Just Accepted by The Journal of Maternal-Fetal & Neonatal Medicine Led Versus Daylight Phototherapy At Low Irradiance In Newborns ≥ 35 Weeks Of Gestation: Randomized Controlled Trial Danielle Cintra Bezerra Brandão, MD, Cecilia Maria Draque, MD, PhD, Adriana Sañudo, MS, Fernando Antonio Ribeiro de Gusmão Filho, MD, PhD, and Maria Fernanda Branco de Almeida, MD, PhD doi: 10.3109/14767058.2014.966678 Abstract
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Objective: To compare the decline in TSB after 24 h of LED or fluorescent phototherapy from below in breastfed neonates ≥35 weeks of gestation. Methods: 74 neonates treated with a 17-bulb blue LED were compared with 76 neonates treated with a 7-bulb daylight device in a rooming-in unit. Spectral irradiance was measured at 5 points on a 30 x 60 cm rectangle on the gel transparent mattress. Results: TSB of 14.0 1.2 mg/dL at 64 15 h after birth when starting phototherapy were similar in both groups. TSB declined by 0.16 ± 0.09 in the LED vs. 0.16 ± 0.08 mg/dL/hour in the daylight group after 24 h of therapy (p = 0.87). Mean irradiance (μW/cm2/nm) was 10.5 0.9 (32.5 at the central, 5.9 at the superior and 3.9 for the inferior points) in the LED vs. 8.7 0.6 (range, 8.3 to 9.8) in the daylight group (p < 0.001). Hypothermia (< 36.0°C) was more frequent in LED than in fluorescent (23% vs. 9%; p = 0.02) group. Conclusion: LED with heterogeneous irradiance was as effective as daylight phototherapy with homogeneous irradiance, however there is a greater need for rigorous control of the room temperature (NCT01340339).
© 2014 Informa UK Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
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TITLE PAGE LED versus DAYLIGHT PHOTOTHERAPY AT LOW IRRADIANCE IN NEWBORNS ≥
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35 WEEKS OF GESTATION: RANDOMIZED CONTROLLED TRIAL
Danielle Cintra Bezerra Brandão1, MD, Cecilia Maria Draque2, MD, PhD, Adriana Sañudo3, MS, Fernando Antonio Ribeiro de Gusmão Filho1, MD, PhD, and Maria Fernanda Branco de Almeida2, MD, PhD Affiliations: 1Professor Fernando Figueira Integral Medicine Institute (Instituto de Medicina Integral Professor Fernando Figueira – IMIP), Recife, PE, Brazil; 2Division of Neonatal Medicine, Federal University of São Paulo/Paulista School of Medicine (Universidade Federal de São Paulo/Escola Paulista de Medicina – EPM-UNIFESP), São Paulo, SP, Brazil; 3
Department of Preventive Medicine, Federal University of São Paulo/Paulista School of
Medicine (Universidade Federal de São Paulo/Escola Paulista de Medicina – EPM-UNIFESP), São Paulo, SP, Brazil,
Corresponding author: Maria Fernanda Branco de Almeida, MD, PhD, Rua Los Angeles, 40, 04564-030, São Paulo, SP, Brazil. Tel +55 (11) 5084-0535. Email [email protected].
Short title: LED phototherapy in breastfed newborns Keywords: bilirubin; hyperbilirubinemia, neonatal; jaundice, neonatal; breast feeding; hypothermia
ABSTRACT
2
Objective: To compare the decline in TSB after 24 h of LED or fluorescent phototherapy from below in breastfed neonates ≥35 weeks of gestation. Methods: 74 neonates treated with a 17-bulb blue LED were compared with 76 neonates treated with a 7-bulb daylight device in a rooming-in unit. Spectral irradiance was measured at 5 points
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on a 30 x 60 cm rectangle on the gel transparent mattress. Results: TSB of 14.0
1.2 mg/dL at 64
15 h after birth when starting phototherapy were
similar in both groups. TSB declined by 0.16 ± 0.09 in the LED vs. 0.16 ± 0.08 mg/dL/hour in the daylight group after 24 h of therapy (p = 0.87). Mean irradiance (μW/cm2/nm) was 10.5
0.9
(32.5 at the central, 5.9 at the superior and 3.9 for the inferior points) in the LED vs. 8.7
0.6
(range, 8.3 to 9.8) in the daylight group (p < 0.001). Hypothermia (< 36.0°C) was more frequent in LED than in fluorescent (23% vs. 9%; p = 0.02) group. Conclusion: LED with heterogeneous irradiance was as effective as daylight phototherapy with homogeneous irradiance, however there is a greater need for rigorous control of the room temperature (NCT01340339).
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INTRODUCTION Phototherapy units with light-emitting diodes (LEDs) have been used to emit highintensity light while generating little heat, in addition to offering low energy consumption and lasting durability [1-3]. While in vitro studies have found a greater reduction of bilirubinemia
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with blue LEDs [3-5], clinical trials have reported similar efficacy when compared with blue fluorescent or halogen lamps in neonates [6-11]. However, the variability of phototherapy units and the lack of a standard technique to measure spectral irradiance hamper the interpretation of patient treatments in these trials. Currently, researchers suggest clinical trials with standardised irradiance measurement methods on a homogenous population of neonates to obtain more solid scientific evidence on the efficacy of LED phototherapy [12-17]. In this context, the present study compares the decrease in total serum bilirubin (TSB) after 24 h of blue LED phototherapy with respect to daylight fluorescent phototherapy in breastfed newborns with a gestational age of ≥35 weeks, as well as adverse clinical events. METHODS Patients This randomised controlled clinical trial was performed at the public maternity rooming-in unit of the Professor Fernando Figueira Integral Medicine Institute (Instituto de Medicina Integral Professor Fernando Figueira – IMIP), Recife, PE, Brazil, in the period from October 2010 to June 2011. Breastfed newborns with a gestational age between 350/7 and 416/7 weeks, birth weight ≥ 2200 g, an Apgar score ≥ 7 in the fifth minute after birth, and a referral for phototherapy by the medical team between 48 and 120 h after birth were included. Patients were excluded from the study if they exhibited any type of congenital malformation or Rh hemolytic disease, were
4
moved to other units or if, due to randomisation, one of the phototherapy units was not available. The project was approved by the Research Ethics Committee of the institution, and all mothers signed the informed consent form. The study was registered as a clinical trial NCT 01340339.
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Intervention The randomisation was stratified into two groups by gestational age (350/7 to 376/7 weeks and 380/7 to 416/7 weeks) by means of drawing lots by a local health care professional unrelated to the study. Each large opaque and numbered envelope contained four small opaque, sealed and identical envelopes; each envelope had one type of phototherapy assignment, and each type of phototherapy was included twice. Treatment was indicated if, by 48 h after birth, TSB levels were 12-14 mg/dL in neonates with a gestational age of 35-37 weeks or 13-16 mg/dL in neonates with a gestational age of 3841 weeks [18]. Three employees with no involvement in the study were trained to measure TSB levels using a capillary tube with a BR-501 bilirubin meter (Apel, Kawaguchi, Japan), which was calibrated on a daily basis. The intervention was performed using a Bilitron Bed® unit (Fanem, São Paulo, Brazil) with 17 LED bulbs of wavelength range 400–520 nm in parallel and at a distance of 12 cm below the transparent acrylic bassinet, providing an illuminated area of 42 x 31 cm. The comparison was made with the Biliberço® unit (Fanem, São Paulo, Brazil), which had the transparent acrylic base positioned 5 cm above 7 TL 20 W fluorescent daylight lamp tubes (Osram, Osasco, Brazil) of wavelength range 380–770 nm and provided an illuminated area of 60 x 35 cm [19]. Both types of units possessed a curved acrylic overlay on the internal reflector surface. The spectral irradiance was measured before initiating treatment and after every 24 h of treatment using a 2620 radiometer (Fanem, São Paulo, Brazil), which absorbs light
5
between 400 and 500 nm. The spectral irradiance was measured at all four corners and at the central point of a 30 cm x 60 cm rectangle to calculate the mean value of the 5 measured points [16] and to obtain a standard irradiance between 8 and 12 μW/cm2/nm. The potency of the LED lamps was adjusted digitally in the Bilitron Bed® unit to maintain this irradiance, whereas
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fluorescent bulbs were substituted in the Biliberço® unit if the value was < 8 μW/cm2/nm. The newborns were laid on a transparent gel mattress wearing mini-diapers and opaque eye covers.
Primary and Secondary Outcomes The primary outcome consisted of determining the TSB level decrease rate, in mg/dL/h, after 24 h of phototherapy. If the newborn remained in therapy, TSB levels were re-assessed every 12 h to 24 h, and suspension of the phototherapy was indicated when the TSB value was ≤ 8 mg/dL or ≤ 11 mg/dL in newborns with a gestational age of 350/7 to 376/7 or 380/7 to 416/7 weeks, respectively. Secondary outcomes included the total time in phototherapy, the reintroduction of therapy after 18 h to 24 h of suspension and/or the need for intensive phototherapy with 30 μW/cm2/nm irradiance or exchange transfusion [18]. Intensive phototherapy was performed by adding conventional overhead phototherapy using the Octofoto 006 OFL unit (Fanem, São Paulo, Brazil), with eight special blue fluorescent bulbs, to the phototherapy from below. During treatment, adverse events comprised the detection of a maximum weight loss with respect to birth weight, episodes of hyperthermia (> 37.5°C) or hypothermia (< 36.0°C). Newborns were weighed daily, and axillary and room temperatures were recorded every 6 h using digital thermometers (Incoterm®, São Paulo, Brazil).
Statistical Analysis
6
The sample size of 73 patients for each group was calculated considering a decrease in the TSB by 30% after 24 h of treatment with LED lamps [8], with a significance level of 5% and a power of 80%. Comparisons between groups were performed by means of Student’s t, the Mann-Whitney U, chi-squared or Fisher’s exact test, in addition to the evaluation of the duration
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of the phototherapy by means of Kaplan-Meier curves (log-rank test), using the statistics software SPSS 17.0 and considering significance at p < 0.05.
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RESULTS During the period of this study, 1,914 newborns with a gestational age between 350/7 and 416/7 weeks were admitted to the rooming-in unit, of which 154 were randomised to the LED (n = 74) and fluorescent (n = 76) groups, with 4 losses: 3 neonates were excluded because they
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had been removed from the unit before the end of treatment and 1 was excluded due to a mistake in the eligibility criteria. Table I shows the similarities between the maternal and neonatal characteristics in both treatment groups. A 27% decrease in TSB was achieved after 24 h of treatment in both types of units (Table II). In one newborn from the LED group, phototherapy was re-introduced after suspension, and one patient from the fluorescent group needed intensive phototherapy. None of the neonates reached TSB levels requiring exchange transfusion. Considering the gestational age range, the 68 neonates between 350/7 and 376/7 weeks initiated therapy within 68 ± 15 h at TSB levels of 13.6 ± 1.1 mg/dL, and a decrease of 4.0 ± 1.8 mg/dL (0.17 ± 0.07 mg/dL/h) in the LED group (34 patients) and 3.9 ± 2.5 mg/dL (0.16 ± 0.1 mg/dL/h) in the fluorescent group (34 patients) after 24 h of phototherapy was achieved (p = 0.87). The 82 newborns between 380/7 and 416/7 weeks were 62 ± 14 h old at the beginning of phototherapy and had TSB levels of 14.5 ± 1.2 mg/dL; a decrease in the TSB of 3.6 ± 2.2 mg/dL (0.15 ± 0.09 mg/dL/h) in the LED group (40 patients) and 3.8 ± 2.2 mg/dL (0.16 ± 0.09 mg/dL/h) in the fluorescent group (42 patients) was achieved (p = 0.64). With respect to the spectral irradiance, 1185 measurements were taken during the study, of which 750 were obtained at the beginning of treatment. Figure 1 shows the heterogeneous distribution of the irradiance at the 5 points of the LED phototherapy and the uniformity of the irradiance in the fluorescent phototherapy. To maintain the irradiance between 8 and
8
12 μW/cm2/nm during treatment, adjustments to the level of potency from 70% up to 90% were necessary in the LED unit, whereas 70 daylight fluorescence bulbs were substituted. With respect to adverse events, the average maximum weight loss during treatment with respect to birth weight was similar in both groups (LED 6.9
2.9% vs. fluorescent 7.4
3.1%;
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p = 0.35), with a maximum of 15% in a patient in the LED group and of 18% in a patient in the fluorescent group. Hypothermia (< 36.0°C) was more frequent in newborns who received LED than fluorescent therapy (23% vs. 9%, respectively; p = 0.02); however, none of the 150 patients developed an axillary temperature below 35.0°C. The average room temperature was 27.4°C, with variations between 21.3°C and 31.4°C; patients exposed to room temperatures below 25.0°C exhibited a relative risk of 6.4 [95% confidence interval (CI): 3.1-13.2] for the occurrence of hypothermia during phototherapy. As for hyperthermia, 1 patient had an episode of a 37.5 C axillary temperature in the LED group, and another patient reached a temperature of 37.8 C in the fluorescent group. No newborn exhibited cutaneous rash or skin burns.
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DISCUSSION This randomised and controlled unicentric clinical trial showed that blue LED phototherapy with heterogeneous irradiance exhibited a similar efficacy as daylight fluorescent lamp phototherapy from below with uniform irradiance in decreasing bilirubinemia in breastfed
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newborns with a gestational age of ≥ 35 weeks in a rooming-in unit. However, patients who received LED phototherapy exhibited more hypothermia than patients treated with fluorescent phototherapy. The primary outcome of this study was in agreement with the results from two metaanalyses of newborns with a gestational age of ≥ 35 weeks [10,11], which showed that LED phototherapy was comparable to halogen and/or fluorescent lamp phototherapy and achieved equal efficacy in TSB reduction. The TSB level decrease rate of 0.16 mg/dL/h obtained with both phototherapy units was similar to the value of 0.13 to 0.20 mg/dL/h calculated in the clinical trials of Seidman et al. [6,7] and Kumar et al. [9]. Only Maisels et al. [8] found a decrease rate of 0.31 mg/dL/h in both groups, due to the use of phototherapy from below with an overhead phototherapy unit, with a consequent increase in spectral power. The present survey differed from previously performed clinical trials due to the use of only two types of lamps, i.e., LED vs. fluorescent, based on a mean standard irradiance between 8 and 12 μW/cm2/nm measured at 5 points at the beginning of and during treatment over an irradiated area of 30 x 60 cm. Seidman et al. [6,7] compared the efficacy of 600 LED-bulb units to 3 halogen-bulb units located above the patients with an irradiance of 5 to 8 μW/cm2/nm in both arms of the study; however, they did not report the points of measurement of the irradiance. Maisels et al. [8] evaluated an experimental group (33 patients) treated with 852 blue, 320 yellow and 13 red LED-bulb units and a conventional group (33 patients) treated with 8 special blue fluorescent-
10
bulb units and irradiances near 40 μW/cm2/nm in both groups as measured at a single point on the abdomen of the newborn. In a randomised clinical trial with 272 newborns, Kumar et al. [9] studied the efficacy of 236 LED-bulb units with an irradiance of 47 μW/cm2/nm compared with units with 6 blue fluorescent bulbs and an irradiance of 28.7 μW/cm2/nm; the irradiance was
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measured only in one third of the units by calculating the mean of 3 points (cephalic pole, abdomen and lower limbs). Thus, the lack of standardisation of the phototherapy units and of the specific irradiance measurement techniques hampers the interpretation of efficacy in randomised clinical trials [12-17]. Further, 3 different types of radiometers were used in these studies [6-9], and because each radiometer possessed a different filter with different range of wavelengths, a variable irradiance can be assumed for the same light source [15]. In the present study, a TSB level decrease rate of 0.16 mg/dL/h was obtained, independent of the unit used. There were two important factors that justified this similarity: the uniformity of the irradiance exposure on most of the newborn’s body surface in the fluorescent group and the heterogeneity of the LED group, which had very high irradiance in the centre and low irradiance in the limbs. Since 2009, the International Electrotechnical Commission has recommended that phototherapy units produce irradiance with a uniform distribution mapped at every 10 cm within the illuminated halo and that the minimum/ maximum ratio should be ≥ 0.40 [17]. In the present survey, this ratio was 0.13 in LED phototherapy and 0.60 in fluorescent phototherapy, demonstrating the uniformity of the irradiance in the distribution of the body surface with optimisation of the efficacy of the phototherapy. The heterogeneity of the LED phototherapy may be explained by the concentration of 9 bulbs in the centre of device providing a higher small illuminated area. Another factor that influences the phototherapy effectiveness is the wavelength of light. The fluorescent daylight lamp tubes have the highest light wavelengths
11
with the highest skin penetrance [20]. Moreover co-binding of fatty acids to the albumin causes alterations of the light absorption spectrum of the complex to higher wavelengths [21]. However, the LED bulbs have a wavelength band with better bilirubin absorption [22]. Among the adverse events, moderate hypothermia was the most frequent in the LED
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group. It is possible that room temperatures below 25 C were the main factor contributing to hypothermia in the present study, both in the LED as well as in the fluorescent group. Another aspect to be considered is the preoccupation with the use of high doses of irradiance in the population with a gestational age of 35 weeks or above, which is currently defended by some authors as a way to shorten the hospital stay [8,23,24]. Despite the associations with the emergence of nevi, melanoma, allergic disease and diabetes mellitus type 1 that have been found in observational studies in patients subjected to phototherapy in the neonatal period, there is no proof of a cause-and-effect relationship [25-27]. In the present clinical trial, which was performed with a mean irradiance of 8 to 12 μW/cm2/nm, a median of 24 h of treatment was obtained for an unfavourable postnatal age for the decrease of bilirubinemia, which has been observed in other trials [6,7]. Both LED phototherapy with a heterogeneous distribution of the irradiance and daylight fluorescent phototherapy with uniformity on the surface of the newborn’s skin were able to optimise treatment to achieve a TSB level decrease rate similar to the rate found with intensive irradiance ( 30 μW/cm2/nm) [8]. If the measurements of the irradiance had been performed only at the central point, we would have affirmed that the newborns who underwent LED phototherapy were receiving intensive phototherapy. Of note, only one in vitro study has measured the irradiance of phototherapy units at 5 points, and that study found both that the heterogeneity in the units with LED lamps was similar to the present study and that there was uniformity of the irradiance of the fluorescent lamps [7].
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This is the first clinical trial to report the measurement of irradiance at 5 points in the attempt to map the mean spectral irradiance offered to the patient in a practical bedside method. The proposal of this form of measurement strengthens the theory that the efficacy of phototherapy is directly related not only to irradiance but also to the body surface exposed to
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constant irradiance, i.e., the optimisation of the spectral power. Additionally, the clinical homogeneity of the population (randomisation into groups by gestational age range, a post-natal age > 48 hours, being breastfed and exhibiting no hemolytic disease) corroborated the findings on the efficacy of phototherapy. Just as post-natal age influences the dynamics of bilirubinemia, gestational age also interferes with the response to treatment with different TSB levels [28,29] for the suspension of phototherapy. By studying a homogenous sample with daily irradiance monitoring by means of the 5-points technique, this study aimed to control the possible factors that could interfere with the interpretation of the efficacy of each phototherapy unit. However, a possible limitation of the study was the use of the same model of radiometer for the two different light sources [15,23]. Given that several factors can interfere with the efficacy of phototherapy, a rigorous control of the irradiance-measuring method becomes necessary as well as the manufacturing of standardised units with uniform irradiance over the newborn’s whole body surface [23]. Additionally, another implication of this trial on daily practice was the frequent exchange of daylight fluorescent bulbs to maintain irradiance in the therapeutic range; there was no need for such exchanges with LED bulbs due to their long half-life [1,2].
13
CONCLUSION Measuring irradiance at 5 points allowed for the practical mapping of the mean spectral irradiance offered to the newborn by LED phototherapy. This measurement allowed for determination of the heterogeneous distribution of the irradiance in LED device with a better
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interpretation of the efficacy of phototherapy. This study showed that blue LED with heterogeneous irradiance (higher in central point) was as efficacious as daylight fluorescent phototherapy with low uniform irradiance of 8-10 μW/cm2/nm at decreasing TSB in newborns with a gestational age of ≥ 35 weeks. However, hypothermia was more frequent in the group of patients who underwent LED phototherapy, so there is a greater need for more rigorous control of the room temperature. Further trials are required to evaluate the effectiveness of a uniform low irradiance phototherapy on a large body surface area to control the hyperbilirubinemia in the newborns. ACKNOWLEDGEMENTS We thank Ana Elizabeth Figueiredo MD, Geisy Maria de Souza Lima MD, and Jucille do Amaral Meneses MD PhD for the research logistic management at the IMIP Rooming-in Unit. DECLARATION OF INTEREST STATEMENT No external funding was secured for this study and the authors report no declarations of interest. IMIP Research and Teaching Support Fund (Fundo de Apoio à Pesquisa e Ensino do IMIP – FAPE/IMIP) acquired the BR-501 bilirubin meter (Apel, Kawaguchi, Japão), and Fanem Inc. (São Paulo, Brazil) loaned two Bilitron Bed and two Biliberço units. FAPE-IMIP and Fanem Inc. were not involved in the study design, data analysis and interpretation, or preparation of the manuscript. Neither the participating institutions nor the authors received any reimbursement for infants enrolled in the study.
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REFERENCES [1]
Mukai T, Motokazu Y, Nakamura S. Characteristics of InGaN-based UV/blue/ green/amber/red light-emitting diodes. Jpn J Appl Phys 1999;38:3976-3981.
[2]
Nakamura S. The roles of structural imperfections in InGaN-based blue light emitting
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Melbourne on 10/11/14 For personal use only.
diodes and laser diodes. Science 1998;281:956-961. [3]
Vreman HJ, Wong RJ, Stevenson DK, Route RK, Reader SD, Fejer MM, et al. Lightemitting diodes: a novel light source for phototherapy. Pediatr Res 1998;44:804-809.
[4]
Chang YS, Hwang JH, Kwon HN, Choi CW, Ko SY, Park WS, et al. In vitro and in vivo efficacy of new blue light emitting diode phototherapy compared to conventional halogen quartz phototherapy for neonatal jaundice. J Korean Med Sci 2005;20:61-64.
[5]
Subramanian S, Sankar MJ, Deodari AK, Velpandian T, Kannan P, Prakash GV, et al. Evaluation of phototherapy devices used for neonatal hyperbilirubinemia. Indian Pediatr 2011;48:689-696.
[6]
Seidman DS, Moise J, Ergaz Z, Laor A, Vreman HJ, Stevenson DK, et al. A new blue light-emitting phototherapy device: a prospective randomized controlled study. J Pediatr 2000;136:771-774.
[7]
Seidman DS, Moise J, Ergaz Z, Laor A, Vreman HJ, Stevenson DK, et al. A prospective randomized controlled study of phototherapy using blue and blue-green light-emitting devices, and conventional halogen-quartz phototherapy. J Perinatol 2003;23:123-127.
[8]
Maisels MJ, Kring EA. DeRidder J. Randomized controlled trial of light-emitting diode phototherapy. J Perinatol 2007;27:565-567.
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[9]
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 multicenter randomized controlled trial. Indian Pediatr 2010;47:131-137.
[10] Tridente A, Luca DD. Efficacy of light-emitting diode versus other light sources for
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Melbourne on 10/11/14 For personal use only.
treatment of neonatal hyperbilirubinemia: a systematic review and meta-analysis. Acta Paediatr 2011;2:1-8. [11] Kumar P, Chawla D, Deorari A. Light-emitting diode phototherapy for unconjugated hyperbilirubinaemia in neonates. Cochrane Database Syst Rev 2011;12:CD007969. [12] Bhutani VK, Wong RJ. Neonatal phototherapy: choice of device and outcome. Acta Paediatr 2012;101:441-443. [13] Vreman HJ. Phototherapy: the challenge to accurately measure irradiance. Indian Pediatr 2010;47:127-128. [14] Vreman HJ, Wong RJ, Murdock JR, Stevenson DK. Standardized bench method for evaluating the efficacy of phototherapy devices. Acta Paediatr 2008;97:308-316. [15] Kuboi T, Kusaka T, Yasuda S, Okubo K, Isobe K, Itoh S. Management of phototherapy for neonatal hyperbilirubinemia: is a new radiometer applicable for all wavelengths and light source types? Pediatr Int 2011;53:689-693. [16] International Electrotechnical Commission. Medical electrical equipment - Part 2-50: Particular requirements for the safety of infant phototherapy equipment. IEC 60601-2-50. 2000. Geneva: International Electrotechnical Commission; 2000 - [cited 2002 Mar 6]; Available from URL:http://webstore.iec.ch/p-preview/info_iec60601-250%7Bed1.0%7Den.pdf
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[17] International Electrotechnical Commission. International Standard. Medical electrical equipment - Part 2-50: Particular requirements for the basic safety and essential performance of infant phototherapy equipment. IEC 60601-2-50. Edition 2.0. Geneva: International Electrotechnical Commission; 2009 - [cited 2010 Dec 28]; Available from
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Melbourne on 10/11/14 For personal use only.
URL:http://webstore.iec.ch/webstore/webstore.nsf/Artnum_PK/42737 [18] American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316. [19] De Carvalho M, De Carvalho D, Trzmielina S, Lopes JM, Hansen TW. Intensified phototherapy using daylight fluorescent lamps. Acta Paediatr 1999;88:768-771. [20] Anderson RR, Parrish JA. The optics of human skin. J invest 1981;77:13-9. [21] Jacobsen J, Brodersen R. Albumin-bilirubin binding mechanism. J Biol Chem 1983;258:6319-26. [22] Sisson TRC, Kendall N, Davies RE, Berger D. Factors influencing the effectiveness of phototherapy in neonatal hyperbilirubinemia. Birth Defects 1970;6:100-5. [23] Bhutani VK, Committee on Fetus and Newborn, American Academy of Pediatrics. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011;128:e1046-e1052. [24] Bhutani VK, Cline BK, Donaldson KM, Vreman HJ. The need to implement effective phototherapy in resource-constrained settings. Semin Perinatol 2011;35:192-197. [25] Csoma Z, Tóth-Molnár E, Balogh K, Polyánka H, Orvos H, Ocsai H, et al. Neonatal blue light phototherapy and melanocytic nevi: a twin study. Pediatrics 2011;128:e856-e864.
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[26] Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008;358:920-928. [27] Xiong T, Qu Y, Cambier S, Mu D. The side effects of phototherapy for neonatal jaundice: what do we know? What should we do? Eur J Pediatr 2011;170:1247-1255.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Melbourne on 10/11/14 For personal use only.
[28] Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and nearterm newborns. Pediatrics 1999;103:6-14. [29] Draque CM, Sañudo A, de Araujo Peres C, de Almeida MF. Transcutaneous bilirubin in exclusively breastfed healthy term newborns up to 12 days of life. Pediatrics 2011;128:e565-e571.
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FIGURE LEGENDS
Figure 1. Spectral irradiance (μW/cm2/nm) in the four corner points and center of a 60 x 30 cm rectangle and average of the 5 points (150 measurements per point) according to the type of
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phototherapy device.
Table I. Maternal and neonatal characteristics in the study groups.
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LED
Fluorescent
n = 74 (%)
n = 76 (%)
Maternal age (years) #
27 ± 7
25 ± 7
0.15
Years of school ≥ 10
40 (54)
36 (47)
0.41
First gestation
41 (55)
48 (63)
0.28
7/33 (21)
6/28 (21)
0.11
1 (1)
3 (4)
0.32
23 (31)
31 (41)
0.14
5 (7)
5 (7)
0.96
Prenatal care ≥ 6 visits
50 (68)
50 (66)
0.82
Vaginal delivery
44 (59)
48 (63)
0.52
Oxytocin
28 (38)
33 (43)
0.58
Birth Weight (g)#
3091 ± 555
3016 ± 510
0.39
Body surface (cm2)#
2048 ± 214
2078 ± 235
0.41
4 (5)
5 (6)
0.87
Male gender
32 (43)
43 (56)
0.10
Mixed and black race
66 (89)
62 (81)
0.16
ABO incompatibility
17 (23)
16 (21)
0.78
4 (5)
7 (9)
0.37
Hematocrit (%)
50 ± 6
50 ± 5
0.63
Reticulocyte (%)
5.7 ± 2.8
5.1 ± 2.8
0.25
2 (3)
3 (4)
0.99
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p
Previous newborn with jaundice needing treatment Twin pregnancy Maternal hypertension Maternal diabetes
Small for gestational age
G-6-PD deficient
Bruising/Cephalhematoma
20
Exclusive breastfeeding # Mean
62 (84)
68 (90)
0.42
s. d. All of the infants had a negative direct coombs test.
Table II. Total serum bilirubin, spectral irradiance, postnatal age and duration of phototherapy,
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in mean
s. d., in the study groups. LED
Fluorescent p
N = 74
N = 76
TSB at initiation of phototherapy (mg/dL)
14.0 ± 1.3
14.1 ± 1.2
0.96
TSB after 24 h of phototherapy (mg/dL)
10.3 ± 2.1
10.2 ± 2.4
0.84
Decline in TSB after 24 h of therapy (mg/dL)
3.8 ± 2.0
3.9 ± 2.3
0.81
0.16 ± 0.09
0.16 ± 0.08
0.81
9.5 ± 1.8
9.2 ± 1.6
(n=37)
(n=33)
TSB at suspension of phototherapy (mg/dL)
8.9 ± 1.6
8.8 ± 1.8
0.51
TSB 18-24 h after the end of therapy (mg/dL)
9.7 ± 2.2
9.5 ± 1.8
0.42
Irradiance (μW/cm2/nm)
10.5 ± 0.9
8.7 ± 0.6
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Objective: To compare the decline in TSB after 24 h of LED or fluorescent phototherapy from below in breastfed neonates ≥35 weeks of gestation. Methods: 74 neonates treated with a 17-bulb blue LED were compared with 76 neonates treated with a 7-bulb daylight device in a rooming-in unit. Spectral irradiance was measured at 5 points on a 30 x 60 cm rectangle on the gel transparent mattress. Results: TSB of 14.0 1.2 mg/dL at 64 15 h after birth when starting phototherapy were similar in both groups. TSB declined by 0.16 ± 0.09 in the LED vs. 0.16 ± 0.08 mg/dL/hour in the daylight group after 24 h of therapy (p = 0.87). Mean irradiance (μW/cm2/nm) was 10.5 0.9 (32.5 at the central, 5.9 at the superior and 3.9 for the inferior points) in the LED vs. 8.7 0.6 (range, 8.3 to 9.8) in the daylight group (p < 0.001). Hypothermia (< 36.0°C) was more frequent in LED than in fluorescent (23% vs. 9%; p = 0.02) group. Conclusion: LED with heterogeneous irradiance was as effective as daylight phototherapy with homogeneous irradiance, however there is a greater need for rigorous control of the room temperature (NCT01340339).
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1
TITLE PAGE LED versus DAYLIGHT PHOTOTHERAPY AT LOW IRRADIANCE IN NEWBORNS ≥
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35 WEEKS OF GESTATION: RANDOMIZED CONTROLLED TRIAL
Danielle Cintra Bezerra Brandão1, MD, Cecilia Maria Draque2, MD, PhD, Adriana Sañudo3, MS, Fernando Antonio Ribeiro de Gusmão Filho1, MD, PhD, and Maria Fernanda Branco de Almeida2, MD, PhD Affiliations: 1Professor Fernando Figueira Integral Medicine Institute (Instituto de Medicina Integral Professor Fernando Figueira – IMIP), Recife, PE, Brazil; 2Division of Neonatal Medicine, Federal University of São Paulo/Paulista School of Medicine (Universidade Federal de São Paulo/Escola Paulista de Medicina – EPM-UNIFESP), São Paulo, SP, Brazil; 3
Department of Preventive Medicine, Federal University of São Paulo/Paulista School of
Medicine (Universidade Federal de São Paulo/Escola Paulista de Medicina – EPM-UNIFESP), São Paulo, SP, Brazil,
Corresponding author: Maria Fernanda Branco de Almeida, MD, PhD, Rua Los Angeles, 40, 04564-030, São Paulo, SP, Brazil. Tel +55 (11) 5084-0535. Email [email protected].
Short title: LED phototherapy in breastfed newborns Keywords: bilirubin; hyperbilirubinemia, neonatal; jaundice, neonatal; breast feeding; hypothermia
ABSTRACT
2
Objective: To compare the decline in TSB after 24 h of LED or fluorescent phototherapy from below in breastfed neonates ≥35 weeks of gestation. Methods: 74 neonates treated with a 17-bulb blue LED were compared with 76 neonates treated with a 7-bulb daylight device in a rooming-in unit. Spectral irradiance was measured at 5 points
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on a 30 x 60 cm rectangle on the gel transparent mattress. Results: TSB of 14.0
1.2 mg/dL at 64
15 h after birth when starting phototherapy were
similar in both groups. TSB declined by 0.16 ± 0.09 in the LED vs. 0.16 ± 0.08 mg/dL/hour in the daylight group after 24 h of therapy (p = 0.87). Mean irradiance (μW/cm2/nm) was 10.5
0.9
(32.5 at the central, 5.9 at the superior and 3.9 for the inferior points) in the LED vs. 8.7
0.6
(range, 8.3 to 9.8) in the daylight group (p < 0.001). Hypothermia (< 36.0°C) was more frequent in LED than in fluorescent (23% vs. 9%; p = 0.02) group. Conclusion: LED with heterogeneous irradiance was as effective as daylight phototherapy with homogeneous irradiance, however there is a greater need for rigorous control of the room temperature (NCT01340339).
3
INTRODUCTION Phototherapy units with light-emitting diodes (LEDs) have been used to emit highintensity light while generating little heat, in addition to offering low energy consumption and lasting durability [1-3]. While in vitro studies have found a greater reduction of bilirubinemia
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with blue LEDs [3-5], clinical trials have reported similar efficacy when compared with blue fluorescent or halogen lamps in neonates [6-11]. However, the variability of phototherapy units and the lack of a standard technique to measure spectral irradiance hamper the interpretation of patient treatments in these trials. Currently, researchers suggest clinical trials with standardised irradiance measurement methods on a homogenous population of neonates to obtain more solid scientific evidence on the efficacy of LED phototherapy [12-17]. In this context, the present study compares the decrease in total serum bilirubin (TSB) after 24 h of blue LED phototherapy with respect to daylight fluorescent phototherapy in breastfed newborns with a gestational age of ≥35 weeks, as well as adverse clinical events. METHODS Patients This randomised controlled clinical trial was performed at the public maternity rooming-in unit of the Professor Fernando Figueira Integral Medicine Institute (Instituto de Medicina Integral Professor Fernando Figueira – IMIP), Recife, PE, Brazil, in the period from October 2010 to June 2011. Breastfed newborns with a gestational age between 350/7 and 416/7 weeks, birth weight ≥ 2200 g, an Apgar score ≥ 7 in the fifth minute after birth, and a referral for phototherapy by the medical team between 48 and 120 h after birth were included. Patients were excluded from the study if they exhibited any type of congenital malformation or Rh hemolytic disease, were
4
moved to other units or if, due to randomisation, one of the phototherapy units was not available. The project was approved by the Research Ethics Committee of the institution, and all mothers signed the informed consent form. The study was registered as a clinical trial NCT 01340339.
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Intervention The randomisation was stratified into two groups by gestational age (350/7 to 376/7 weeks and 380/7 to 416/7 weeks) by means of drawing lots by a local health care professional unrelated to the study. Each large opaque and numbered envelope contained four small opaque, sealed and identical envelopes; each envelope had one type of phototherapy assignment, and each type of phototherapy was included twice. Treatment was indicated if, by 48 h after birth, TSB levels were 12-14 mg/dL in neonates with a gestational age of 35-37 weeks or 13-16 mg/dL in neonates with a gestational age of 3841 weeks [18]. Three employees with no involvement in the study were trained to measure TSB levels using a capillary tube with a BR-501 bilirubin meter (Apel, Kawaguchi, Japan), which was calibrated on a daily basis. The intervention was performed using a Bilitron Bed® unit (Fanem, São Paulo, Brazil) with 17 LED bulbs of wavelength range 400–520 nm in parallel and at a distance of 12 cm below the transparent acrylic bassinet, providing an illuminated area of 42 x 31 cm. The comparison was made with the Biliberço® unit (Fanem, São Paulo, Brazil), which had the transparent acrylic base positioned 5 cm above 7 TL 20 W fluorescent daylight lamp tubes (Osram, Osasco, Brazil) of wavelength range 380–770 nm and provided an illuminated area of 60 x 35 cm [19]. Both types of units possessed a curved acrylic overlay on the internal reflector surface. The spectral irradiance was measured before initiating treatment and after every 24 h of treatment using a 2620 radiometer (Fanem, São Paulo, Brazil), which absorbs light
5
between 400 and 500 nm. The spectral irradiance was measured at all four corners and at the central point of a 30 cm x 60 cm rectangle to calculate the mean value of the 5 measured points [16] and to obtain a standard irradiance between 8 and 12 μW/cm2/nm. The potency of the LED lamps was adjusted digitally in the Bilitron Bed® unit to maintain this irradiance, whereas
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fluorescent bulbs were substituted in the Biliberço® unit if the value was < 8 μW/cm2/nm. The newborns were laid on a transparent gel mattress wearing mini-diapers and opaque eye covers.
Primary and Secondary Outcomes The primary outcome consisted of determining the TSB level decrease rate, in mg/dL/h, after 24 h of phototherapy. If the newborn remained in therapy, TSB levels were re-assessed every 12 h to 24 h, and suspension of the phototherapy was indicated when the TSB value was ≤ 8 mg/dL or ≤ 11 mg/dL in newborns with a gestational age of 350/7 to 376/7 or 380/7 to 416/7 weeks, respectively. Secondary outcomes included the total time in phototherapy, the reintroduction of therapy after 18 h to 24 h of suspension and/or the need for intensive phototherapy with 30 μW/cm2/nm irradiance or exchange transfusion [18]. Intensive phototherapy was performed by adding conventional overhead phototherapy using the Octofoto 006 OFL unit (Fanem, São Paulo, Brazil), with eight special blue fluorescent bulbs, to the phototherapy from below. During treatment, adverse events comprised the detection of a maximum weight loss with respect to birth weight, episodes of hyperthermia (> 37.5°C) or hypothermia (< 36.0°C). Newborns were weighed daily, and axillary and room temperatures were recorded every 6 h using digital thermometers (Incoterm®, São Paulo, Brazil).
Statistical Analysis
6
The sample size of 73 patients for each group was calculated considering a decrease in the TSB by 30% after 24 h of treatment with LED lamps [8], with a significance level of 5% and a power of 80%. Comparisons between groups were performed by means of Student’s t, the Mann-Whitney U, chi-squared or Fisher’s exact test, in addition to the evaluation of the duration
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of the phototherapy by means of Kaplan-Meier curves (log-rank test), using the statistics software SPSS 17.0 and considering significance at p < 0.05.
7
RESULTS During the period of this study, 1,914 newborns with a gestational age between 350/7 and 416/7 weeks were admitted to the rooming-in unit, of which 154 were randomised to the LED (n = 74) and fluorescent (n = 76) groups, with 4 losses: 3 neonates were excluded because they
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had been removed from the unit before the end of treatment and 1 was excluded due to a mistake in the eligibility criteria. Table I shows the similarities between the maternal and neonatal characteristics in both treatment groups. A 27% decrease in TSB was achieved after 24 h of treatment in both types of units (Table II). In one newborn from the LED group, phototherapy was re-introduced after suspension, and one patient from the fluorescent group needed intensive phototherapy. None of the neonates reached TSB levels requiring exchange transfusion. Considering the gestational age range, the 68 neonates between 350/7 and 376/7 weeks initiated therapy within 68 ± 15 h at TSB levels of 13.6 ± 1.1 mg/dL, and a decrease of 4.0 ± 1.8 mg/dL (0.17 ± 0.07 mg/dL/h) in the LED group (34 patients) and 3.9 ± 2.5 mg/dL (0.16 ± 0.1 mg/dL/h) in the fluorescent group (34 patients) after 24 h of phototherapy was achieved (p = 0.87). The 82 newborns between 380/7 and 416/7 weeks were 62 ± 14 h old at the beginning of phototherapy and had TSB levels of 14.5 ± 1.2 mg/dL; a decrease in the TSB of 3.6 ± 2.2 mg/dL (0.15 ± 0.09 mg/dL/h) in the LED group (40 patients) and 3.8 ± 2.2 mg/dL (0.16 ± 0.09 mg/dL/h) in the fluorescent group (42 patients) was achieved (p = 0.64). With respect to the spectral irradiance, 1185 measurements were taken during the study, of which 750 were obtained at the beginning of treatment. Figure 1 shows the heterogeneous distribution of the irradiance at the 5 points of the LED phototherapy and the uniformity of the irradiance in the fluorescent phototherapy. To maintain the irradiance between 8 and
8
12 μW/cm2/nm during treatment, adjustments to the level of potency from 70% up to 90% were necessary in the LED unit, whereas 70 daylight fluorescence bulbs were substituted. With respect to adverse events, the average maximum weight loss during treatment with respect to birth weight was similar in both groups (LED 6.9
2.9% vs. fluorescent 7.4
3.1%;
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p = 0.35), with a maximum of 15% in a patient in the LED group and of 18% in a patient in the fluorescent group. Hypothermia (< 36.0°C) was more frequent in newborns who received LED than fluorescent therapy (23% vs. 9%, respectively; p = 0.02); however, none of the 150 patients developed an axillary temperature below 35.0°C. The average room temperature was 27.4°C, with variations between 21.3°C and 31.4°C; patients exposed to room temperatures below 25.0°C exhibited a relative risk of 6.4 [95% confidence interval (CI): 3.1-13.2] for the occurrence of hypothermia during phototherapy. As for hyperthermia, 1 patient had an episode of a 37.5 C axillary temperature in the LED group, and another patient reached a temperature of 37.8 C in the fluorescent group. No newborn exhibited cutaneous rash or skin burns.
9
DISCUSSION This randomised and controlled unicentric clinical trial showed that blue LED phototherapy with heterogeneous irradiance exhibited a similar efficacy as daylight fluorescent lamp phototherapy from below with uniform irradiance in decreasing bilirubinemia in breastfed
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newborns with a gestational age of ≥ 35 weeks in a rooming-in unit. However, patients who received LED phototherapy exhibited more hypothermia than patients treated with fluorescent phototherapy. The primary outcome of this study was in agreement with the results from two metaanalyses of newborns with a gestational age of ≥ 35 weeks [10,11], which showed that LED phototherapy was comparable to halogen and/or fluorescent lamp phototherapy and achieved equal efficacy in TSB reduction. The TSB level decrease rate of 0.16 mg/dL/h obtained with both phototherapy units was similar to the value of 0.13 to 0.20 mg/dL/h calculated in the clinical trials of Seidman et al. [6,7] and Kumar et al. [9]. Only Maisels et al. [8] found a decrease rate of 0.31 mg/dL/h in both groups, due to the use of phototherapy from below with an overhead phototherapy unit, with a consequent increase in spectral power. The present survey differed from previously performed clinical trials due to the use of only two types of lamps, i.e., LED vs. fluorescent, based on a mean standard irradiance between 8 and 12 μW/cm2/nm measured at 5 points at the beginning of and during treatment over an irradiated area of 30 x 60 cm. Seidman et al. [6,7] compared the efficacy of 600 LED-bulb units to 3 halogen-bulb units located above the patients with an irradiance of 5 to 8 μW/cm2/nm in both arms of the study; however, they did not report the points of measurement of the irradiance. Maisels et al. [8] evaluated an experimental group (33 patients) treated with 852 blue, 320 yellow and 13 red LED-bulb units and a conventional group (33 patients) treated with 8 special blue fluorescent-
10
bulb units and irradiances near 40 μW/cm2/nm in both groups as measured at a single point on the abdomen of the newborn. In a randomised clinical trial with 272 newborns, Kumar et al. [9] studied the efficacy of 236 LED-bulb units with an irradiance of 47 μW/cm2/nm compared with units with 6 blue fluorescent bulbs and an irradiance of 28.7 μW/cm2/nm; the irradiance was
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measured only in one third of the units by calculating the mean of 3 points (cephalic pole, abdomen and lower limbs). Thus, the lack of standardisation of the phototherapy units and of the specific irradiance measurement techniques hampers the interpretation of efficacy in randomised clinical trials [12-17]. Further, 3 different types of radiometers were used in these studies [6-9], and because each radiometer possessed a different filter with different range of wavelengths, a variable irradiance can be assumed for the same light source [15]. In the present study, a TSB level decrease rate of 0.16 mg/dL/h was obtained, independent of the unit used. There were two important factors that justified this similarity: the uniformity of the irradiance exposure on most of the newborn’s body surface in the fluorescent group and the heterogeneity of the LED group, which had very high irradiance in the centre and low irradiance in the limbs. Since 2009, the International Electrotechnical Commission has recommended that phototherapy units produce irradiance with a uniform distribution mapped at every 10 cm within the illuminated halo and that the minimum/ maximum ratio should be ≥ 0.40 [17]. In the present survey, this ratio was 0.13 in LED phototherapy and 0.60 in fluorescent phototherapy, demonstrating the uniformity of the irradiance in the distribution of the body surface with optimisation of the efficacy of the phototherapy. The heterogeneity of the LED phototherapy may be explained by the concentration of 9 bulbs in the centre of device providing a higher small illuminated area. Another factor that influences the phototherapy effectiveness is the wavelength of light. The fluorescent daylight lamp tubes have the highest light wavelengths
11
with the highest skin penetrance [20]. Moreover co-binding of fatty acids to the albumin causes alterations of the light absorption spectrum of the complex to higher wavelengths [21]. However, the LED bulbs have a wavelength band with better bilirubin absorption [22]. Among the adverse events, moderate hypothermia was the most frequent in the LED
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group. It is possible that room temperatures below 25 C were the main factor contributing to hypothermia in the present study, both in the LED as well as in the fluorescent group. Another aspect to be considered is the preoccupation with the use of high doses of irradiance in the population with a gestational age of 35 weeks or above, which is currently defended by some authors as a way to shorten the hospital stay [8,23,24]. Despite the associations with the emergence of nevi, melanoma, allergic disease and diabetes mellitus type 1 that have been found in observational studies in patients subjected to phototherapy in the neonatal period, there is no proof of a cause-and-effect relationship [25-27]. In the present clinical trial, which was performed with a mean irradiance of 8 to 12 μW/cm2/nm, a median of 24 h of treatment was obtained for an unfavourable postnatal age for the decrease of bilirubinemia, which has been observed in other trials [6,7]. Both LED phototherapy with a heterogeneous distribution of the irradiance and daylight fluorescent phototherapy with uniformity on the surface of the newborn’s skin were able to optimise treatment to achieve a TSB level decrease rate similar to the rate found with intensive irradiance ( 30 μW/cm2/nm) [8]. If the measurements of the irradiance had been performed only at the central point, we would have affirmed that the newborns who underwent LED phototherapy were receiving intensive phototherapy. Of note, only one in vitro study has measured the irradiance of phototherapy units at 5 points, and that study found both that the heterogeneity in the units with LED lamps was similar to the present study and that there was uniformity of the irradiance of the fluorescent lamps [7].
12
This is the first clinical trial to report the measurement of irradiance at 5 points in the attempt to map the mean spectral irradiance offered to the patient in a practical bedside method. The proposal of this form of measurement strengthens the theory that the efficacy of phototherapy is directly related not only to irradiance but also to the body surface exposed to
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constant irradiance, i.e., the optimisation of the spectral power. Additionally, the clinical homogeneity of the population (randomisation into groups by gestational age range, a post-natal age > 48 hours, being breastfed and exhibiting no hemolytic disease) corroborated the findings on the efficacy of phototherapy. Just as post-natal age influences the dynamics of bilirubinemia, gestational age also interferes with the response to treatment with different TSB levels [28,29] for the suspension of phototherapy. By studying a homogenous sample with daily irradiance monitoring by means of the 5-points technique, this study aimed to control the possible factors that could interfere with the interpretation of the efficacy of each phototherapy unit. However, a possible limitation of the study was the use of the same model of radiometer for the two different light sources [15,23]. Given that several factors can interfere with the efficacy of phototherapy, a rigorous control of the irradiance-measuring method becomes necessary as well as the manufacturing of standardised units with uniform irradiance over the newborn’s whole body surface [23]. Additionally, another implication of this trial on daily practice was the frequent exchange of daylight fluorescent bulbs to maintain irradiance in the therapeutic range; there was no need for such exchanges with LED bulbs due to their long half-life [1,2].
13
CONCLUSION Measuring irradiance at 5 points allowed for the practical mapping of the mean spectral irradiance offered to the newborn by LED phototherapy. This measurement allowed for determination of the heterogeneous distribution of the irradiance in LED device with a better
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interpretation of the efficacy of phototherapy. This study showed that blue LED with heterogeneous irradiance (higher in central point) was as efficacious as daylight fluorescent phototherapy with low uniform irradiance of 8-10 μW/cm2/nm at decreasing TSB in newborns with a gestational age of ≥ 35 weeks. However, hypothermia was more frequent in the group of patients who underwent LED phototherapy, so there is a greater need for more rigorous control of the room temperature. Further trials are required to evaluate the effectiveness of a uniform low irradiance phototherapy on a large body surface area to control the hyperbilirubinemia in the newborns. ACKNOWLEDGEMENTS We thank Ana Elizabeth Figueiredo MD, Geisy Maria de Souza Lima MD, and Jucille do Amaral Meneses MD PhD for the research logistic management at the IMIP Rooming-in Unit. DECLARATION OF INTEREST STATEMENT No external funding was secured for this study and the authors report no declarations of interest. IMIP Research and Teaching Support Fund (Fundo de Apoio à Pesquisa e Ensino do IMIP – FAPE/IMIP) acquired the BR-501 bilirubin meter (Apel, Kawaguchi, Japão), and Fanem Inc. (São Paulo, Brazil) loaned two Bilitron Bed and two Biliberço units. FAPE-IMIP and Fanem Inc. were not involved in the study design, data analysis and interpretation, or preparation of the manuscript. Neither the participating institutions nor the authors received any reimbursement for infants enrolled in the study.
14
REFERENCES [1]
Mukai T, Motokazu Y, Nakamura S. Characteristics of InGaN-based UV/blue/ green/amber/red light-emitting diodes. Jpn J Appl Phys 1999;38:3976-3981.
[2]
Nakamura S. The roles of structural imperfections in InGaN-based blue light emitting
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Melbourne on 10/11/14 For personal use only.
diodes and laser diodes. Science 1998;281:956-961. [3]
Vreman HJ, Wong RJ, Stevenson DK, Route RK, Reader SD, Fejer MM, et al. Lightemitting diodes: a novel light source for phototherapy. Pediatr Res 1998;44:804-809.
[4]
Chang YS, Hwang JH, Kwon HN, Choi CW, Ko SY, Park WS, et al. In vitro and in vivo efficacy of new blue light emitting diode phototherapy compared to conventional halogen quartz phototherapy for neonatal jaundice. J Korean Med Sci 2005;20:61-64.
[5]
Subramanian S, Sankar MJ, Deodari AK, Velpandian T, Kannan P, Prakash GV, et al. Evaluation of phototherapy devices used for neonatal hyperbilirubinemia. Indian Pediatr 2011;48:689-696.
[6]
Seidman DS, Moise J, Ergaz Z, Laor A, Vreman HJ, Stevenson DK, et al. A new blue light-emitting phototherapy device: a prospective randomized controlled study. J Pediatr 2000;136:771-774.
[7]
Seidman DS, Moise J, Ergaz Z, Laor A, Vreman HJ, Stevenson DK, et al. A prospective randomized controlled study of phototherapy using blue and blue-green light-emitting devices, and conventional halogen-quartz phototherapy. J Perinatol 2003;23:123-127.
[8]
Maisels MJ, Kring EA. DeRidder J. Randomized controlled trial of light-emitting diode phototherapy. J Perinatol 2007;27:565-567.
15
[9]
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 multicenter randomized controlled trial. Indian Pediatr 2010;47:131-137.
[10] Tridente A, Luca DD. Efficacy of light-emitting diode versus other light sources for
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Melbourne on 10/11/14 For personal use only.
treatment of neonatal hyperbilirubinemia: a systematic review and meta-analysis. Acta Paediatr 2011;2:1-8. [11] Kumar P, Chawla D, Deorari A. Light-emitting diode phototherapy for unconjugated hyperbilirubinaemia in neonates. Cochrane Database Syst Rev 2011;12:CD007969. [12] Bhutani VK, Wong RJ. Neonatal phototherapy: choice of device and outcome. Acta Paediatr 2012;101:441-443. [13] Vreman HJ. Phototherapy: the challenge to accurately measure irradiance. Indian Pediatr 2010;47:127-128. [14] Vreman HJ, Wong RJ, Murdock JR, Stevenson DK. Standardized bench method for evaluating the efficacy of phototherapy devices. Acta Paediatr 2008;97:308-316. [15] Kuboi T, Kusaka T, Yasuda S, Okubo K, Isobe K, Itoh S. Management of phototherapy for neonatal hyperbilirubinemia: is a new radiometer applicable for all wavelengths and light source types? Pediatr Int 2011;53:689-693. [16] International Electrotechnical Commission. Medical electrical equipment - Part 2-50: Particular requirements for the safety of infant phototherapy equipment. IEC 60601-2-50. 2000. Geneva: International Electrotechnical Commission; 2000 - [cited 2002 Mar 6]; Available from URL:http://webstore.iec.ch/p-preview/info_iec60601-250%7Bed1.0%7Den.pdf
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[17] International Electrotechnical Commission. International Standard. Medical electrical equipment - Part 2-50: Particular requirements for the basic safety and essential performance of infant phototherapy equipment. IEC 60601-2-50. Edition 2.0. Geneva: International Electrotechnical Commission; 2009 - [cited 2010 Dec 28]; Available from
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URL:http://webstore.iec.ch/webstore/webstore.nsf/Artnum_PK/42737 [18] American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316. [19] De Carvalho M, De Carvalho D, Trzmielina S, Lopes JM, Hansen TW. Intensified phototherapy using daylight fluorescent lamps. Acta Paediatr 1999;88:768-771. [20] Anderson RR, Parrish JA. The optics of human skin. J invest 1981;77:13-9. [21] Jacobsen J, Brodersen R. Albumin-bilirubin binding mechanism. J Biol Chem 1983;258:6319-26. [22] Sisson TRC, Kendall N, Davies RE, Berger D. Factors influencing the effectiveness of phototherapy in neonatal hyperbilirubinemia. Birth Defects 1970;6:100-5. [23] Bhutani VK, Committee on Fetus and Newborn, American Academy of Pediatrics. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011;128:e1046-e1052. [24] Bhutani VK, Cline BK, Donaldson KM, Vreman HJ. The need to implement effective phototherapy in resource-constrained settings. Semin Perinatol 2011;35:192-197. [25] Csoma Z, Tóth-Molnár E, Balogh K, Polyánka H, Orvos H, Ocsai H, et al. Neonatal blue light phototherapy and melanocytic nevi: a twin study. Pediatrics 2011;128:e856-e864.
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[26] Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008;358:920-928. [27] Xiong T, Qu Y, Cambier S, Mu D. The side effects of phototherapy for neonatal jaundice: what do we know? What should we do? Eur J Pediatr 2011;170:1247-1255.
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Melbourne on 10/11/14 For personal use only.
[28] Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and nearterm newborns. Pediatrics 1999;103:6-14. [29] Draque CM, Sañudo A, de Araujo Peres C, de Almeida MF. Transcutaneous bilirubin in exclusively breastfed healthy term newborns up to 12 days of life. Pediatrics 2011;128:e565-e571.
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FIGURE LEGENDS
Figure 1. Spectral irradiance (μW/cm2/nm) in the four corner points and center of a 60 x 30 cm rectangle and average of the 5 points (150 measurements per point) according to the type of
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phototherapy device.
Table I. Maternal and neonatal characteristics in the study groups.
19
LED
Fluorescent
n = 74 (%)
n = 76 (%)
Maternal age (years) #
27 ± 7
25 ± 7
0.15
Years of school ≥ 10
40 (54)
36 (47)
0.41
First gestation
41 (55)
48 (63)
0.28
7/33 (21)
6/28 (21)
0.11
1 (1)
3 (4)
0.32
23 (31)
31 (41)
0.14
5 (7)
5 (7)
0.96
Prenatal care ≥ 6 visits
50 (68)
50 (66)
0.82
Vaginal delivery
44 (59)
48 (63)
0.52
Oxytocin
28 (38)
33 (43)
0.58
Birth Weight (g)#
3091 ± 555
3016 ± 510
0.39
Body surface (cm2)#
2048 ± 214
2078 ± 235
0.41
4 (5)
5 (6)
0.87
Male gender
32 (43)
43 (56)
0.10
Mixed and black race
66 (89)
62 (81)
0.16
ABO incompatibility
17 (23)
16 (21)
0.78
4 (5)
7 (9)
0.37
Hematocrit (%)
50 ± 6
50 ± 5
0.63
Reticulocyte (%)
5.7 ± 2.8
5.1 ± 2.8
0.25
2 (3)
3 (4)
0.99
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p
Previous newborn with jaundice needing treatment Twin pregnancy Maternal hypertension Maternal diabetes
Small for gestational age
G-6-PD deficient
Bruising/Cephalhematoma
20
Exclusive breastfeeding # Mean
62 (84)
68 (90)
0.42
s. d. All of the infants had a negative direct coombs test.
Table II. Total serum bilirubin, spectral irradiance, postnatal age and duration of phototherapy,
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in mean
s. d., in the study groups. LED
Fluorescent p
N = 74
N = 76
TSB at initiation of phototherapy (mg/dL)
14.0 ± 1.3
14.1 ± 1.2
0.96
TSB after 24 h of phototherapy (mg/dL)
10.3 ± 2.1
10.2 ± 2.4
0.84
Decline in TSB after 24 h of therapy (mg/dL)
3.8 ± 2.0
3.9 ± 2.3
0.81
0.16 ± 0.09
0.16 ± 0.08
0.81
9.5 ± 1.8
9.2 ± 1.6
(n=37)
(n=33)
TSB at suspension of phototherapy (mg/dL)
8.9 ± 1.6
8.8 ± 1.8
0.51
TSB 18-24 h after the end of therapy (mg/dL)
9.7 ± 2.2
9.5 ± 1.8
0.42
Irradiance (μW/cm2/nm)
10.5 ± 0.9
8.7 ± 0.6
