Over the past five decades, phototherapy has become a bastion of neonatal practice although it was met initially with scepticism. Through its wide clinical application in developed nations, phototherapy not only effectively reduces bilirubin levels and the need for exchange transfusions; but also, has reduced the occurrence of kernicterus as well as having a possible role in reversing early acute bilirubin encephalopathy (ABE) when used in a ‘crash-cart mode’ (1,2). However, ensuing commercial and indigenous device adaptations of current (or available devices) have often been performed without rigour of scientific inquiry as to the safety, efficacy and actual performance of these devices prior to their clinical use. In 1998, Vreman et al. (3) pioneered the use of unique semiconductor light-emitting diodes (LEDs) that emitted blue light within a narrow bandwidth as a light source for neonatal phototherapy, which not only may provide higher irradiance levels, but also lead to the development and design of direct contact phototherapy with a mattress-like device that has minimal heat production, is portable, has limited glass parts and is energy-efficient (4,5). Now, two systematic reviews of four randomized controlled trials show comparable rates of declines in total serum bilirubin (TSB) levels and in the duration of phototherapy using current LED-based devices versus other light sources (6,7). The theory that a phototherapy light source should be designed to emit light at the wavelength that matches the specific peak bilirubin absorption was the goal of Cremer et al. (8) and Perryman et al. (9) when they first developed the phototherapy device. Since then, the choice of light sources has been primarily dependent on the manufacturer with occasional input from expert photobiologists, but has been limited by the manufacturer’s ability to provide ‘optimal’ wavelength light, varying irradiance and maximal and uniform light exposure to an infant’s body surface area (2). These ‘newer’ devices expose the limited evidentiary basis for our current use of the commercially available phototherapy devices. Use of light as a potential ‘drug’ needs to be a ‘prescriptive approach’ that is based on the dose of light given, adjusted for the exposed body surface area with a predictable and consistent response, and prescribed for specific indications. Indications for use are distinct: (i) prevention and treatment of progressive ABE or (ii) reduction of bilirubin load. The inherent biological variability of infants with severe hyperbilirubinaemia is known to be dependent of the dynamic rates of bilirubin production and bilirubin elimination with resultant changes of the hour-specific bilirubin value often described by the Valaes Equation (10). Vulnerability to bilirubin neurotoxicity is also associated with gestational age, postnatal age, concurrent haemolysis and rate of bilirubin–albumin binding (1). Unmeasured clinical factors include the refraction of light below the skin surface, confounding effects of other pigments such as melanin, haemoglobin, chromophores and subcutaneous water content (11). In brief summation, neonatal phototherapy is confounded by infant biology, infant maturation, disease process, light source, device design and consistent clinical implementation (12). An ideal clinical study would control for most of these known variables to provide an in vivo comparison of either the devices and/or different light sources. Both Kumar et al. and De Luca and Tridente (6,7) independently take on the challenge to review the current literature that compares diverse devices broadly categorized as LED-based and conventional, with the source of light either being halogen (13,14) or fluorescent (CFL) (15,16). The studies that these authors review have inconsistent study designs and limited in device comparisons almost akin to comparing infusion pumps to deliver a drug rather than the efficacy of the drug itself. The largest study (13) is well conducted and primarily drives the entire meta-analysis (61.4%) and leads the direction of comparison between two delivery systems. Table 1 shows the similarities and the diverse perspectives of both systematic reviews (6,7). These comparisons illustrate the need to characterize light properties, emitted and delivered, as well as the defined dynamic state of an infant’s bilirubin load, such that one can test whether the precision of light properties alters the ‘drug properties’. All investigators whose studies were selected for the meta-analysis used TSB decline as the primary outcome. The selection of the TSB may be considered appropriate if the clinical goal is to reduce the excessive bilirubin load. There are at least three limitations of using TSB as an outcome variable. Firstly, the differential responses among infants with increasing bilirubin load or delayed elimination cannot be tested. Secondly, the interval of timing of TSB sampling impacts the duration of exposure to phototherapy. And thirdly, recent studies attest to the rapid (within minutes) photo-isomerization upon exposure to light without a concomitant decline in TSB (17). For infants at risk for progressive ABE, characterization of indices other than TSB would be more informative and possibly relevant. Decline in unconjugated bilirubin levels, as crude surrogate for reduction in bilirubin load or bilirubin neurotoxicity, is most crucial within the first 3–4 h to verify the efficacy of phototherapy in reversing the accumulation of bilirubin, and thereby mitigating any neurotoxic manifestation and impacting the continued use of phototherapy. The ensuing decreasing TSB levels are not predictably linear and likely to be influenced by other process of bilirubin elimination. A clinical response to phototherapy should thus be determined by the rate of bilirubin decline within the first 4 h of light exposure and its correlation to the magnitude of the bilirubin load. With the advent and continued adaptation of LED, light into neonatal phototherapy devices has availed us an opportunity and capability to deliver a much narrower wavelength light and also to achieve a more uniform light exposure footprint. More recently, Vreman et al. (17) revealed the pattern of non-uniformity of the footprint with traditional fluorescent light sources and the ability to correct these flaws with appropriate LED-based devices. Because of inconsistencies in light exposure to body surface area and the inability to measure wavelength-specific irradiance (9,18) across different devices (see Table 1) (2) has most likely led to intervention heterogeneity (17). A more precise device irradiance mapping could enhance the International Electrotechnical Commission’s recommendation (adopted by most manufacturers) for the minimal requirement to assure irradiance uniformity as measured by a ratio of maximum to minimum values >0.4 (19). One approach could be a process that determines the distribution of irradiance over an entire illuminated area footprint plotted on a newborn homunculus (Fig. 1), starting at 1.25 cm from the edges and then measured at every 2.5 cm of the length and width to best illustrate the degree of heterogeneity of individual device light emission (17,20). Irradiance mapping of illuminated footprint with a silhouette of a newborn homunculus (as described by a methodology described by Vreman et al. (17) and used (20). Irradiance (μW/cm2/nm) is plotted for square centimetre of the illuminated surface. We have yet to determine the extent of light safety during the first week after birth regarding both immediate and long-term consequences. Even though for our postnatal life routine lifelong exposure to sunlight is generally considered safe, foetal life and development is shaded away from direct light exposure. Furthermore, to determine the reduction in the duration of phototherapy light exposure (and its surrogate, duration of hospitalization) as well as parent–infant separation, interruption of breastfeeding and use of formula supplements require prospective determination of actual implementation and time-precise data collection. Recent two meta-analyses (6,7) and the American Academy of Pediatrics Technical Report (2) are initial steps that can help build evidence to aid our choice in selecting the optimal light source for phototherapy and the need to accurately measure its safe clinical outcomes in a predictable manner consistent with standards for pharmacotherapy. Supported by the Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine. None.
To summarize the principles and application of phototherapy consistent with the current 2022 American Academy of Pediatrics "Clinical Practice Guideline Revision for the Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation."
Background: Hyperbilirubinemia is a benign transitional phenomenon that occurs in 60% to 80% of all term infants. The degree of hyperbilirubinemia and hence risk for developing bilirubin-induced neurologic dysfunction or BIND is dependent upon two major processes: (i) bilirubin production and its elimination. Objective: The aim of this review is to address the importance of hemolysis and its clinical detection in neonates with hyperbilirubinemia. Results: In newborns, an increased bilirubin production rate due to hemolysis is often the primary cause of hyperbilirubinemia during the first week of life. If undiagnosed or untreated, it may lead to an increased risk for BIND. Therefore, the ability to identify infants with hemolytic disease is important in assessing those at risk for developing BIND. In addition, an infant's genetic profile and bilirubin binding status can also affect their overall capacity to cope with the resultant tissue bilirubin load and affect risk and guide appropriate management strategies. Conclusion: Therefore, the determination of a newborn's bilirubin production rate is critical to the assessment of a newborn's risk for developing unpredictable extreme hyperbilirubinemia and preventing BIND. Keywords: Bilirubin, carbon monoxide, end-tidal breath, heme oxygenase, jaundice, hyperbilirubinemia.
