A study to evaluate the effect of Calcium on the duration of blue light therapy required for the treatment of babies with jaundice
- Conditions
- Neonatal jaundice, unspecified,
- Registration Number
- CTRI/2022/03/041203
- Lead Sponsor
- Dr Arnab Ghorui
- Brief Summary
1. Title of the dissertation: Evaluation of efficacy of Oral Calcium Phosphate as an adjunct to standard of care regular phototherapy in cases of neonatal jaundice: A hospital based double blind randomized control trial.
2. Introduction:
Neonatal Hyperbilirubinemia:
Newborns are very prone to develop jaundice , approximately 85% of all term newborns and most of the preterm infants develop clinical jaundice, however most of them are physiological .[1] Hyperbilirubinemia in neonates results from varying contributions of multiple mechanisms such as increased bilirubin production from lysis of more RBCs as RBCs are more in them compared to adults, reduced lifespan of RBCs due to presence of fetal hemoglobin, decreased clearance of bilirubin by the immature hepatic enzyme system and increased reabsorptions by entero-hepatic circulations.[2] Increased entero hepatic circulation is due to deficiency of clostridium ramosum and over activity of beta glucuronidase in the gut, which rapidly de-conjugate conjugated bilirubin and unconjugated bilirubin being fat soluble crosses the gut wall and enter into entero hepatic circulation.[3] Stasis/delay in passage of meconium too increases enterohepatic circulation.
Bilirubin is a potent endogenous antioxidant preventing reactive oxidative damage, thus physiologic jaundice of newborn may act as natural protective mechanism. But
very high serum bilirubin (SB) can cause bilirubin induced neurological dysfunction (bilirubin encephalopathy) in some babies.[2,3] Thus among all the cases of
neonatal hyperbiliubinemia approximately 5 to 10% cases requires treatment to lower bilirubin level in order to prevent bilirubin induced neurological dysfunction.
[2] But as per recent studies newborn requiring phototherapy can goes up to 15- 23%.[4,5] Over the period of time different pharmacological and non-pharmacological
therapies had been tried for treatment of neonatal jaundice with different mechanism of action such as –
Pharmacological therapies:
a. Inhibiting Heme degradation - Metalloporphyrins [like- Tin-mesoporphyrin(SnMP), Chromium mesoporphyrin(CrMP)], D-Penicillamine , IV IG
b. Increasing conjugation of bilirubin – Phenobarbital, Clofibrate
c. Agents to decrease the entero-hepatic re-circulation of bilirubin – Oral charcoal, Agar
Non Pharmacological therapies:
Exchange transfusion
Phototherapy
But among all these, phototherapy remains the mainstay of treatment. Although phototherapy was developed in late 1950s but it took long time to prove its scientific efficacy over exchange transfusion; which finally came from a randomized control trials in 1968.[6,7] There after phototherapy was introduced in clinical practice in the 1970s.[6] Since then Phototherapy is the mainstay of treatment for hyperbilirubinemia in neonates for the past 50 years.[8] Phototherapy acts by converting water insoluble unconjugated bilirubin into water soluble isomers by using blue green light of wavelength between 460 – 490 nm that can be excreted via urine and faces. Phototherapy acts by multiple mechanism such as configurational isomerization also known as photo isomerism (Z isomer of bilirubin are converted into E isomers), structural isomerization (Bilirubin converted into lumirubin) and photo oxidation. Out of all these structural isomerization is the main mechanism of action. For effective phototherapy there should be maximum exposure, minimal interruption, adequate hydration, 460-490 nm wave length light source and distance between baby and light to be kept between 30 – 45 cm, with minimum irradiance of 30 microWatt/cm²/nm [8]. Although phototherapy is not associated with any major side effects but it may cause some side effects such as dehydration, hyperthermia, skin rashes and hypocalcemia. Phototherapy leads to decreased level of melatonin in blood, decrease in melatonin in blood leads to decreased production of corticosterone ,which in turn leads to decreased bone resorption, resulting in hypocalcemia.[1,9] Increased urinary excretion of calcium during phototherapy can also attribute to hypocalcemia.[10]
Calcium phosphate
Amorphous calcium phosphate have property of selectively bind to unconjugated bilirubin (fat soluble) in a dose dependent manner and covert into ionic compound which can’t cross the intestinal wall, thus it acts as trapping agent for bilirubin in the intestine.[11,12] In case of marked unconjugated hyperbilirubinemia such as as Crigler Najjar syndrome type I, Crigler Najjar syndrome type II, and other defects of UDP glucuronosyl transferase(UGT) enzyme as well as other conditions considerable amount of unconjugated bilirubin diffuse from the blood across the intestinal wall into the intestinal lumen .[12] In its pharmacodynamic action oral calcium phosphate acts as a trapping agent for bilirubin in the intestinal lumen, therefore it prevents back diffusion of bilirubin from intestinal lumen into the blood via entero-hepatic circulation.[13] Normally around 10-20% bilirubin enter into entero-hepatic circulation [3], thus with use of oral calcium phosphate we can expect 10-20% fall in bilirubin load , to which the hepatic conjugation system or phototherapy needs to deal with. Thus theoretically (in principle) calcium phosphate promises to be a good adjuvant to phototherapy. Calcium phosphate is not associated with any major systemic side effect .[13] Rather it’s is useful in prevention of hypocalcemia as newborns undergoing phototherapy are at high risk of developing hypocalcemia and preterm newborns having additional risk of hypocalcemia due to premature termination of transplacental supply of calcium.[2] Thus using Calcium Phosphate as an adjunct appears to be an exciting prospect in unconjugated hyperbilirubinemia.
A. Problem statement: Newborns are very prone to develop jaundice, approximately 85% of all term newborns and most of the preterm infants develop clinical jaundice. Very high serum bilirubin can cause bilirubin induced neurological dysfunction in some newborns. Among all the cases of neonatal hyperbiliubinemia approximately 5 to 10% cases requires treatment to lower bilirubin level in order to prevent bilirubin induced neurological dysfunction. But as per recent studies newborn requiring phototherapy can goes up to 15- 23%. Phototherapy is the mainstay of treatment for hyperbilirubinemia. Though phototherapy is not associated with any serious side effects but it definitely prolongs the hospital stay, interference with maternal-infant interaction and adds to financial burden.
B. Rationale: Though phototherapy is not associated with any serious side effects but it definitely prolongs the separation of baby from mother and hospital stay, thus has psychosocial and financial implications too. The average duration of phototherapy required to bring two consecutive serum total bilirubin levels less than the cut-off for the age in hours and risk profile , measured 6 hours apart for a non haemolytic jaundice about 25 to 26 hours [14] .We are expecting 10-20% fall in serum bilirubin with oral calcium phosphate supplementation, thus addition of oral calcium phosphate can reduce the duration of phototherapy by approx. 10-20%. Thus it can bring the average duration of phototherapy under 24 hours, helping us to reduce the financial burden for the parents also. So, calcium phosphate can be considered as an adjunct to regular phototherapy, which might reduce the duration of phototherapy, chances of rebound hyperbilirubinemia, and also financial burden for the parents.
C. Novelty:
1. Till now there have been only one study from worldwide but there had been no study from India on usage of oral calcium phosphate in neonates for treatment of neonatal jaundice.
2. In the previous study from Iran in the year 2021, only term newborns were included ,and did not determine the incidence of rebound hyperbilirubinemia; but in our study we are including all, term as well as preterm and post-term newborns, along with this in our study we are also determining the incidence of rebound hyperbilirubinemia.
3. In the previous study from Iran referred above, oral calcium gluconate dose used was of 50mg/kg/day but in this study we propose to use calcium phosphate at a dose of 75-80 mg/kg/day (range in order to make the dose as whole number)
D. Expected outcome and application:
a. Oral calcium phosphate likely to reduce SB faster and hence reduce the duration of phototherapy.
b. Oral calcium phosphate expected to reduce the chances of rebound hyperbilirubinemia. And thus, oral calcium phosphate can be a useful adjunct to phototherapy in treatment of neonatal jaundice.
G. Aim and objectives:
Aim:
i) To evaluate the effect of oral calcium phosphate on the duration of phototherapy in cases of neonatal jaundice.
ii) To evaluate the effect of oral calcium phosphate supplementation on rebound hyperbilirubinemia post phototherapy.
Objectives:
I. Primary objective(s): To evaluate the efficacy of oral calcium phosphate as an adjunct to standard of care phototherapy as compared to regular standard of care phototherapy alone in reducing the duration of phototherapy.
II. Secondary objective(s): To compare the incidence of rebound hyperbilirubinemia post phototherapy in both the groups.
**H.****Review of literature:****(up to 1000 words):**
Newborns are very prone to develop jaundice , approximately 85% of all term newborns and most of the preterm infants develop clinical jaundice .[1]. Hyperbilirubinemia in neonates results from varying contributions of multiple mechanisms such as increased bilirubin production from degradation of immature RBCs, decreased clearance of bilirubin by the immature liver and increased reabsorptions by entero-hepatic circulations. Phototherapy was developed in late 1950s but it take long time to prove its scientific efficacy over exchange transfusion; finally it came from a randomized control trial in 1968.[6,7]There after phototherapy was introduced in clinical practice in the year 1970s[6], since then Phototherapy is the mainstay of treatment for hyperbilirubinemia in neonates for the past 50 years.[8]
Over the period of time different pharmacological and non-pharmacological therapies had been tried for treatment of neonatal jaundice with different mechanism of action such as –
Pharmacological therapies:
a. Inhibiting Heme degradation- Metalloporphyrins [like- Tin-mesoporphyrin(SnMP), Chromium mesoporphyrin(CrMP)], D-Penicillamine ,IV IG.
b. Increasing conjugation of bilirubin – Phenobarbital, Clofibrate
c. Agents to decrease the entero-hepatic re-circulation of bilirubin – Oral charcoal, Agar
Non Pharmacological therapies:
Exchange transfusion, Phototherapy
Despite all of these phototherapy remains the mainstay of treatment as because other treatments either ineffective or having major side effects.[13,16]
Even though the first trial on newborns has been published in 2021, the topic had always been a matter of interest in researchers.In the year 1995, Christa N. Van et al.
conducted a study on oral calcium phosphate as a treatment option for unconjugated hyperbirubinemia in gunn rats. Gunn rats does not have the enzyme required for
conjugation of bilirubin (UGT), thus they have unconjugated hyperbilirubinemia .In case of unconjugated hyperbilirubinemia some unconjugated bilirubin diffuse from
blood across intestinal wall into the lumen of intestine. In the study it was hypothesized that use of oral calcium phosphate acts as trapping agent for bilirubin in the
intestine thereby preventing back diffusion thus it helps to reduce blood bilirubin level. In the study also found that with high calcium phosphate diet there was
reduction of bilirubin level in blood by 30 to 50% in male gunn rats and 23% in female gunn rats at the same time, the fecal output of bilirubin was more than double in
the first 3 days. There was no difference in plasma concentration of calcium, phosphate and chloride in both the groups but plasma magnesium declined in the rats those
received oral calcium phosphate. [11]
Two year later in the year 1997, Christa N. Van *et al.* conducted another study to evaluate the effect of oral calcium phosphate supplementation on plasma bilirubin
levels in patients with Crigler Najjar syndrome. It was a double blinded cross over randomized control trial which included 5 patients of type I those were primarily
treated with Phototherapy and 6 patients of type II those were primarily treated with phenobarbital. There was significant decrease in serum bilirubin with use of oral
calcium phosphate in type I patients by about 18% +/- 6% but not in patients of type II disease. This could be explained by the fact that in Type I there is no conjugation
of bilirubin thus there is higher amount of unconjugated bilirubin, the substrate to bind for oral calcium phosphate. But in case of type II with use of phenobarbital
induces the UDP glucuronosyl transferase (UGT) enzyme activity by only 10 to 30% [17], so the level of unconjugated bilirubin, the substrate on which calcium
phosphate works is little bit less here. So, technically there should be some benefit, but in this study it is not clinically or statistically significant with this sample sample
size. [12]
M. Habibi et al. conducted a double blinded randomized control trial including 50 term neonates on comparison of the effect of phototherapy with oral calcium versus
phototherapy alone in the treatment of unconjugated hyperbilirubinemia in healthy term infants in Iran, published in the year 2021. Bilirubin levels were measured at
the beginning of hospitalization then at 24, 48 and 72 hours after hospitalization in both the groups. The mean total serum bilirubin showed a significant difference of
1.1mg/dl, 1.9mg/dl and 2.3mg/dl between intervention and control group at 24 hours, 48 hours, and at final assessment respectively.[18]
**I.****Methodology:**
A. Study design: Double blind, Randomized control trial.
Study Settings: NICU of AIIMS Patna, a tertiary care hospital setting.
B. Study participants
a. Inclusion criteria: All newborns of either sex with neonatal jaundice requiring phototherapy as per AAP/NICE guidelines.
b. Exclusion criteria:
1. Newborns kept on nil per mouth due to any cause.
2. Newborns with conjugated hyperbilirubinemia. (Direct bilirubin >2mg/dl or direct bilirubin is >20% of total serum bilirubin).
3. Newborns with renal anomalies on antenatal ultrasound.
4. Newborn at any point of time requiring calcium supplements or therapy for any medical indication.
c. Number of groups to be studied, identify groups after randomization
1 Intervention group: Newborns with neonatal jaundice those requiring phototherapy will receive oral calcium phosphate supplementation along with the standard of care phototherapy.
2 Control group: Newborns with neonatal jaundice those requiring phototherapy, will receive standard of care phototherapy.
C. Sampling :
a. Sampling population: All newborns admitted at AIIMS, Patna Paediatrics & Neonatology Department.
b. Sampling Frame: Admitted newborns those requiring phototherapy.
c. Sample size calculation:
According to the study by M. Habibi et al.[18], the mean total bilirubin in intervention group (phototherapy with oral calcium) was 10.1±1.3 mg/dl & mean total bilirubin in control group (phototherapy only) was 12.4±2.4 mg/dl in the final assessment.
Formula: n = (Zα/2+Zβ)**2**\*2\*σ**2** / d**2**
Where " n " is minimum sample size for each groups, " Zα/2 " is the critical value of the normal distribution at α/2(e.g. for a confidence level of 95%, α is 0.05 and the critical value Zα/2 is 1.96), " Zβ " is the critical value of the normal distribution at β (e.g. for a power of 80%, β is 0.2 and the critical value is 0.84), " σ**2**" is the population variance, and " d " is the difference we would like to detect.
So, according to this, we would need a minimum sample size of 40 in each groups (i.e, a total sample size of 80) to detect a minimum difference in the means of
(–) 2.3 mg/dl in between the Intervention and control groups at 95% confidence interval & 5% margin of error with 10% superiority margin and 10% drop out rate.
d. Sampling technique: Non- Probability consecutive sampling technique will be applied with complete enumeration over the study period.
*D.*Randomization details: Block randomization by using sealed envelope (<https://www.sealedenvelope.com/simple-randomiser/v1/lists> ).
E. Study procedure: The study to be done after IRC (Institutional Research Committee) approval, CTRI (Clinical Trials Registry-India) registration and IEC (Institutional Ethics Committee) approval. All newborns admitted at AIIMS, Patna in patient department will be examined clinically for jaundice. On clinical examination if there is suspicion that newborns might having high bilirubin level(according to kramer’s dermal rule[18]) and may need phototherapy, venous blood will be withdrawn and serum bilirubin levels (TSB, Direct SB) will be determined. Newborns requiring phototherapy and whose parents give informed consent, will be enrolled in the study. If TSB level is above phototherapy cut off considering the gestational age at birth, the risk factors (according to American Academic of Pediatrics (AAP) nomogram (<https://pediatrics.aappublications.org/content/114/1/297>) for phototherapy in newborn of 35 or more weeks of gestation [20] and National Institute for Health & Care Excellence (NICE) guidelines [(https://www.nice.org.uk/guidance/cg98/evidence/full-guideline-245411821)](file:///C:/Users/Arnab/Desktop/calcium/(https:/www.nice.org.uk/guidance/cg98/evidence/full-guideline-245411821)) for phototherapy in newborn of 34 weeks or less weeks of gestation[21] ) standard of care phototherapy will be started. All the antenatal USG scan will be reviewed, assessed for eligibility and newborns falling under exclusion criteria will be excluded from the study. Eligible newborns will be randomly allocated into intervention and control group by means of block randomization using sealed envelope (<https://www.sealedenvelope.com/simple-randomiser/v1/lists> ) and it will also serve the purpose of allocation concealment.Total and indirect bilirubin levels will be recorded at the beginning of phototherapy in both the groups.
In the Intervention group, oral calcium phosphate @ 75-80 mg/kg/day plus vitamin D3(200-800 IU) (range in order to make the dose as whole number) [22-25] will be supplied in liquid forms as drops, from the Department of Pharmacy, School of Pharmaceutical Education and Research, Jamia Hamdard, Delhi with acknowledgement of Department of Pharmacology, AIIMS, Patna, in a strength of (125mg calcium phosphate + 400 IU of vitamin D3 /ml) and it will be administered in four divided doses as per the weight of the child along with the standard of care phototherapy. In the control group standard of care phototherapy and Drop vitamin D3 (400IU/ml) will be administered at a dose similar to that of intervention group for the purpose of blinding as well as matching. Oral calcium phosphate is available in the form of tablet in combination with Vitamin D3 as Tab Ostocalcium plus (250 mg elemental calcium + 400IU of Vitamin D3), it will be converted into liquid form in a strength of (125mg calcium phosphate + 400 IU of vitamin D3 /ml) by mixing pulverized tablet with 1ml of distilled water and 1ml of drop D3 . Oral vitamin D3 is available as Drop Calcijoint D3 in a strength of (Vitamin 400IU/ml) both the drops will have same physical nature, and it will labeled as bottle A or bottle B by the Pharmacology department of AIIMS Patna which will be handling and supplying the drugs, and it will be kept with the NICU SNO, for the purpose of keeping the investigators blinded. As the new neonatal jaundice case is enrolled, participant ID number is allotted and randomized, using premade block randomization table by the department of Pharmacology, on getting information from pharmacology, the SNO will hand over the small bottle bearing the randomization number and participant ID containing the assigned medicine to the treating team, and it will be administered to the baby as per the weight of the baby, thus blinding and allocation concealment will be ensured. Total and indirect bilirubin levels will be determined from venous blood samples 6 hours after the starting of phototherapy in both the groups. Thereafter total and indirect bilirubin level will be determined from venous blood sample every 12 hourly in both the groups till it comes 2mg/dl below phototherapy cutoff for that hours of life (as per AAP nomograms/ NICE guidelines for phototherapy). After that total and indirect bilirubin level will be determined 6 hours after the stoppage of phototherapy to look for rebound hyperbilirubinemia. Finally rate of fall of bilirubin level and incidence of rebound hyperbilirubinemia 6 hours after phototherapy will be recorded for both the study groups and statistical analysis will be done.
Short procedure for preparation of drops:
One pulverized tablet Ostocalcium plus having 250 mg of elemental calcium phosphate and 400 IU of Vitamin D3 to be mixed with 400 µl of Polysorbate 80 and 1000 µl of Water q.s and 1000 µl of drop calcijoint D3 to make a drop having strength of (125mg+400IU/ml)
Vitamin D3 is available from the market as drop calcijoint D3 in the strength of 400IU/ml
The CONSORT flow chart is given below
Approval from IRC, CTRI registration and approval from IEC
All newborns admitted at AIIMS, Patna paediatrics & neonatology department will be examined clinically for jaundice as part of routine procedure.
On clinical examination if there is suspicion that newborn might having high bilirubin level(according to kramer’s dermal rule) and may need phototherapy, venous blood will be drawn and bilirubin level will be determined, if bilirubin level is above phototherapy cut-off (according to AAP nomogram & NICE guideline),then phototherapy will be considered.
Newborns those requiring phototherapy, and whose parents gives consent will be enrolled in the study.
Review of Antenatal USG scan, History and Clinical Examination to assess for eligibility.
Newborns will be excluded from our study if newborns falling under exclusion criteria and they will continue to get routine care
Eligible newborns will be randomly allocated into intervention and control group by means of block randomization table using sealed envelope plus it will also serve the purpose of allocation concealment. (<https://www.sealedenvelope.com/simple-randomiser/v1/lists> )
Total and indirect Bilirubin level will be noted at the beginning of phototherapy in both the groups
| | |
| --- | --- |
|Intervention Group:Weight appropriate dose of Drop calcium phosphate (calcium 125mg + vitamin D3 400IU /ml) will be administered in four divided doses along with standard of care phototherapy Control Group: Standard of care phototherapy and similar weight appropriate dose of drop vitamin D3 (Vitamin D3 400IU/ml) will be administered in four divided doses the purpose of matching as well as blinding
| Total & indirect bilirubin level will be determined from venous blood 6 hours after the starting of phototherapy Total & indirect bilirubin level will be determined from venous blood 6 hours after the starting of phototherapy
| Total & indirect bilirubin level will be determined from venous blood 12 hourly till it comes 2mg/dl below the phototherapy cutoff for that hours of life Total & indirect bilirubin level will be determined from venous blood 12 hourly till it comes 2mg/dl below the phototherapy cutoff for that hours of life
| Total and indirect bilirubin level will be determined 6 hours after the stoppage of phototherapy to look for rebound hyperbilirubinemia Total and indirect bilirubin level will be determined 6 hours after the stoppage of phototherapy to look for rebound hyperbilirubinemia
Hours of Phototherapy, rate of fall of bilirubin level and incidence of rebound hyperbilirubinemia will be compared between both the groups
F. Data collection methods including settings and periodicity:
i) At the starting of phototherapy: Total and Indirect bilirubin levels will be measured in both the groups along with this demographic profile , Gestational age , Hours of life will also be noted .
ii) After 6 hours of phototherapy: Total and indirect bilirubin levels will be measured in both the groups. If it found to be above age specific phototherapy cut off, then treatment (standard of care phototherapy +/- oral calcium phosphate) needs to be continued and to repeat total and indirect bilirubin levels every 12 hourly till it comes 2mg/dl below the age specific cut off for phototherapy as per AAP nomogram or NICE guidelines.
iii) 6 hours after stoppage of phototherapy: Total and Indirect bilirubin levels will be measured in both the groups to check for rebound hyperbilirubinemia.
iv)Total duration of phototherapy needed will be compared among both the groups.
v) Rate of fall of indirect bilirubin level (mg/dl/hour) will be compared among both the groups.
vi)Incidence of rebound hyper bilirubinemia will be compared among both the groups.
vii)Daily stool frequency and stool amount by means of diaper weight will be measured.
viii) Statistical analysis will be done as per statistical analysis plan.
G. If the clinical trial, whether registration with CTRI will be done: YES
H. Are the drugs/devices to be used approved for these indications by Drug Controller General of India (DCG-I)? (Enclose the approval letter for the drug/device from DCG-I for trial on humans or give undertaking to get the approval from DCGI; For all drugs and devices submit documents showing DCGI approval for the proposed indication of the study- NA
I. List of variables and their measurement methods with standardization techniques:
a. Independent variables:
Maternal:
1. Mother’s age at the time of pregnancy:
2. Comorbidities (Hypothyroid):
3. Blood group of mother:
4. ICT status of mother (if applicable):
5. Gestational age as per LMP:
6. Gestational age as per USG:
7. Birth Order:
8. Obstetric Score (G,P,L,A):
9. Mode of delivery (Vaginal / Instrumental /LSCS):
10. Indication of LSCS (if applicable):
11. Antenatal USG for any malformation:
Baby:
1. Date and time of birth:
2. Sex of the baby:
3. Birth weight:
4. Birth injuries (Cephalhematoma):
5. Congenital anomalies(Ano-rectal malformation):
6. Cord clamping (Early/Delayed):
7. Hour of life at which meconium passed :
8. Frequency of stool per day:
9. Colour of stool (Black/Greenish(Transitional)/Yellow):
10. Blood group of baby:
11. DCT status of baby:
12. TSB & DB level of baby (if clinical examination revels high level of jaundice):
13. Hour of life at which phototherapy started :
14. Requirements of Exchange transfusion / IVIG ( if any):
b. Outcome variables:
1. Rate of fall of bilirubin in mg/dl/hour.
2. Duration of phototherapy required in hours.
3. Incidence of rebound hyperbilirubinemia in proportion/percentage
c. Confounding and interacting variables:
1. Duration of Interruption of phototherapy during feeding: Matched group analysis.
2. Gestational age of the newborn at the time of birth: Regression analysis for Gestational age.
J. Data Collection & statistical analysis plan:
Collected data is entered in MS excel, coded and analysed for results (e CRF attached with)
· For analyses MS Excel and IBM SPSS (Statistical Package for the Social Sciences) Version 20 will be used
· All Continuous variables will be expressed as Mean ± SD, median if outliers present.
· All discrete variables will be expressed as Proportions
· Analysis of significance will be done using Chi-square test/Fischer’s exact test for discrete data, and Independent student’s t test or Mann Whitney test for continuous data, whichever is appropriate.
· All statistical analysis will be carried out at 95% Confidence intervals and Significance is attributed to P value of < 0.05.
a. Limitations of Study:
In our study we are not able to measure bilirubin level in faeces due to limitation in resources.
K. List risks and benefits of the study:
Risk: Calcium is a nutritional supplement prescribed in newborns, including preterms thus have minimal risk.
Benefits:
i) Calcium can be a low cost adjunct to routine phototherapy in treatment of neonatal jaundice, it can reduce both the duration of phototherapy and incidence of rebound hyperbilirubinemia.
ii) Average duration of phototherapy 25 to 26 hours and we expecting 10 to 20% fall in duration with oral calcium phosphate supplementation that means average duration of phototherapy can comes under 24 hours ,thus it can reduce the duration of hospital stay, financial costs/wages loss of the parents associated with the treatment.
L. Plagiarism Check: YES (1%)
N. Relevant references for the project:
(Minimum 10, Maximum 20) (In Vancouver style)
1. Eichenwald EC, Hansen AR, Martin C, Stark AR. Cloherty and Stark’s manual of neonatal car, New Delhi, Wolters Kluwer(India) Pvt Lt ; 2020.
2. Agarwal Ramesh, AIIMS Protocols in Neonatology Volume 1,Second Edition, Delhi, Noble Vision Medical Book Publishers ; 2019.
3. Riyaz A. Paediatric Gastroenterology & Hepatology, Forth Edition, Hyderabad, New Delhi: Paras Medical Publisher ; 2019.
4. Narang A, Gathwala G, Kumar P. Neonatal Jaundice: An Analysis of 551 Cases. INDIAN PEDIATRICS 1997;34:4.
5. Newman TB, Kuzniewicz MW, Liljestrand P, Wi S, McCulloch C, Escobar GJ. Numbers Needed to Treat With Phototherapy According to American Academy of Pediatrics Guidelines. PEDIATRICS 2009;123:1352–9.
6. Weiss EM, Zimmerman SS. A Tale of Two Hospitals: The Evolution of Phototherapy Treatment for Neonatal Jaundice. PEDIATRICS 2013;131:1032–4.
7. Lucey J, Ferreiro M, Hewitt J. Prevention of Hyperbilirubinemia of Prematurity by Phototherapy. Pediatrics 1968;41:1047–54.
8. Paul VK. GHAI Essential Pediatrics, Ninth Edition, New Delhi, CBS Publishers & Distributors Pvt Ltd; 2020.
9. Bhat JA, Sheikh SA, Wani ZA, Ara R. Prevalence of hypocalcemia, its correlation with duration of phototherapy and persistence in healthy term newborns after intensive phototherapy: A prospective observational hospital�’based observational study. 2019;4:5.
10. Taksande A, Selvam S. Side Effects of Phototherapy in Neonatal Hyperbilirubinemia. 2018;7.
11. Van Der Veere CN, Schoemaker B, Bakker C, Van Der Meer R, Jansen PL, Elferink RP. Influence of dietary calcium phosphate on the disposition of bilirubin in rats with unconjugated hyperbilirubinemia. Hepatology 1996;24:620–6.
12. Rapid association of unconjugated bilirubin with amorphous calcium phosphate. :11.
13. Van der Veere C, Jansen P, Sinaasappel M, Van der Meer R, Van der Sijs H, Rammeloo J, et al. Oral calcium phosphate: A new therapy for Crigler-Najjar disease? Gastroenterology 1997;112:455–62.
14. Kumar P, Murki S, Malik GK, Chawla D, Deorari AK, Karthi N, et al. Light-emitting diodes versus compact fluorescent tubes for phototherapy in neonatal jaundice: A multi-center randomized controlled trial. Indian Pediatr 2010;47:131–7.
15. Dennery PA. Pharmacological interventions for the treatment of neonatal jaundice. Seminars in Neonatology 2002;7:111–9.
16. Lester R, Schmid R. Intestinal Absorption of Bile Pigments: Bilirubin Absorption in Man. N Engl J Med 1963;269:178–82.
17. Rahman MA, Islam MSU, Tasnim N. Crigler Najjar Syndrome Type 2: a Case of Unexplained Jaundice in an Adult. Faridpur Med Coll J 2020;15:43–5.
18. Habibi M, Karbord A, Vahidi M, Rad FS. Comparison of the Effect of Phototherapy with Oral Calcium Versus Phototherapy Alone in the Treatment of Unconjugated Hyperbilirubinemia in Healthy Term Infants. 2021;6.
19. Kramer LI. Advancement of Dermal Icterus in the Jaundiced Newborn. Arch Pediatr Adolesc Med 1969;118:454.
20. Subcommittee on Hyperbilirubinemia. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. PEDIATRICS 2004;114:297–316.
21. National Institute for Health and Clinical Excellence. Neonatal jaundice (Clinical Guideline
May 2010):https://www.nice.org.uk/guidance/cg98/evidence/full-guideline-245411821
22. The Johns Hopkins Hospital (Baltimore, Maryland), editor. The harriet lane handbook. 22nd ed. Philadelphia: Elsevier; 2020.
23. WHO | Micronutrient supplementation in low-birth-weight and very-low-birth-weight infants [Internet]. WHO [cited 2021 Jun 28];Available from: http://www.who.int/elena/titles/supplementation\_lbw\_infants/en/
24. Abrams SA, Nutrition the CO. Calcium and Vitamin D Requirements of Enterally Fed Preterm Infants. Pediatrics 2013;131:e1676–83.
25. Khadilkar A, Khadilkar V, Chinnappa J, Rathi N, Khadgawat R, Parekh B, et al. Prevention and Treatment of Vitamin D and Calcium Deficiency in Children and Adolescents: Indian Academy of Pediatrics (IAP) Guidelines. INDIAN PEDIATRICS 2017;54:7.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Not Yet Recruiting
- Sex
- All
- Target Recruitment
- 80
All newborns of either sex with neonatal jaundice requiring phototherapy as per AAP(American Academic of Pediatrics)/NICE(National Institute for Health & Care Excellence) guidelines.
- 1.Newborns kept on nil per mouth due to any cause.
- 2.Newborns with conjugated hyperbilirubinemia.
- (Direct bilirubin >2mg/dl or direct bilirubin is >20% of total serum bilirubin).
- 3.Newborns with renal anomalies on antenatal ultrasound.
- 4.Newborn at any point of time requiring calcium supplements or therapy for any medical indication.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method To compare the rate of fall of total serum bilirubin in both the groups. Starting point- TSB at the beginning of phototherapy | Thereafter, TSB every 6th hourly | End point-When TSB comes 2md/dl below the phototherapy cut off for that hours of life
- Secondary Outcome Measures
Name Time Method Rate of fall of bilirubin in mg/dl/hour. Total serum bilirubin 6 hours after starting of phototherapy, then 12th hourly till total serum bilirubin comes 2mg/dl below the phototherapy cutoff for that hours of life Incidence of rebound hyperbilirubinemia in proportion/percentage 6 hours after stoppage of phototherapy
Trial Locations
- Locations (1)
All India Institute of Medical Sciences, Patna
🇮🇳Patna, BIHAR, India
All India Institute of Medical Sciences, Patna🇮🇳Patna, BIHAR, IndiaDr Arnab GhoruiPrincipal investigator8759948784arnabmck999@gmail.com