the efficacy of vitamins A, D, E and K supplementation in children and adults with CF in preventing effects of the deficiency of these vitamins would help guide clinical practice. Vitamins D, E and K supplementation will be addressed in other Cochrane Reviews. This review will evaluate vitamin A supplementation in children and adults with CF.
Objectives
To determine if vitamin A supplementation in children and adults with CF:
(1) reduces the frequency of vitamin A deficiency disorders;
(2) improves general and respiratory health;
(3) increases the frequency of vitamin A toxicity.
Methods
Criteria for considering studies for this review
Types of studies
Randomised (RCTs) and quasi‐randomised trials (controlled clinical trials).
Types of participants
Children or adults with CF (defined by sweat tests or genetic testing) with and without pancreatic insufficiency.
Types of interventions
All preparations of oral vitamin A used as a supplement compared to either no supplementation or placebo at any dose for at least three months.
Types of outcome measures
Attempts will be made to obtain data on at least one of the following outcome measures:
Primary outcomes
(1) Vitamin A deficiency disorders
(a) visual impairment
(b) any other ocular dysfunction
(c) skin manifestations (e.g. phrynoderma)
(2) Growth and nutritional status (e.g. weight, height, body mass index, z score for weight, etc.)
(3) Mortality
Secondary outcomes
(4) Respiratory outcomes
(a) bronchiectasis severity control (e.g. Likert scale, visual analogue scale)
(b) lung function indices (spirometry e.g. FEV1 and FVC)
(c) proportions of participants who had respiratory exacerbations or hospitalisations or both
(d) total number of hospitalised days or days off work or school
(5) Quality of life
(6) Adverse events (e.g. vomiting, loss of appetite, osteoporosis, fractures or any other adverse event noted)
(7) Possible toxicity events (e.g. liver dysfunction)
(8) Measured levels of vitamin A
All outcomes will be evaluated based on
(i) short term (12 months or less), and
(ii) medium to long term (longer than one year)
We plan to group outcome data into those measured at 3, 6 and 12 months and annually thereafter. If outcome data are recorded at other time periods, then consideration will be given to examining these as well.
Search methods for identification of studies
We will identify relevant trials from the Group's Cystic Fibrosis Trials Register using the term: vitamin A.
The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of EMBASE to 1995 and the prospective handsearching of two journals ‐ Pediatric Pulmonology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Conference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all searching activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group Module.
Searches of bibliographies and texts of selected studies will be conducted to identify additional studies.
Data collection and analysis
Selection of studies
From the title, abstract, or descriptors, two authors will independently review results of the literature searches to identify studies potentially relevant to the review according to our inclusion criteria for further assessment. From these studies, the same two authors will independently examine the papers in further detail in order to select studies for inclusion using the criteria stated before. The authors will resolve disagreement by consensus.
The authors will review studies that satisfy the inclusion criteria for the review and record the following information: study setting; year of study; source of funding; participant recruitment details (including number of eligible participants); inclusion and exclusion criteria; randomisation and allocation concealment method; numbers of participants randomised; blinding (masking) of participants, care providers and outcome assessors; dose and type of intervention; duration of therapy; co‐interventions; numbers of participants not followed up; reasons for withdrawals from study protocol (clinical, side effects, refusal and other); side effects of therapy; and whether intention‐to‐treat analyses were possible. The authors will extract data on the outcomes described previously and request further information from the primary investigators where required.
Two review authors will independently assess the quality of the studies included in the review according to the criteria described by Jüni (Jüni 2001):
Allocation concealment
Allocation concealment in each study will be assessed as follows:
(1) Adequate, if the allocation of participants involved a central independent unit, on‐site locked computer, identically appearing numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed opaque envelopes;
(2) Unclear, if the method used to conceal the allocation was not described;
(3) Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised.
Generation of the allocation sequence
Each study will be graded for allocation concealment as follows:
(1) Adequate, if methods of randomisation include using a random number table, computer‐generated lists or similar methods;
(2) Unclear, if the trial is described as randomised, but no description of the methods used to allocate participants to treatment group was described;
(3) Inadequate, if methods of randomisation include alternation; the use of case record numbers, dates of birth or day of the week, and any procedure that is entirely transparent before allocation.
Blinding (or masking)
Each study will be graded for blinding as follows:
(1) blinding of clinician (person delivering treatment) to treatment allocation;
(2) blinding of participant to treatment allocation;
(3) blinding of outcome assessor to treatment allocation.
Follow up
Each study will be graded as to whether numbers of and reasons for dropouts and withdrawals in all intervention groups were described; or if it was specified that there were no dropouts or withdrawals.
We will also report on whether the investigators had performed a sample‐size calculation and if they used an intention‐to‐treat (ITT) analysis.
Statistics
The results from studies that meet the inclusion criteria and reports any of the outcomes of interest will be included in the subsequent meta‐analyses if any data are applicable.
For the dichotomous outcome variables of each individual study, we will calculate the odds ratio (OR) using a modified ITT analysis, i.e. if ITT analysis was not used by the original investigators, dropouts will be considered failures. We will also calculate the summary weighted odds ratios and 95% confidence intervals (CIs) (fixed‐effect model) using the Cochrane Collaboration's statistical package (RevMan 2005). Numbers needed to treat (NNT) and their 95% CIs will be calculated from the pooled OR and its 95% CI for a specific baseline risk, which is the sum of all the events in the control groups (in all trials) divided by the total participant numbers in control groups in all trials using an online calculator (Cates 2003). For continuous outcomes, we will record the mean relative change from baseline for each group or mean post‐treatment or post‐intervention values and standard deviation. If standard errors are reported, we will calculate the standard deviations. We will then calculate a pooled estimate of treatment effect by the weighted mean difference and 95% confidence interval (fixed‐effect model) again using RevMan (RevMan 2005).
For cross‐over studies, we will calculate the mean treatment differences where possible and enter these using the fixed‐effect generic inverse variance (GIV) analysis in RevMan, to provide summary weighted differences and 95% CIs (RevMan 2005). In cross‐over studies, if we believe there is a carryover effect which will outlast any washout period included in the study, we will include only data from the first arm in the meta‐analysis (Elbourne 2002).
If studies report outcomes using different measurement scales, we will estimate the standardised mean difference and 95% CIs. We will describe any heterogeneity between the study results and test this to see if it reached statistical significance using the chi‐squared test. We will consider heterogeneity to be significant when the P value is less than 0.10 (Higgins 2006). We also plan to use the I2 statistic where heterogeneity is categorised such that a value of under 25% is considered low, around 50% is considered moderate and over 75% is considered a high degree of heterogeneity (Higgins 2003). We will include the 95% CI, estimated using a random‐effects model, whenever there are concerns about statistical heterogeneity. We plan to perform the following to investigate any heterogeneity which has been identified.
Subgroup analyses
The following a priori subgroup analyses are planned:
(1) children (aged 18 years or less) and adults (over 18 years);
(2) formulations of the vitamin (single or multivitamin);
(3) presence of significant liver synthetic dysfunction (low baseline albumin);
(4) presence of previous bowel resections;
(5) presence of pancreatic insufficiency;
(6) method of CF diagnosis (i.e. screening versus symptomatic diagnosis).
Sensitivity analyses
Sensitivity analyses are also planned to assess the impact of the potentially important factors on the overall outcomes:
(1) analysis using a random‐effects model
(2) analysis by "treatment received" (as opposed to ITT analysis)
