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hototherapy: Current Methodsnd Future Directionsendrik J. Vreman, Ronald J. Wong, and David K. Stevenson

Phototherapy is the most common therapeutic intervention used for the treatment ofhyperbilirubinemia. Although it has become a mainstay since its introduction in 1958, abetter understanding of the photobiology of bilirubin, characteristics of the phototherapydevices, the efficacy and safety considerations of phototherapy applications, and improve-ments in spectroradiometers and phototherapy devices are necessary for more predictableand improved clinical practices and outcomes. A step forward in instituting consistent,uniform, and effective use of phototherapy is the recent American Academy of Pediatricsclinical guideline on the management of hyperbilirubinemia in the newborn infant 35 ormore weeks of gestation, which outlines a clinical strategy for the diagnosis of hyperbil-irubinemia and contains direct recommendations for the application of phototherapy. Thisarticle reviews the parameters that determine the efficacy of phototherapy, briefly dis-cusses current devices and methods used to deliver phototherapy, and speculates onfuture directions and studies that are still needed to complement our presently incompleteknowledge of the facets of this common mode of therapy.Semin Perinatol 28:326-333 © 2004 Elsevier Inc. All rights reserved.

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ost pediatricians understand phototherapy as the useof visible light for the treatment of hyperbilirubinemia

jaundice). In a recent article, McDonagh reviewed the his-ory of phototherapy from the use of heliotherapy in ancientgypt to the use of blue high intensity gallium nitride light-mitting diodes (LEDs) in the new millennium.1 For treat-ent of hyperbilirubinemia, light, in the range of approxi-ately 400 to 500 nm with a peak at 460 � 10 nm, is

onsidered the most effective. The efficacy of phototherapy isependent on the fundamental laws of photobiology andhotochemistry. The interaction of blue light with bilirubinauses a photochemical change that is therapeutically usefulnd this what makes phototherapy of neonatal jaundice pos-ible. Phototherapy causes rapid oxidative reactions and in-ermolecular rearrangements of bilirubin to produce mutantilirubin isomers,2 which are more polar and thus excretable

nto bile and urine without conjugation. Nonetheless, despitehis knowledge, pediatricians sometimes still resort to helio-herapy or apply visible light in homeopathic doses for pho-otherapy.

epartment of Pediatrics, Division of Neonatal and Developmental Medi-cine, Stanford University School of Medicine, Stanford, CA.

ddress reprint requests to: Hendrik J. Vreman, Department of Pediatrics,Division of Neonatal and Developmental Medicine, Stanford UniversitySchool of Medicine, 300 Pasteur Dr, S-214, Stanford, CA 94305-5208.

E-mail: henk.vreman@stanford.edu.

26 0146-0005/04/$-see front matter © 2004 Elsevier Inc. All rights reserved.doi:10.1053/j.semperi.2004.09.003

Understanding neonatal jaundice is fundamental to thestablishment of a sound and safe rationale for applying pho-otherapy. Jaundice is a commonly encountered problem af-er birth and occurs in 60 to 70% of term infants and nearlyll of preterm infants, including those near-term infants 35 to8 weeks gestational age. The etiology of this transitionalyperbilirubinemia of the newborn is complex, but can beest understood simply as an imbalance between increasedroduction (approximately two to three times higher on aody weight basis compared with an adult) and decreasedlimination of bilirubin related to a temporarily impairedonjugation system of the liver. In near-term infants, peakotal bilirubina levels may be higher and occur later than thatn term infants, near the end rather than at the beginning ofhe first week of life, and may therefore be discharged beforehey have reached peak total bilirubin levels. In addition,ecause of a shorter red blood cell (RBC) lifespan coupled

Historically, blood bilirubin fraction concentrations were determined inserum and hence the term serum bilirubin fractions and the abbrevia-tions with the letter “S” have become common usage (eg, TSB). However,bilirubin concentrations in the circulation are currently almost exclu-sively measured in anticoagulated blood, which upon centrifugation,yield RBCs and plasma, in which the bilirubin fractions are then mea-sured. For convenience, plasma total, albumin-bound, conjugated, andfree bilirubin fractions will be referred to as “total bilirubin” withoutreference to either plasma or serum since there are no differences be-

tween total bilirubin levels in these two matrices.

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Phototherapy 327

ith an impaired hepatic conjugation system, the near-termnfant has a relatively increased bilirubin production rate asompared with the term infant. Therefore, when superim-osed on a propensity for a later and higher peak total bili-ubin, near-term infants are even at a greater risk for devel-ping hyperbilirubinemia than the term newborn. Moreover,ny infant that has a pathologic increase in bilirubin produc-ion caused by increased RBC destruction or any other patho-ogic increase in heme degradation, or a genetically impairedonjugation system, is also at a greater risk for developingyperbilirubinemia.Treatment of neonatal hyperbilirubinemia using photo-

herapy was introduced in the late 1950s3 and was appliedrincipally to avoid exchange transfusions. Gradually, its useas been increasingly recommended for prophylaxis againsthe acute and reversible manifestations of bilirubin toxicityalled “acute bilirubin encephalopathy” and the chronic andermanent clinical sequelae called “kernicterus.”4 Ratherhan identifying a singular threshold of hyperbilirubinemiaie, exclusively on total bilirubin levels) for the diagnosis ofathologic jaundice, the American Academy of PediatricsAAP) has published a clinical practice guideline on theManagement of Hyperbilirubinemia in the Newborn Infant5 or more Weeks of Gestation” that will hopefully providereater uniformity and consistency in the application of pho-otherapy in this newborn population.4 The AAP outlines anpproach that provides a clinical pathway, using appropriateomograms, to help direct the use of phototherapy and/orxchange transfusion for the management of the newbornnfant being readmitted for jaundice.

Despite scientific knowledge about the mechanisms ofction and over half a century of clinical experience, de-ivery of phototherapy by pediatricians has remainedighly variable and influenced by beliefs, which would beest characterized as “half truths” or, sometimes, blatantfalsehoods,” despite being one of this country’s mostommonly prescribed medical therapies. Its practice istill too often characterized by homeopathic, ineffective,r unnecessarily intense applications for sometimes ap-ropriate, but other times inappropriate, indications.ompliance with the AAP guideline will hopefully lead tomore consistent use of phototherapy.Collective experience suggests that the efficacy of photo-

herapy applied to smaller, less mature newborns can bessumed. But the overall safety of its use in this populationemains uncertain and may have unknown potential toxicffects, which are less likely to occur in the larger, moreature and less translucent near-term and term newborns.lthough phototherapy is probably safe in short-term appli-ations, especially in near-term and term newborns, the long-erm effects of phototherapy and applications in less matureewborns need further consideration and study. Moreover,he methods by which phototherapy is currently being ap-lied are probably far from optimal. This review is intendedo comment on current devices and methods used to deliverhototherapy. In addition, we comment and speculate on

uture directions where studies are still needed to comple- m

ent our presently incomplete knowledge of all the facets ofhis frequently used mode of therapy.

hotobiology of Bilirubinhe rate of removal of unconjugated bilirubin from the bodyuring phototherapy depends on the following three relatedrocesses: (1) the rate of bilirubin photoalteration; (2) theransport of photoproducts from the skin to the circulation;nd (3) the excretion of these photoproducts by the liver andidney.2,5,6 Of these processes, the photoalteration of biliru-in (Fig. 1) is a complex set of photochemical reactions andelieved to be the rate-limiting step in the elimination ofilirubin from the body. Photo-oxidation involves the de-truction of bilirubin to colorless polar molecules that arexcreted primarily in the urine, and probably accounts fornly a small fraction in the elimination of bilirubin in vivo.2,6

ecause it is difficult to identify and measure all the metabo-ites before they are excreted, this fraction could be largerhan is presently assumed.7 A second process is configura-ional isomerization, which is the conversion of the stable,ative bilirubin isomer (4Z,15Z) to more water soluble and

ess toxic isomers (4Z,15E; 4E,15Z; and 4E,15E).7,8 Thesehotochemical reactions are reversible, but contribute to theemoval of bilirubin from the body without conjugation. Theredominant process of bilirubin elimination, and probablyhe rate-limiting mechanism, is the irreversible photoalter-tion of bilirubin to a structural isomer called lumirubin,hich is the major photoproduct excreted with the bile andrine. Lumirubin is a water soluble compound with an ab-orption peak of 453 nm and a molar absorption coefficientf 33,000 A453 units/cm, approximately 70% of that of bili-ubin (47,000 A460 units/cm).2 It does not test positive in theiazo reaction.

fficacyhe therapeutic efficacy of phototherapy is dependent pri-

igure 1 The major mechanisms of bilirubin photoalteration. (Re-rinted with permission.26)

arily on the following factors: the spectral qualities of the

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328 H.J. Vreman, R.J. Wong, and D.K. Stevenson

elivered light (wavelength range and peak),b intensity ofight (irradiance), exposed body surface area (BSA), skinhickness and pigmentation, the total bilirubin at clinicalresentation, and duration of exposure.

pectral Qualitieshe optimum light quality for the most efficient use of pho-

otherapy is still under active investigation and discussion.5,9

he yellow bilirubin absorption spectrum in plasma and inuffer/human serum albumin has been well established. Ineneral, the in vitro bilirubin light absorption spectrum issed as the basis for the design of phototherapy light sources.hus, the most effective light sources for degrading bilirubin

n the skin and the circulation are those that emit light in aelatively narrow wavelength range (400-520 nm) and cen-ered around a peak of 460 � 10 nm, which most closelyatches the bilirubin absorption spectrum. The rationale for

his belief is supported by the results of in vitro10 and in vivo3

xperiments conducted to determine the bilirubin photo-hemical degradation or action spectrum. Most research sup-orts the observation that blue light most closely matches theilirubin absorbance spectrum and, therefore, is expected toe the most effective light for photodegrading bilirubin inivo.5,11 However, more research is warranted in light of theecent and puzzling observations that the use of green orlue-green (turquoise) light, with peak emission of 490 nm,

s nearly as effective as blue light in decreasing total bilirubinevels in vivo.9,12 Unfortunately, performance of a completenalysis of the action spectrum of bilirubin in the human

When the spectral range for a light source or spectroradiometer is given, itrepresents the wavelength range and peak (in nm) where the light isdetectable. In some cases, the spectral range is defined as the spectralwidth at half the maximum intensity or “full width at half max” (FWHM).

able 1 Preliminary Results of a Study Comparing Spectralommercially Available Spectroradiometers at Commonly U

Light Meter (Manufacturer)[Range, Peak nm]

Light Source Irr

HalogenMini-BiliLite(Olympic)

HaloBiliBl

40 cm High S

iliBlanket Meter II (Ohmeda)[400-520, 450] 19.5 (100%)lympic Bili-Meter (Olympic)[425-475, 460] 18.9 (97%)

oey, JD-100 (Healthdyne)[420-550, 470] 40.0 (205%)

MA-2123 Bilirubin Detector(Solar Light Co.) [400-520, 460] 18.3 (94%)

If a light source produced a heterogeneous light pattern, the areaometer.

Because the Solar PMA-2123 meter only reports irradiance as �Wthe irradiance by the 60 nm bandwidth of the meter. This meter

tThis is also sometimes referred to as “bandwidth.”

ewborn will be impossible because it would be unethical topply the “less safe” shorter or “less efficient” longer wave-engths to pathologically jaundiced infants.

rradiancerradiance or light intensity refers to the number of photonss directed to or received per square cm of the exposed BSA.ecause the irradiance is quantitated as �W/cm2 within theffective wavelength range for efficacy, it is also referred to asspectral irradiance” and is expressed as �W/cm2/nm.13 “De-iverable spectral irradiance” is different for each type of lightource, and is dependent on the its design and the distanceetween the light source and patient in an inverse square rootelationship, where the light intensity of a point source ofight will decrease by the square of the distance. The spectralrradiance, like the amount of drug at a given level of purity,etermines the efficacy of treatment, with the higher dosageeing associated with greater efficacy of treatment. This rela-ionship has been studied with many of the older devices, buttill needs to be studied with some of the newer devices. Forxample, it has been concluded from some clinical studieshat a spectral irradiance of approximately 30 �W/cm2/nmepresents the beginning of a “plateau region” beyond whichurther increases in irradiance would not increase bilirubinegrading capability.14 However, in these same studies, thefficacy of irradiance was also apparently dependent onhe initial total bilirubin concentration. In the current AAPuideline, intensive phototherapy is defined as these of blue light (in the 430-490 nm band) delivered at0 �W/cm2/nm or higher to the greatest BSA as possible.In clinical practice, irradiance is traditionally measured

ith a hand-held spectroradiometer, which is designed to beensitive only to blue light at a wavelength range centered at60 � 10 nm. Thus, these radiometers, most of which appear

ances of Different Light Sources as Measured with Someistances

ce, �W/cm2/nm (% BiliBlanket Meter Reading)

Fiberoptict (Ohmeda)

Fluorescent BiliLite,Model 33 (Olympic)

N � 4 BB;N � 4 CW

LED (neoBLUE)(Natus)

g (Contact) 40 cm 30 cm

100%) 11.0 (100%) 35.7 (100%)

91%) 15.1 (137%) 27.8 (78%)

113%) 18.1 (164%) 61.7 (173%)

68%) 12.4 (112%) 37.8 (106%)

he highest spectral irradiance was measured by each spectroradi-

ver 400-520 nm, the spectral irradiance was calculated by dividinglimit of 43.5 �W/cm2/nm.

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Phototherapy 329

ootnote b), measure only the light assumed to be effective forhe photoalteration of bilirubin. There are a number of lighteters that are commercially available for quantitating spec-

ral irradiance. However, most of these are designed by aanufacturer for measuring spectral irradiance of its partic-lar light source. In practice, however, such discrimination isardly ever appreciated by the practitioner. Because mosturseries deploy several types of phototherapy devices andhe cost of the appropriate radiometers is prohibitively higho have one for each respective phototherapy device, spectralrradiance levels of all the devices are not uncommonly mea-ured with a single and, often inappropriate, spectroradiom-ter. As a result, these practices may result in clinically unre-iable and inaccurate assessments of phototherapy dose,esulting in ineffective phototherapy (overly sensitive meteror the light source) and consequent longer treatment dura-ion, over-treatment due to a low reading meter, or delayed orccelerated replacement of bulbs (Table 1). A universal andortable, “gold standard” meter usable for all types of lightources, regrettably, is not available. This situation requiresesolution if phototherapy is to be used consistently and ef-ectively. This problem may eventually be resolved if andhen all phototherapy devices are using narrow spectrumED light with 460 � 10 nm peak wavelength. But, in theeantime, when reporting light spectral irradiance measure-ents, it is important to describe clearly the characteristics of

he meter being used. This should include the name of theanufacturer, model number, sensitivity range, peak, band-idth, and time of last calibration. In an effort to at least

ystematize spectroradiometric assessment of the various de-ices, the authors use the Ohmeda BiliBlanket Meter II spec-roradiometer (Ohmeda Medical, Columbia, OH) as the ref-rence device (Table 1). This meter is chosen because it is onef the most commonly used devices and its spectral responseange (400-520 nm), peak (460 nm), and bandwidth60 nm) closely matches the bilirubin degradation spectrum.his spectroradiometer is also very stable over time (requir-

ng only yearly calibration) and measurements within andetween individual spectroradiometers and models for aiven light source are virtually identical.

xposed Surface Areaffective phototherapy is very much dependent on exposure

o the largest BSA of the newborn. The greater the area ex-osed, the greater the rate of total bilirubin decline.15 Atresent, the limited BSA exposure by all light sources is thereatest impediment to effective phototherapy. In general,ith the present overhead and underneath devices used sin-ly, only up to 30% of BSA is exposed to light. The variabilitynd limitation is attributable to the dimensions of a device’sight footprint at the manufacturers’ recommended distance.or example, a halogen spotlight at a distance of 25 cm fromhe newborn casts a spot of light of �15 cm in diameter with

high intensity spot in the center of �20 �W/cm2/nm,hich dramatically declines to �7 �W/cm2/nm at the outer

ight edge. Depending on the length of the newborn (average

f 60 and 30 cm for terms and preterms, respectively), these e

evices even incompletely illuminate the maximally possibleorizontal BSA. Moreover, the heterogeneity of the spectral

rradiance spot further decreases the efficacy of these devices.rom a practical perspective, a more appropriate design forhese devices would be the projection of an oblong spot ofight. For example, one of the most recently introduced spot-ight, the Giraffe Spot PT Lite (Ohmeda Medical) does notncorporate such a design feature even though, with its gel-lled light pipe, projection of a oblong light spot could haveasily been accomplished, at least from a technical perspec-ive. Thus, when using spotlights, use of multiple devicesay be necessary to ensure sufficient BSA coverage. Suchractice is not uncommon in the nursery, probably deter-ined by empirical observations of nursing staff and physi-

ians at the bedside.16 Another example is the BiliBlanketOhmeda Medical), which has a fairly high spectral irradi-nce of 35 �W/cm2/nm in the center, which gradually fallsff to �25 �W/cm2/nm at the edges of the 10 � 5 cm pad.he unavoidably small size of its illumination footprint se-erely limits the usefulness of this device as a single applica-ion source on larger newborns. Nonetheless, it can be useduccessfully in double phototherapy, combined with a stan-ard overhead device.16 In contrast, the BiliLite (Model 33,lympic Medical, Seattle WA), at a distance of 40 cm, gen-

rates a 60�60 cm footprint of light with a fairly uniform (nootspot) spectral irradiance of �11, 24, and 26 �W/cm2/nmhen fitted with 4BB � 4CW, BB, TL-52 tubes, respectively,

nd completely illuminates a newborn’s treatable ventral BSA�30% of the total BSA). Unfortunately, the clinical advan-age is offset by the large size of the device (with its sharpdges) which takes up much needed space over the newbornnd forces the staff to move the device during procedures.he newest overhead device, the LED-based neoBLUETM

Natus Medical, Inc., San Carlos, CA), has several advan-ages. Because each LED emits light through a lens, a moreocused light is cast in comparison to conventional devices.he arrangement of LEDs in conjunction with the diffuseranel provides, at 30-cm distance, a uniform spectral irradi-nce pattern across an infant’s entire ventral BSA with a lightootprint of 50 � 20 cm with an irradiance of up to 35W/cm2/nm. The device is also relatively small, lightweight,enerates little heat, and has rounded edges.

kin Thicknessnd Pigmentation andnitial Total Bilirubin Levelatient parameters, such as increases skin thickness (ie, inlder Crigler-Najjar patients)17 and highly pigmented skin,ave been reported to impede effective phototherapy.18 Fur-hermore, the initial total bilirubin level as well as an imbal-nce between bilirubin production and elimination also neg-tively affects phototherapy efficacy.19

uration of Exposurelthough duration of exposure to elevated total bilirubin lev-

ls could be an important factor in understanding risk for

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330 H.J. Vreman, R.J. Wong, and D.K. Stevenson

cute bilirubin encephalopathy or kernicterus, informationbout the duration of bilirubin exposure is generally lackingn the literature. Moreover, most of the literature addressingisk has been focused on peak total bilirubin levels. Thisimited perspective may need to be broadened to include theuration of exposure to total bilirubin or its fractions and isiscussed elsewhere in this issue (see article by Drs. Ahlforsnd Wennberg). Nonetheless, the rationale for lowering totalilirubin quickly under some conditions seems intuitivelybvious. In principle, increased duration of phototherapyoes translate into an increased rate of decline in total biliru-in levels. The AAP guideline now provides an hour-specificotal bilirubin nomogram, which serves to inform the clini-ian at what total bilirubin level phototherapy should bepplied in infants with varying risks for acute bilirubin en-ephalopathy or kernicterus.4 Highly effective phototherapyill decrease total bilirubin to safe levels more quickly than

ess effective phototherapy applied at a lower spectral irradi-nce and over a smaller BSA. In fact, Maisels has coined aerm called “spectral power” (mW/nm), which normalizespectral irradiance across a treated BSA.15

ide Effectsore effective phototherapy probably represents less risk for

he newborn, assuming that, in the photochemical reactions,he light does not affect molecules other than bilirubin. Thisatter possibility is one that should be explored more seri-usly for smaller, less mature and more translucent new-orns, who are often treated with photosensitizing drugs,uch as riboflavin (RF), Vitamin K, and others. RF, a powerfulndogenous photosensitizer, which has been extensivelytudied, decreases significantly in the circulation during blueight phototherapy.20 During this process, singlet O2 mole-ules are produced, which oxidize and destroy intracellularntegrity.21,22 Currently, a randomized trial of aggressive ver-us conservative phototherapy for extremely low birth weightELBW) infants is underway in 16 centers in the Nationalnstitute of Child Health and Human Development (NICHD)eonatal Research Network.Although bilirubin may represent a risk for auditory disabil-

ties and poor neurodevelopmental outcome, some degree ofyperbilirubinemia may provide beneficial antioxidant protec-ion in otherwise antioxidant-deficient newborns.23,24 For themall immature translucent newborn, phototherapy may repre-ent an unknown oxidative injury risk. Damage to RBC mem-ranes increases the susceptibility to lipid peroxidation and he-olysis has been described. Oxidation and free radicals have

een proposed as a contributing factor in the genesis of neonataliseases such as bronchopulmonary dysplasia (BPD), retinopa-hy of prematurity (ROP), necrotizing entercolitis (NEC), andatent ductus arteriosus (PDA), all of these occurring more fre-uently in ELBW infants who are almost all exposed to photo-herapy. Although phototherapy may be useful for avoidingigh levels of bilirubin that could contribute to auditory disabil-

ty or other neurodevelopmental problems, the over-applicationf phototherapy might eliminate from circulation and tissues

aturally occurring antioxidants that may be important in the c

ransitional newborn period, thus predisposing ELBW infants toore conditions caused or exacerbated by free radical reactions.

mportantly, the new LED light technology can potentially allowor the design of more finely-tuned devices that could minimizehe photo-oxidizing effects, while still achieving the desiredhotochemical reactions with bilirubin.Acute phototherapy is relatively a safe and simple method

f treatment. The reported side effects have been subject toxtensive and controversial debate.18,25,26 Side effects thatay occur, especially in premature infants, include rashes

erythema), oxidative injury, and dehydration (transepider-al water loss). Although irradiation of cells with light inten-

ities similar to those used in phototherapy can produce DNAamage,27 no change in growth, development, or infant be-avior have been reported in long-term follow-up studies of

nfants who have received phototherapy.28-30

urrent Light Sourceshere is a considerable selection of various custom-made andommercial phototherapy devices, which have been pro-uced for investigative and clinical applications. However, aomplete discussion of these is beyond the scope of this re-iew. In summary, phototherapy devices can be categorizedy their light source as follows: (1) fluorescent tube (TL12,0 cm, 20W) devices with different colors of light [cool whiteCW), blue, special blue (BB, 52, and 03), turquoise, orreen] of straight or U-shaped (18 cm, 18W tubes); (2) metalalide bulbs used in spotlights and incubator lights; (3) metalalide bulb and fiberoptic light guide combinations as used

n pads, blankets or spotlights; and (4) high intensity LEDssed presently as canopies and in the future as pads, blan-ets, or even clothing.

luorescent Tubeshe most commonly used light source in the U.S. is thepecial blue tube, such as F20 T12/BB or TL52/20W (Philips,he Netherlands). CW light has also been used together withpecial blue tubes to ameliorate caretakers’ complaints re-arding the blue hue of the light,31 but this combination ofubes dramatically decreases efficacy by as much as 50%—epending on the proportion of CW to special blue tubes. Atstandard distance of 40 cm, the devices with a 1:1 ratio of

ubes can deliver up to 11 �W/cm2/nm, while a unit contain-ng only special blue tubes can deliver up to 24 �W/cm2/nm.owever, the use of CW light typically provides only homeo-athic doses of phototherapy and may be inadequate in suf-ciently decreasing total bilirubin levels in a jaundiced infantnless the lights are positioned in close proximity, such asirectly below the infant.32

alogen Spotlightsalogen spotlight systems utilize a single or multiple metalalide lamps as the light source and can provide fairly high

rradiance often exceeding 20 �W/cm2/nm. However, thesenits can generate considerable heat, which can, in turn,

ause thermal injury to the infant and to unwary staff if ap-

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Phototherapy 331

lied too closely, and can emit ultraviolet (UV) radiation ifot appropriately shielded. The use of spotlights is some-imes preferred in the intensive care nursery because withremature or critically ill neonates on radiant warmers, itsesign allows for ad hoc positioning of these devices for theonvenience of caregivers. However, their variable position-ng with respect to the distance from the infant and angle ofpplication as well as their irradiance heterogeneity can leado unreliable dosing and unpredictable clinical responses.

iberoptic Systemsiberoptic phototherapy has been available since the late980s.33 Since that time, there have been improvements inhe way the plastic fibers are woven into the light pad, but theetal halide bulb remains the source of infrared (IR) andV-filtered light that enters the fiberoptic cable. Because theads or blankets emit insignificant levels of heat, they can belaced in direct contact with the infant and, thereby, caneliver up to 35 �W/cm2/nm of spectral irradiance. The ori-ntation of the fiberoptic fibers determines the uniformity ofmission and is unique to each of the commercially availableevices. Ultimately, the main advantages of this system arehat, while receiving phototherapy, the infant can be held orven nursed and the covering of the infant’s eyes is not nec-ssary. Although a boon to the home phototherapy market,hese systems often provide only homeopathic doses of lightor treatment of hyperbilirubinemia because they have a lowverage spectral power and treat only a small portion of BSA.hese devices can be used as an adjunct to conventionalverhead application of phototherapy providing “double”hototherapy, thereby more closely approximating circum-erential phototherapy, which has greater efficacy because ofreater BSA exposed to the light.34,35

EDshe new semiconductor phototherapy devices using high

ntensity gallium nitrate LEDs have many advantages overonventional light sources.36 In particular, blue light LEDsmit high intensity, narrow spectrum light (470 � 60 nm or70 � 15 nm FWHM) that overlaps the peak of the bilirubinbsorption spectrum. Electrical energy is converted to lightnergy more efficiently in LEDs than standard light devicesnd thus greater efficiency is possible. Practically, they have auch longer lifetime (�20,000 hrs) and have become cost-

ffective for use in phototherapy devices. Because a singleED emits little heat and requires little power, arrays of LEDsan easily match or exceed the useful light intensity of fluo-escent tubes, particularly when one considers that most ofhe light output of the latter is wasted into space, whereasEDs project light toward the target. Moreover, becauseEDs emit little IR or no UV radiation, they can thereforeventually be applied closer to the infant than the presentlyvailable neoBLUETM overhead device. Using surface-mountEDs applied to flexible circuit boards enclosed in siliconeubber or vinyl, devices can be fashioned into blankets,raps, or even clothing (Fig. 2).37 Because the peak wave-

ength of LEDs can be selected, this light source is ideal for in l

ivo photodegradation of bilirubin while possibly minimiz-ng the activation of endogenous or administered photosen-itizers (eg, RF). When used as contact devices, any sideffects to the caregiver are avoided. In vitro36 and in vivo12,38

xperimentation have established that the efficacy of thisight source is a match for the most intense halogen or fluo-escent sources, but with a number of safety advantages.

ith LED technology, the ability to deliver narrow bilirubin-pecific band spectral irradiances of up to 100 �W/cm2/nm isow technically possible. However, this does not only raisehe possibility of accessing bilirubin in the circulation andhereby degrade bilirubin before it enters the skin, but also aoncern regarding the potential of light not only causinghotochemical reactions in the skin, but also in the circula-ion itself.39 The safety of contact or high intensity LED pho-otherapy is not known at this juncture and cannot be rec-mmended for routine use without a carefully controlledtudy.

ther ConcernsBlue Hue” Effectlue light may be most therapeutic for jaundiced infants, butaregivers have reported a range of “irritations” from the usef blue fluorescent tubes, including headaches, nausea, andertigo.31 Initially, it was thought that the direct currentDC)-powered, LED-based devices would be free of suchffects because this light does not “flicker” at 50 to 60 Hz/sec,s do AC-powered fluorescent tubes. This appears not to behe case and the true cause for the visual irritation is moreikely due to the blue color itself. Thus, Natus Medical has

odified the second generation of the neoBLUE™ device byncorporating strategically spaced amber LEDs to “wash out”he “blue hue” effect for the caregiver, without decreasing thefficacy of the device. We resolved this caregiver irritationuccessfully by installing a 300 � 600 � 0.07 mm thickellow-colored flexible polycarbonate shield (Roscolux312, Musson, Santa Clara, CA) to the front lower edge of theevice.

hototherapy and Carbon Monoxidelthough most clinicians are familiar with the equimolar re-

igure 2 Present and future applications of lens-type and surface-ount LED-based devices (in cross-section). (A) Canopy; (B) LEDed; and (C) Blanket or circumferential (360°) Wrap. IR, infrared;ICU, neonatal intensive care unit. (Reprinted with permission.26)

ationship between bilirubin production and carbon monox-

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2

332 H.J. Vreman, R.J. Wong, and D.K. Stevenson

de (CO) production and the ability to estimate total bodyilirubin production by measuring CO concentrations or ex-retion rates in breath,40 the relationship between the appli-ation of phototherapy and CO production is less well appre-iated. We have reported on CO production as the result ofhotosensitizer-mediated oxidation of organic mole-ules.26,41,42 Grünhagen and coworkers, studying the fairlyontroversial issue of transepidermal water loss (TEWL) dur-ng halogen spotlight phototherapy in premature infants,ound that TEWL increases approximately 20% during pho-otherapy, despite a constant skin temperature and relativeumidity.43 They concluded that the increase in the evapo-ation rate caused by halogen spot phototherapy cannot bescribed to a change in thermal regulation. They suggestedhat, in premature infants who lack the ability to sweat, thereight be a relationship between skin blood flow and TEWL.any others have also studied the relationship between pho-

otherapy and blood flow.44

Phototherapy increases skin blood flow through a mecha-ism known as photorelaxation, the pathway of which haseen incompletely investigated, but is believed to involve theroduction and action of nitric oxide (NO) in the vasculaturef the skin.45 However, endogenous CO production has alsoeen associated with vasorelaxation.46 CO production in theermis through RF-mediated photo-oxidation of endoge-ous substrates could account for the difficulties in definingclear vasorelaxation role of NO in the context of photother-py. RF is a photosensitizer which is destroyed during pho-otherapy, and CO is one of the products of photo-oxida-ion.21,26,47 At the very least, the interaction of the NO and COnzymatic systems needs to be explored in the context ofhototherapy to fully appreciate the impact of phototherapyn vascular responses in the skin. Moreover, if photo-oxida-ion were to generate CO in tissues such as neuronal mem-ranes because of the penetration of significant levels of lighteeper into translucent ELBW infants due to intensive pho-otherapy,39 then adverse impacts on neuronal development,ncluding the formation of synapses, may have profound ef-ects on neurodevelopmental outcome. Lack of correlationetween surrogates of central nervous system injury, such as

ntracranial hemorrhage and long-term neurodevelopmentalutcome, raises the specter of more generalized factors thatould adversely affect neurodevelopmental outcome. Photo-herapy is one such influence in the lives of most ELBWnfants that could theoretically benefit or harm such infantsepending on the appropriateness of its application, dose, oruration.

onclusionsn conclusion, phototherapy is one of the most commonedical interventions with well-established efficacy androbably safety for most short-term applications in near-termnd term infants with neonatal hyperbilirubinemia. Thereas been recent clarification of management of hyperbiliru-inemia in the newborn infant 35 or more weeks of gestationith the publication of the AAP guideline with direct recom-

endations for the application of phototherapy. Nonethe-

ess, a better understanding of the photobiology, character-stics of the devices employed for phototherapy, the efficacynd safety of phototherapy applications, and improvementsn spectroradiometers and phototherapy devices are all nec-ssary for more predictable and improved clinical practicesnd outcomes.

cknowledgmentshis work was supported by unrestricted gifts from the H.M.ui Research Fund, the Hess Research Fund, and the Mary L.ohnson Research Fund.

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