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Use of reflective materials during phototherapy for newborn infants with unconjugated hyperbilirubinaemia

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Versión publicada: 19 diciembre 2015 Historial de versiones

https://doi.org/10.1002/14651858.CD012011

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of reflective materials in combination with phototherapy compared with phototherapy alone for unconjugated hyperbilirubinaemia in neonates.

Background

Description of the condition

Neonatal jaundice occurs in about 60% of otherwise healthy newborn infants. Although most infants with jaundice recover without major morbidity, severe jaundice can lead to kernicterus, deposition of bilirubin in parts of the brain, resulting in permanent brain damage (AAP 2004).

When neonates develop jaundice during first week of life, it is because the newborn infant has an increased rate of breakdown of haemoglobin in the presence of immature liver function, leading to unconjugated hyperbilirubinaemia. This is considered to be part of a normal physiological process. Pathological jaundice may occur if there is increased haemolysis such as occurs when there is incompatibility between the mother and infant blood groups and can also occur when there is extravasation of blood during the delivery, resulting in, for example, cephalohematoma and subaponeurotic haemorrhage, both of which are haemorrhages into the scalp. Other causes include impaired conjugation, as in Gilbert’s Syndrome, and increased enterohepatic circulation, as seen in breast‐feeding jaundice. In certain populations, glucose‐6‐phosphate dehydrogenase deficiency is an important cause of pathological jaundice (Lu 1966; Singh 1986). These causes all result in an increase in unconjugated bilirubin and it is this form of bilirubin that can be treated with phototherapy. Conjugated hyperbilirubinaemia, regarded as a separate entity, is much less common, generally occurs later in the neonatal period, and is not treated with phototherapy.

Description of the intervention

Before phototherapy was discovered, the mainstay of treatment for hyperbilirubinaemia was blood exchange transfusion (BET). Although BET is effective in removing the bilirubin, it is associated with many complications, including those related to the use of blood products (infection, haemolysis of transfused blood), metabolic derangement (metabolic acidosis, deranged serum calcium), cardiorespiratory complications (arrhythmia, apnoea) and complications related to umbilical venous catheteristion.The morbidity of BET ranges from 5% to 10% and mortality ranges from 0% to 7% (Ip 2004).

Other modalities of treatment either have no effects (e.g. phenobarbitone) (Arya 2004; Murki 2005) or, if effective, only for very specific conditions, e.g. infusion of immunoglobulin (Alcock 2002).

Phototherapy has been used since 1958 for the treatment of neonatal hyperbilirubinaemia (Cremer 1958); it has been the mainstay of treatment since then.

The energy provided by light converts bilirubin to water soluble forms through two main processes. These processes are called photoisomerization and photo‐oxidation. They result in minor changes of the molecular structure that allow it to be excreted via the liver or kidneys without having to undergo the process of conjugation in the liver. Conjugation is the rate‐limiting step of normal bilirubin excretion and this is exacerbated by the relative liver immaturity of the newborn (Maisels 2008).

The rate of production of the water soluble forms of bilirubin is dependant firstly on the wavelength of light. It is most efficient if the light wavelength is within the range of 450 nm to 490 nm. Secondly, the intensity of the light is a factor. The rate of bilirubin conversion increases linearly with the intensity of the light from about 5 to 30 microWatt*cm‐2*nm‐1. It was initially perceived that light intensities higher than this did not appear to confer clinical benefits (Tan 1982). However, a study using light‐emitting diodes, found a linear relation between light irradiance in the range of 20 to 55 microWatt*cm‐2*nm‐1 and a decrease in bilirubin after 24 hours of therapy, with no evidence of a saturation point (Vandborg 2012). To achieve the maximal effective level of light intensity, more or stronger lights can be used and light sources can be brought as close as possible to the skin surface (Kang 1995). Thirdly, the surface area of the skin exposed to the light will affect the rate of bilirubin conversion.

Higher light intensities can be obtained by the use of multiple phototherapy units, but this increases the cost of phototherapy, and theoretically, has an increased potential to cause hyperthermia. Curtains made of reflective materials placed around the phototherapy unit (while infants are receiving phototherapy) have the potential to increase the irradiance.

How the intervention might work

Bright surfaces such as white cloth, mirrors and aluminium foil can reflect dispersed phototherapy light. Curtains made from reflective materials, would usually be attached to the phototherapy unit and hung around the infant's cot to capture light that might be dispersed away from the infant, and by their reflective nature, reflect it back on to the infant. This might increase the photo irradiance and hence result in increased bilirubin conversion. The reflective materials used may differ in their ability to reflect dispersed light. The expected increase in light intensity that reflective materials would provide is uncertain and has not been studied in detail. Such curtains may also reflect heat, and as such, increase the risk of hyperthermia. It is possible that such curtains could obstruct visibility of the infant and affect nursing observation, and feasibly, this obstruction could also affect mother‐infant bonding. When properly used, they should not confer an increased infection risk.

Why it is important to do this review

A recent Cochrane review suggests that light sources from light emitting diodes are as effective as conventional light sources (Kumar 2011). These lights are power efficient with low heat production and have an extremely long life‐span. (Kumar 2011). However, light emitting diodes are currently expensive and further data are needed on their safety. Therefore, conventional phototherapy is likely to continue to be used for some time to come. The reflective materials used with conventional phototherapy are inexpensive, and if found to increase intensity, and more importantly, the efficiency of phototherapy, and shorten the duration of treatment with little or no extra cost this would be important in resource‐constrained settings. The aim of this review is to systematically compile and assess available evidence from randomised or quasi‐randomised trials comparing the effect of phototherapy with and without reflective curtains.

This is the first review about this type of intervention.

Objectives

To assess the effects of reflective materials in combination with phototherapy compared with phototherapy alone for unconjugated hyperbilirubinaemia in neonates.

Methods

Criteria for considering studies for this review

Types of studies

We will include only randomised controlled trials (RCTs) and quasi‐RCTs. We will include only studies with individual participant allocation and will not include cross‐over studies.

Types of participants

We will include studies of term and preterm neonates up to the age of 14 days (for term infants) and 21 days (for preterm infants) with unconjugated hyperbilirubinaemia receiving phototherapy. We will not include studies solely focusing on neonates with relapsed hyperbilirubinaemia (rebound neonatal jaundice).

Types of interventions

We will include studies in which participants received phototherapy in combination with curtains made of reflective materials of any type in the treatment arm(s), and phototherapy alone in the comparison arm(s). The setup of the phototherapy units and its relation to the infants should be similar in both arms, except for the use of the reflective materials. The reflective materials used, are hung from overhead phototherapy units around the cot on at least the two long sides of the cot. If incubators are used, the surface of the reflective materials and the position should be similar as for their use in cots.

We will not include studies where phototherapy was given as fibreoptic phototherapy.

Types of outcome measures

Primary outcomes

  1. Decline in serum bilirubin levels per unit of time over the first four to eight hours, or until the first measurement of bilirubin (micromol/L per unit of time).

Secondary outcomes

  1. Duration of treatment with phototherapy (hours).

  2. Number of exchange transfusions within neonatal period.

  3. All‐cause mortality at discharge.

  4. Acute life‐threatening event (ALTE) during phototherapy.

  5. Cost of the intervention (since there may be a large variation depending on materials used and the type of phototherapy units used, we will adopt a purely descriptive approach for individual studies).

  6. Parental satisfaction (questionnaire based assessment, during or within a reasonable time after admission).

  7. Medical staff satisfaction (questionnaire based assessment, during or within a reasonable time after admission).

  8. Exclusive breast‐feeding on discharge.

  9. Partial breast‐feeding on discharge.

  10. Neurodevelopmental follow‐up.

  11. Actual measures of the light intensity on the infants skin during phototherapy.

Adverse Effects

  1. Dehydration (more than expected weight loss for the age during phototherapy or by clinical assessment.

  2. Hyperthermia (axillary temperature > 37.5 oC).

  3. Hypothermia (axillary temperature < 36.5 oC).

  4. Body rash.

  5. Bronze discolouration of the skin.

  6. Interference with mother‐infant interaction (through observational‐ or questionnaire‐based assessment).

  7. Adverse effects related to problems with observation of infant (e.g. intravenous line problems).

Search methods for identification of studies

We will use the standard search strategy of the Cochrane Neonatal Review Group (CNRG), as documented in the Cochrane Library. See the CNRG search strategy (http://neonatal.cochranehttp://neonatal.cochrane.org/resources‐review‐authors.org/resources‐review‐authors).

Electronic searches

We will use the standard search strategy for the Cochrane Neonatal Review Group. We will search the Cochrane Neonatal Review Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; latest issue), MEDLINE (from 1966 to date), EMBASE (from 1988 to date) and CINAHL (from 1982 to date) using the strategy shown in Appendix 1.

Search will be limited to publications in English Language.

Searching other resources

We will communicate with experts and search the reference lists of any identified reviews and included trials for references to other trials. We will also search abstracts and conference and symposia proceedings of the Perinatal Society of Australia and New Zealand, and other Paediatric Academic Societies (American Pediatric Society/Society for Pediatric Research and European Society for Paediatric Research) from 1990 to the current date. If we identify an unpublished trial, we will contact the corresponding investigator for information. We will consider unpublished studies or studies reported only as abstracts as eligible for review, if the methods and data can be confirmed by the author. We will also contact the corresponding authors of identified RCTs for additional information about their studies when further data are required.

Data collection and analysis

Selection of studies

The lead review author will perform the search for trials with the assistance of the Cochrane Neonatal Review Group. Two review authors (LCH and IJ) will independently screen the titles and abstracts obtained from the electronic searches to create a pool of eligible studies. The lead review author will obtain the full articles of the latter, which two review authors (HVR and LCH) will then independently scrutinise for relevance using a standardised eligibility form with a predefined inclusion criteria. Any disagreement will be handled by a third author (JJH). Possible duplicate publications will be assessed by comparing author names, location and setting, specific details of the intervention, numbers of participants and their baseline data, date and duration of study. We will obtain data sets that are as complete as possible. We will record the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009) and 'Characteristics of excluded studies' table.

Data extraction and management

For included studies, we will extract data concerning study identity (title, authors, reference), design, methodology, eligibility, risk of bias, clinical features of the participants, interventions and outcomes, and treatment effects, using a specially designed data extraction form. For studies that we initially considered eligible for inclusion, but which we excluded after reading the full report, we will document the reason for exclusion.

Two review authors (HVR and IJ) will independently extract and compare all data; they will resolve any discrepancies by discussion or by the judgement of a third author (JJH). Unresolved disagreements will be referred for arbitration by a third review author or mentor.

Assessment of risk of bias in included studies

Two review authors (HVR and IJ) will independently assess the risk of bias for each included trial using the Cochrane 'Risk of bias' tool; any disagreement(s) will be resolved by discussion.

We will assess risk of bias based on the following:

1. Sequence generation (checking for possible selection bias)

For each included study, we will categorise the method used to generate the allocation sequence as:

  • low risk (any truly random process, e.g. random number table, computer random number generator);

  • high risk (any non‐random process, e.g. odd or even date of birth, hospital or clinic record number);

  • unclear (not stated in the article).

2. Allocation concealment (checking for possible selection bias)

For each included study, we will categorise the method used to conceal the allocation sequence as:

  • low risk (e.g. telephone or central randomisation, consecutively numbered sealed opaque envelopes);

  • high risk (e.g. open random allocation, unsealed or non‐opaque envelopes, alternation, date of birth);

  • unclear (not stated in the article).

3. Blinding (checking for possible performance bias)

For each included study, we will categorise the methods used to blind study personnel from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes. We will categorise the methods as:

  • low risk, high risk or unclear for participants;

  • low risk, high risk or unclear for study personnel;

  • low risk, high risk or unclear for outcome assessors.

4. Incomplete outcome data (checking for possible attrition bias through withdrawal, dropouts, protocol deviations)

For each included study and for each outcome, we will describe the completeness of data, including attrition and exclusions from the analysis. We will note whether the study reported attrition and exclusions, the numbers included in the analysis at each stage (compared with the total randomised participants), reason for attrition or exclusion (where reported), whether there was balanced missing data across groups. Where the trial authors reported or supplied sufficient information, we will re‐include missing data in the analyses. We categorised the methods as:

  • low risk (e.g. no missing outcome data, missing outcome data balanced across groups);

  • high risk (e.g. numbers or reasons for missing data imbalanced across groups, 'as treated' analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk.

5. Selective reporting bias (checking for reporting bias)

For each included study, we will describe how we investigate the possibility of selective outcome reporting bias and what we found. We will assess the methods as:

  • low risk (where it is clear that the trial authors have reported all of the study's prespecified outcomes and all expected outcomes of interest to the review);

  • high risk (where the trial authors have not reported all the study's prespecified outcomes, they did not prespecify one or more reported primary outcomes, they reported outcomes of interest incompletely so that they cannot be used, study failed to include results of a key outcome that the authors should have reported);

  • unclear risk (no information provided or study protocol not available).

6. Other source of bias (checking for bias due to problems not covered by 1 to 5 above)

For each included study, we will describe any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early owing to some data‐dependent process). We will assess whether each study was free of other problems that could put it at risk of bias, as:

  • low risk;

  • high risk;

  • unclear risk.

We plan to explore the impact of the level of bias through undertaking sensitivity analyses if needed.

Quality of evidence

We will assess the quality of evidence for the main comparison at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2011a). This methodological approach considers evidence from RCTs as high quality that may be downgraded based on consideration of any of five areas: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias (Guyatt 2011a). The GRADE approach results in an assessment of the quality of a body of evidence in one of four grades: 1. high ‐ we are very confident that the true effect lies close to that of the estimate of the effect; 2. moderate ‐ we are moderately confident in the effect estimate (the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different); 3. low ‐ our confidence in the effect estimate is limited (the true effect may be substantially different from the estimate of the effect); 4. very low ‐ we have very little confidence in the effect estimate (the true effect is likely to be substantially different from the estimate of effect) (Schünemann 2013).

The review authors will independently assess the quality of the evidence found for the following outcomes identified as critical or important for clinical decision making.

  1. Decline in serum bilirubin levels per unit of time over the first four to eight hours, or until the first measurement of bilirubin (micromol/L per unit of time).

  2. Duration of treatment with phototherapy (hours).

  3. Number of exchange transfusions within neonatal period.

  4. All‐cause mortality at discharge.

  5. Acute life‐threatening event (ALTE) during phototherapy.

  6. Exclusive breast‐feeding on discharge.

In cases where we consider the risk of bias arising from inadequate concealment of allocation, randomised assignment, complete follow‐up or blinded outcome assessment to reduce our confidence in the effect estimates, we will downgrade the quality of evidence accordingly (Guyatt 2011b). We will evaluate consistency by similarity of point estimates, extent of overlap of confidence intervals and statistical criteria, including measurement of heterogeneity (I2 statistic). We will downgrade the quality of evidence if inconsistency across study results is large and unexplained (i.e. some studies suggest important benefit and others no effect or harm without a clinical explanation) (Guyatt 2011c). We will assess precision according to the 95% confidence interval (CI) around the pooled estimation (Guyatt 2011d). When trials were conducted in populations other than the target population, we will downgrade the quality of evidence because of indirectness (Guyatt 2011e).

We will enter data (i.e. pooled estimates of the effects and corresponding 95% CI) and explicit judgments for each of the above aspects assessed into GRADEProGDT, the software used to create 'Summary of findings' tables (GRADEproGDT 2015). We will explain all judgements involving the assessment of the study characteristics described above in footnotes or comments in the 'Summary of findings' table.

Measures of treatment effect

We will carry out data analysis using Review Manager 5 (RevMan 2014). If it is possible to conduct a meta‐analysis of identified trials, the effect measures for binary outcomes will be the risk ratio (RR), and risk difference (RD). For binary outcome(s), we will calculate the number needed to benefit (NNTB), or number needed to harm (NNTH) when the RD is statistically significant. For continuous outcomes, the effect measures will be the mean difference (MD). If scales of different lengths are used and we judge that the outcome measured is similar enough, we will used standardised mean difference. For all estimates, we will provide 95% CIs.

Unit of analysis issues

We do not anticipate any problems with unit of analysis issues.

Dealing with missing data

We will contact the respective investigators in cases where adequate information was not available within the papers.

Assessment of heterogeneity

If it is possible to conduct a meta‐analysis, we will estimate the amount of heterogeneity of treatment effect across trials using the I2 statistic. We will use the following cut‐offs and labels: < 25% no heterogeneity, 25% to 49% low, 50% to 74% moderate, and 75%+ high heterogeneity. If substantial heterogeneity is present, we will explore its source(s), taking into account differences in study design, participants and the interventions used in the trials. We will explore possible differences using the limited number of prespecified subgroup analyses (see Subgroup analysis and investigation of heterogeneity).

Assessment of reporting biases

We will create a funnel plot if there are 10 or more studies included in the meta‐analysis of the same outcome. If there is skewing with positive results being published and negative results not being published, we will report this and attempt to explain, recognising that not all funnel plot asymmetry is due to publication bias.

Data synthesis

We will use a fixed‐effect model for analysis as recommended by the Cochrane Neonatal Group (http://neonatal.cochrane.org/resources‐review‐authors). When meta‐analysis is appropriate, we will perform the analysis using RevMan 5 software supplied by Cochrane (RevMan 2014).

Subgroup analysis and investigation of heterogeneity

We will visually inspect the forest plot, if indicated. We will perform subgroup analyses, if possible, based on the following.

  • Types, sizes and configuration of different reflective materials (as stated by the authors).

  • The phototherapy methods and irradiance of units used in conjunction.

  • Preterm versus term gestational age (< 28 weeks, 28 to 32 weeks, > 32 weeks to 38 weeks and term).

  • Severity of baseline jaundice (≤ 340 mmol/L and > 340 mmol/L).

The exact cut‐offs we use for these subgroups will depend on the availability of subgroups in the included studies.

Sensitivity analysis

We will conduct a sensitivity analysis based on trial quality to test judgements made in our risk of bias assessment.