Cycled Phototherapy Dose-Finding Study for Extremely Low-Birth-Weight Infants

Abstract

IMPORTANCE Cycled (intermittent) phototherapy (PT) might adequately control peak total serum bilirubin (TSB) level and avoid mortality associated with usual care (continuous PT) among extremely low-birth-weight (ELBW) infants (401-1000 g). OBJECTIVETo identify a cycled PT regimen that substantially reduces PT exposure, with an increase in mean peak TSB level lower than 1.5 mg/dL in ELBW infants. DESIGN, SETTING, AND PARTICIPANTS This dose-finding randomized clinical trial of cycled PT vs continuous PT among 305 ELBW infants in 6 US newborn intensive care units was conducted from March 12, 2014, to November 14, 2018. INTERVENTIONS Two cycled PT regimens (Ն15 min/h and Ն30 min/h) were provided using a simple, commercially available timer to titrate PT minutes per hour against TSB level. The comparator arm was usual care (continuous PT). MAIN OUTCOMES AND MEASURESMean peak TSB level and total PT hours through day 14 in all 6 centers and predischarge brainstem auditory-evoked response wave V latency in 1 center. Mortality and major morbidities were secondary outcomes despite limited power. RESULTSConsent was requested for 452 eligible infants and obtained for 305 (all enrolled) (mean [SD] birth weight, 749 [152] g; gestational age, 25.7 [1.9] weeks; 81 infants [27%] were multiple births; 137 infants [45%] were male; 112 [37%] were black infants; and 107 [35%] were Hispanic infants). Clinical and demographic characteristics of the groups were similar at baseline. After a preplanned interim analysis of 100 infants, the regimen of 30 min/h or more was discontinued, and the study proceeded with 2 arms. Comparing 128 infants receiving PT of 15 min/h or more with 128 infants receiving continuous PT among those surviving to 14 days, mean peak TSB levels were 7.1 vs 6.4 mg/dL (adjusted difference, 0.7; 95% CI, 0.4-1.1 mg/dL) and mean total PT hours were 34 vs 72 (adjusted difference, −39; 95% CI, −45 to −32). Wave V latency adjusted for postmenstrual age was similar in 37 infants receiving 15 min/h or more of PT and 33 infants receiving continuous PT: 7.42 vs 7.32 milliseconds (difference, 0.10; 95% CI, −0.11 to 0.30 millisecond). The relative risk for death was 0.79 (95% CI, 0.40-1.54), with a risk difference of −4.5% (95% CI, −10.9 to 2.0). Morbidities did not differ between groups.CONCLUSIONS AND RELEVANCE Cycled PT can substantially reduce total PT with little increase in peak TSB level. A large, randomized trial is needed to assess whether cycled PT would increase survival and survival without impairment in small, preterm infants.

Challenges of phototherapy for neonatal hyperbilirubinemia (Review)

“…It was previously demonstrated that unbound bilirubin may stimulate the production of endogenous ROS in platelets, thereby inducing platelet apoptosis, which is a process mediated mainly by the p38 mitogen activated protein kinase pathway; in addition, bilirubin may damage mitochondria, inhibiting the energy metabolic process of the cell and causing cell apoptosis ( 99 ). Low levels of bilirubin may also be harmful ( 8 ). Phototherapy may disrupt the protective role of the cell membrane by lowering serum bilirubin, causing production of free oxygen radicals; it may also damage lymphocyte DNA and cause a disturbance of the skin cytokine environment, which disrupts the Th2 to Th1 conversion, thus leading to allergic diseases such as asthma and allergic rhinitis ( 42 , 100 ).…”

“…Although there are several treatment schemes available in the clinical setting, blue light is generally the preferred choice for preventing the development of bilirubin encephalopathy or nuclear jaundice caused by excessive accumulation of unconjugated bilirubin ( 6 , 7 ). A high serum level of free bilirubin may cause neurotoxicity, but mildly elevated bilirubin concentrations are beneficial due to their protective antioxidant role in cell membranes, while markedly low concentrations may also be harmful ( 8 , 9 ). However, during the treatment of neonatal hyperbilirubinemia, the level of free bilirubin in the serum is decreased, which may weaken the protective effect of bilirubin on the cell membrane, thus making the cell membrane susceptible to injury and causing cell apoptosis.…”

Effect of Reduced Versus Usual Lipid Emulsion Dosing on Bilirubin Neurotoxicity and Neurodevelopmental Impairment in Extremely Preterm Infants: Study Protocol for a Randomized Controlled Trial

“…For the standard deviation of the center random effect, a half-Normal (0,1) prior will be used. Similar neutral informative priors (19) will be used for non-binary outcomes. We will report posterior medians and 95% credible intervals for group differences and relative risks.…”

“…Recent evidence suggests that cycled phototherapy has similar effectiveness with less photo-oxidative injury than with conventional continuous phototherapy for ELBW infants. (17)(18)(19) However, further titration of phototherapy dosing is needed for the < 750 g birthweight infants because aggressive phototherapy in comparison to conservative phototherapy had higher rates of death with a reduction in profound NDI in infants < 750 g birthweight with aggressive phototherapy but no difference when profound NDI and death were assessed as a composite. (14) For this reason, the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) is conducting a RCT to determine whether cycled versus continuous phototherapy reduces mortality for ELBW infants.…”

Error in Byline

“…In the Original Investigation titled “Cycled Phototherapy Dose-Finding Study for Extremely Low-Birth-Weight Infants: A Randomized Clinical Trial,” published online April 27, 2020, there was an error in the author byline. The fourth author’s middle initial should be “A,” not “F,” so his name reads “Wally A. Carlo.” This article was corrected online.…”