The Role of Phototherapy in the Crash-Cart Approach to Extreme Neonatal Jaundice

The Role of Phototherapy in the Crash-Cart Approach to Extreme Neonatal Jaundice Thor Willy Ruud Hansen, MD, PhD, MHA*,† Extreme neonatal jaundice occurs infrequently but carries a high risk of permanent sequelae (kernicterus) when it does. Rapid therapeutic intervention has the potential to reduce this risk in some infants. Several case reports of infants with acute intermediate to advanced bilirubin encephalopathy shows that reversal may be possible. Phototherapy can be instituted at the flip of a switch, whereas other therapeutic measures necessarily involve delays. Therefore, highintensity phototherapy must be regarded as an emergency measure in infants presenting with extreme jaundice and even more so in the presence of neurological symptoms. The principal and well-described effect of phototherapy involves conversion of bilirubin IX␣ (z, z) to more polar isomers, which are excreted in bile and urine. When care is taken to maximize the spectral power of phototherapy lights, and whenever possible with measures added to reduce the enterohepatic circulation of bilirubin, very rapid reductions in total serum bilirubin levels are possible. A hypothesis has been advanced that conversion of bilirubin to more polar photoisomers, which can reach relative concentrations of 20%-25% of total serum bilirubin within 1-2 hours, might have a direct neuroprotective effect. This theory posits that because polar molecules generally require a transporter to cross the blood– brain barrier, bilirubin photoisomers should be less prone to enter the brain. Although this theory has some support in in vitro toxicity studies, the evidence is controversial. Until further experimental support can be gained, photoconversion of bilirubin does not constitute a viable argument against instituting further measures against bilirubin neurotoxicity, such as intravenous immune globulin (when indicated) and exchange transfusion. Conversely, neither is the state of evidence an argument against immediate and effective phototherapy in the medical emergency of extreme neonatal jaundice. Semin Perinatol 35:171-174 © 2011 Elsevier Inc. All rights reserved. KEYWORDS acute bilirubin encephalopathy, bilirubin, bilirubin isomers, kernicterus, neonatal jaundice, phototherapy

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xtreme neonatal jaundice continues to occur despite measures to identify infants at risk before they are discharged from the birth hospital.1 The incidence of extreme jaundice in neonates has been studied in several countries, and estimates have ranged from 7.1/100,000 live births to 150/100,000.1– 4 Kernicterus, the often devastating sequelae of inadequately treated neonatal jaundice, also still happens.5–7 Until recently it has been believed that acute bilirubin encephalopathy, when it has reached the intermediate to

*Department of Neonatology, Women’s and Children’s Division, Oslo University Hospital–Rikshospitalet, Oslo, Norway. †Institute for Clinical Medicine, Faculty of Med, University of Oslo, Oslo, Norway. Address reprint requests to Professor Thor Willy Ruud Hansen, MD, PhD, MHA, Kvinne-og Barneklinikken, Oslo Universitetssykehus, Rikshospitalet, N-0027 Oslo, Norway. E-mail: [email protected]

0146-0005/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2011.02.012

advanced stages, is irreversible.8 However, recent case series suggest that complete or at least very significant reversal of toxicity may be possible.9 –11 Although the data do not allow for an estimate of the proportion of such cases that may be reversed, there is evidence to suggest that the likelihood of a successful outcome depends on rapid and effective institution of treatment.10 With this background, the need for a “crash-cart approach” to the management of infants with extreme neonatal jaundice has been argued.12,13 The purpose herein is to review the role of phototherapy and photoisomerization of bilirubin in a crash-cart approach.

The Mechanism of Phototherapy The beneficial effect of light on neonatal jaundice was discovered by an astute English nurse who noted that the skin of jaundiced infants who had been exposed to bright daylight 171

172 appeared less yellow than skin that had been protected by diapers or clothing14,15 Subsequent trials documented the effect of this, largely innocuous, treatment as far as lowering serum bilirubin levels.16 The bleaching effect of light on jaundiced skin explains why transcutaneous measurement of bilirubin does not correlate well with serum bilirubin values in infants undergoing phototherapy, as there will be an unpredictable gradient between skin and serum bilirubin.17 The relative importance of skin bleaching in the therapeutic effect of phototherapy has long been thought to be considerable and was manifested by the common practice of turning infants in phototherapy over between supine and prone positions at intervals to irradiate skin that had not been exposed to the lights.18 Recent data from Donneborg et al19 show that turning the infant over does not significantly impact on the effect of phototherapy and suggest that bilirubin circulating in skin capillaries may be a more important target for photoconversion. This also seems compatible with recent data from our group, which show that significant conversion of bilirubin to photoisomers can be measured in serum within a few minutes of starting phototherapy.20 Indeed, significant photoconversion of serum and tissue bilirubin happens long before changes in total serum bilirubin (TSB) are detectable.20,21 When exposed to light, a fraction of bilirubin in tissues and blood undergoes photochemical conversion reactions occurring at different rates and resulting in several different products. Configurational isomerization results in Z,E and E,Z isomers; is reversible; and is much faster than structural isomerization, which is irreversible and results in lumirubin (see Maisels and McDonagh21 for a review). Photooxidation was initially thought to be the main mechanism for phototherapy. This reaction occurs much more slowly than the other 2, and is thought to be less important than configurational and structural isomerization.22 Elimination of bilirubin photoproducts occurs both in bile and in urine, and depends both on the rates of formation as well as the rates of clearance of these products. It is important to remember that reduced ability to conjugate and excrete bilirubin are key factors in the mechanisms of jaundice in the neonate, and that phototherapy is effective because it bypasses these relative defects. Bilirubin absorbs most light at 460 nm in the blue region of the spectrum. So-called “special blue,” turquoise, and green lights are more effective than white/daylight lamps.23-26 Considering that longer wavelengths penetrate more deeply into the skin, these data seem compatible with the concept that conversion of bilirubin circulating in skin capillaries is very important in the clinical effect of phototherapy.19

Clinical Use of Phototherapy The clinical effect of phototherapy, in addition to wavelength, also depends on the energy of the light, also called irradiance, and the number of molecules which is concurrently irradiated. The number of exposed bilirubin molecules obviously depends on the TSB level, ie, the greater the TSB the more bilirubin molecules will be present in skin as well as in circulating blood.27 However, it also follows that the num-

T.W.R. Hansen ber of exposed bilirubin molecules in skin and capillary circulation will depend on the size of the irradiated skin area. Indeed, the product of irradiance and irradiated area of skin, known as spectral power, is a key concept in effective phototherapy. Irradiance is typically reported in watts per square meter or in microwatts per square cm per nm over a certain wavelength band. Unfortunately, the devices for measuring irradiance are not standardized. Conventional daylight phototherapy lamps can be expected to deliver an irradiance of approximately 8-10 ␮W/cm2/nm, although this may be improved by bringing the light source closer to the infant (no more than 20 cm away) and using bright reflecting surfaces in and around the bed.28 With special blue fluorescent lamps irradiance levels may reach 30-40 ␮W/cm2/nm.29 The American Academy of Pediatrics defines intensive phototherapy as a spectral irradiance of at least 30 ␮W/cm2/nm delivered to as much of the infant’s body-surface area as possible.30 The effect of phototherapy is typically measured in reduction of the infant’s TSB level. The effect you can anticipate will depend on several factors. First, if phototherapy is initiated during the first 3-4 days of life when TSB levels would normally be expected to increase, a satisfactory effect of phototherapy might be a leveling off of TSB levels, or a reduced rate of increase. Thus, an absolute reduction of TSB levels may not always be achievable during this phase. If phototherapy is started after this period, effective phototherapy should lead to a measurable reduction of TSB within 4-6 hours.29 In extreme neonatal jaundice (TSB levels ⬎30 mg/dL [⫽513 ␮mol/L]), we have previously documented reductions up to 10 mg/dL (⫽171 ␮mol/L) during the first 2 hours.31 Others have shown a decrement of TSB values of 30-40% over the first 24 hours, with the most pronounced decline occurring in the first 4-6 hours.32 Even greater reductions have recently been shown in patients with extreme jaundice and acute intermediate to advanced stage bilirubin encephalopathy where phototherapy was used in conjunction with intravenous immune globulin and/or exchange transfusion.11 Thus, in infants treated for extreme jaundice key points are to maximize irradiance and spectral power, in addition to reducing the enterohepatic circulation of bilirubin because some of the isomer excretion occurs in bile. Irradiance is maximized by bringing the lights (except quartz lights!) as close to the infant as possible—no more than 10-20 cm distance between the infant’s skin and the phototherapy lights. Light bulbs should be as fresh as possible, and any optical filters in the unit should be cleaned regularly. Spectral power is optimized by exposing as much skin as possible, exceptions being the need for protective covering of the eyes and, if absolutely necessary, diapers cut down to minimal working size. Reflecting white linen or other material inside the basinette or incubator and along the sides of the phototherapy unit will increase irradiance.28 Whether double or triple phototherapy33 will help further has not been tested using modern, high-energy phototherapy units, although such deployment apparently continues to occur. The risk– benefit ratio of this approach in an infant threatened by neurotoxicity, at least until further data accrue, appears to be extremely low.

Role of phototherapy in neonatal jaundice Enterohepatic circulation of bilirubin may, in some cases, contribute both to excessive and prolonged neonatal jaundice. There is evidence that breast milk substitutes can augment the effect of other therapies for neonatal jaundice.34 However, there is only anecdotal evidence for benefit in extreme jaundice.31 Nevertheless, unless clearly contraindicated for reasons of abdominal/bowel disease, it is difficult to see strong arguments against this approach, at least until further evidence can be obtained.

Phototherapy and Bilirubin Toxicity It was proposed a quarter of a century ago that photoisomerization of bilirubin would “detoxify” the molecule.35 In a recent study of bilirubin isomerization during near-intensive phototherapy in a neonatal intensive care unit, Mreihil et al20 argued as follows: “With respect to bilirubin toxicity, there are, a priori, three possibilities: the photoisomer has similar toxicity to the ‘natural’ isomer; the photoisomer is more toxic; or the photoisomer is less toxic. Of these, the first is unlikely because of the different structures and physicochemical properties of the two forms and the need for pigment to enter the brain to cause toxicity. The second possibility also seems unlikely because countless phototherapy treatments over the last half-century seem never to have caused or exacerbated CNS toxicity. This leaves the third possibility; the most likely in view of the much lower lipophilicity of the photoisomer compared with the 4Z,15Z isomer, which would be expected to make it less prone to cross the blood– brain barrier and enter the brain.” Unfortunately, no studies appear to be on record in which the authors investigated the transfer of bilirubin photoisomers to brain. The evidence regarding bilirubin photoisomer toxicity from in vitro studies is conflicting. In some studies, there appears to be evidence of increased cellular toxicity when cells are exposed to phototherapy in the presence of bilirubin.36-38 However, given the study conditions the results may not be relevant for our question. Mainly, irradiation conditions were such that it seems likely significant amounts of photooxidation products were formed, leading to oxidative cell damage.38 Other studies seem to support a hypothesis of less toxicity for the bilirubin photoproducts.39-44 However, the interpretation of these results should be guarded, because the experimental conditions both as far as light flux and isomer composition are variable and in several papers not well defined. It is notable that Broughton as early as in 196539 argued that “the toxicity of bilirubin has been attributed to its fat solubility, and it seems probable that the water-soluble products would, therefore, be less toxic, and also more easily excreted.” This discussion was renewed by McDonagh and Lightner 20 years later35 and reiterated by McDonagh in 2006,45 Maisels and McDonagh in 200821 and by our group in 2010.20 Because of the increasing concern about the apparent resurgence of kernicterus and the need to refocus our approach to infants with extreme jaundice who are threat-

173 ened by neurotoxicity in the direction of emergency care, it seems more necessary than ever to attempt to answer the questions discussed in this section. As we approach this task, we are likely to confront significant methodological problems connected with the solubility and stability of bilirubin and its isomers in aqueous solutions.

Conclusions Phototherapy has an undisputable role to play in the “crashcart approach” to treatment of extreme neonatal jaundice, with or without concomitant signs of neurotoxicity. All hospitals in which newborn infants are treated need to have a paradigm for expedient management of such infants. Whether photoisomerization per se is neuroprotective remains for the time being a theoretically attractive and logical, but experimentally unproven hypothesis. The practical implication of this is that there is no evidence at present to support the use of photoisomer concentrations in an arithmetic exercise to avoid exchange transfusion. However, this lack of evidence cannot be construed as an argument against the aggressive use of phototherapy in neurotoxicity-threatened infants while preparing for, as well as during the execution of adjunctive therapeutic options, such as intravenous immunoglobulin, exchange transfusion, and efforts to reduce the enterohepatic circulation of bilirubin.

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