CHAPTER ONE
1.0 INTRODUCTION
Jaundice as a clinical sign has been recorded for over 2300 years, and quite logically anything written about it, in a purely clinical sense, is often mostly repetitious. However, the jaundiced patient is frequently ill, uncomfortable, unsightly and unable to work; thus it is worthwhile to review this problem from time to time. There has been a progressive unraveling of the many facets of the jaundice problem in the past 10 years which has been of great value to the practicing physician
. A good portion of this paper will be devoted to reviewing these research aspects as they have contributed to our knowledge and aided in our interpretation of recognized clinical disorders. More than a century ago, Virchow noticed the presence of crystals of bilirubin; however, it was Hans Fischer who, shortly after the turn of the century, isolated these crystals in pure form and established the whole field of porphyry chemistry as a concern of clinical medicine. Very soon thereafter, van den Bergh and Snapper adopted Ehrlich's specific test for bilirubin in the urine in a quantitative manner. It would be helpful to recall that the van den Bergh test consists of the addition of diazotized sulfanilic acid to serum, urine or bile. with the production of a red color which is then Quantitated for interpretation. It was noted by these authors that in hemolytic states the. Red colour would not appear when the sulfanilic acid was added to the serum unless alcohol was also present. However, the red color could be obtained without the addition of alcohol if the serum was obtained from patients with obstructive jaundice or if fresh bile was used. These workers concluded that the liver acts on the serum to permit the second type of reaction to occur, a reaction they termed direct; they called the former reaction indirect. In the years that followed, physiologists, largely on the Continent, put forward the theory that bilirubin was not separated from the globin of hemoglobin at the site of red-cell breakdown in the reticuloendothelial system. It was indicated on rather incomplete experimental evidence that this globin-bilirubin compound circulated in the blood to the liver, where the globin was split off and the birubin was excreted as a sodium salt. The globin biirubin was thought to be the cause of the indirect van den Bergh reaction, whereas the direct reaction was ascribed to the sodium bilirubinate.
CHAPTER TWO
2.0 LITERATURE REVIEW
Although the problems of at least 80% of patients presenting with jaundice lend themselves to accurate diagnosis by conventional clinical and laboratory findings, the remainder present an ever-increasing problem. The widespread and often indiscriminate use of many drugs has made the diagnosis of jaundice more difficult. It is now well established that many of these substances may affect liver function in a very selective fashion, resulting in a pattern of laboratory findings similar to those usually associated with surgical lesions of the biliary tree.
Neonatal jaundice affects up to 84% of term newborns and is the common cause of hospital readmission in the neonatal period 2. Severe hyperbilirubinemia ( total serum Bilirubin [ JSB] level of more than 20 mg per DL (342.1NMOL per]) occurs I less than 2% of term infants and can lead to Kernicterus (i.e chronic Bilirubin encephalopathy) and permanent neuro- developmental delay. Therefore , it is important to systematically evaluate all infants for hyperbilirubin.
2.1 CAUSES OF JAUNDICE
Excess bilirubin is the main cause of jaundice. Bilirubin which is responsible for the yellow colour of jaundice is a normal part of of the pigment released from the breakdown of ‘used’ red blood cells.A new born liver cant remove the bilirubin quickly enough, causing an excess of bilirubin.
2.2 PREVENTIONS
2.2.1 PRIMARY PREVENTION
In numerous policy statements, the AAP recommends breastfeeding for all healthy term and near-term newborns. This guideline strongly supports this general recommendation.
RECOMMENDATION 1.0: Clinicians should advise mothers to nurse their infants at least 8 to 12 times per day for the first several days (American Academy of Pediatrics, 2002) (evidence quality C: benefits exceed harms). Poor caloric intake and/or dehydration associated with inadequate breastfeeding may contribute to the development of hyperbilirubinemia (Maisels and Newman,1995).
Increasing the frequency of nursing decreases the likelihood of subsequent significant hyperbilirubinemia in breastfed infants (Varimo et al.,1986) Providing appropriate support and advice to breastfeeding mothers increases the likelihood that breastfeeding will be successful.
RECOMMENDATION 1.1: The AAP recommends against routine supplementation of nondehydrated breastfed infants with water or dextrose water (evidence quality B and C: harms exceed benefits). Supplementation with water or dextrose water will not prevent hyperbilirubinemia or decrease TSB levels (Carvalho et al.,1981).
2.2.2 SECONDARY PREVENTION
RECOMMENDATION 2.0: Clinicians should perform ongoing systematic assessments during the neonatal period for the risk of an infant developing severe hyperbilirubinemia.
2.3 BLOOD TYPING
RECOMMENDATION 2.1: All pregnant women should be tested for ABO and Rh (D) blood types and have a serum screen for unusual isoimmune antibodies (evidence quality B: benefits exceed harms).
RECOMMENDATION 2.1.1: If a mother has not had prenatal blood grouping or is Rh-negative, a direct antibody test (or Coombs’ test), blood type, and an Rh (D) type on the infant’s (cord) blood are strongly recommended (evidence quality B: benefits exceed harms).
RECOMMENDATION 2.1.2: If the maternal blood is group O, Rh-positive, it is an option to test the cord blood for the infant’s blood type and direct antibody test, but it is not required provided that there is appropriate surveillance, risk assessment before discharge, and follow-up (Madlon-Kay,1992).
2.4 CLINICAL ASSESSMENT
RECOMMENDATION 2.2: Clinicians should ensure that all infants are routinely monitored for the development of jaundice, and nurseries should have established protocols for the assessment of jaundice. Jaundice should be assessed whenever the infant’s vital signs are measured but no less than every 8 to 12 hours (evidence quality D: benefits versus harms exceptional). In newborn infants, jaundice can be detected by blanching the skin with digital pressure, revealing the underlying color of the skin and subcutaneous tissue. The assessment of jaundice must be performed in a well-lit room or, preferably, in daylight at a window. Jaundice is usually seen first in the face and progresses caudally to the trunk and extremities( Kramer,1969) but visual estimation of bilirubin levels from the degree of jaundice can lead to errors( Moyer et al.,2000). In most infants with TSB levels of less than 15 mg/dL (257 μmol/L), noninvasive TcB-measurement devices can provide a valid estimate of the TSB level( Bhutani et al.,2000).
RECOMMENDATION 2.2.1: Protocols for the assessment of jaundice should include the circumstances in which nursing staff can obtain a TcB level or order a TSB measurement (evidence quality D: benefits versus harms exceptional).
2.5 LABORATORY EVALUATION
RECOMMENDATION 3.0: A TcB and/or TSB measurement should be performed on every infant who is jaundiced in the first 24 hours after birth. The need for and timing of a repeat TcB or TSB measurement will depend on the zone in which the TSB falls,(Bhutani et al.,2000) the age of the infant, and the evolution of the hyperbilirubinemia.
2.6 GUIDELINES FOR PHOTOTHERAPY IN HOSPITALIZED INFANTS OF 35 OR MORE WEEKS’ GESTATION.
These guidelines are based on limited evidence and the levels shown are approximations. The guidelines refer to the use of intensive phototherapy which should be used when the TSB exceeds the line indicated for each category. Infants are designated as “higher risk” because of the potential negative effects of the conditions listed on albumin binding of bilirubin(Soskolne et al.,1996), the blood-brain barrier,(Cashore,1980) and the susceptibility of the brain cells to damage by bilirubin(Bratlid,1990). “Intensive phototherapy” implies irradiance in the blue-green spectrum (wavelengths of approximately 430–490 nm) of at least 30 μW/cm2 per nm (measured at the infant’s skin directly below the center of the phototherapy unit) and delivered to as much of the infant’s surface area as possible. Note that irradiance measured below the center of the light source is much greater than that measured at the periphery. Measurements should be made with a radiometer specified by the manufacturer of the phototherapy system. If total serum bilirubin levels approach or exceed the exchange transfusion line, the sides of the bassinet, incubator, or warmer should be lined with aluminum foil or white material( Eggert et al.,1984). This will increase the surface area of the infant exposed and increase the efficacy of phototherapy. If the total serum bilirubin does not decrease or continues to rise in an infant who is receiving intensive phototherapy, this strongly suggests the presence of hemolysis. Infants who receive phototherapy and have an elevated direct-reacting or conjugated bilirubin level (cholestatic jaundice) may develop the bronze-baby syndrome. G6PD deficiency is widespread and frequently unrecognized, and although it is more common in the populations around the Mediterranean and in the Middle East, Arabian peninsula, Southeast Asia, and Africa, immigration and intermarriage have transformed G6PD deficiency into a global problem(Kaplan and Hammerman,1998).
Furthermore, G6PD deficiency occurs in 11% to 13% of African Americans, and kernicterus has occurred in some of these infants( Johnson et al.,2002). In a recent report, G6PD deficiency was considered to be the cause of hyperbilirubinemia in 19 of 61 (31.5%) infants who developed kernicterus.
2.7 RISK ASSESSMENT BEFORE DISCHARGE
RECOMMENDATION 5.1: Before discharge, every newborn should be assessed for the risk of developing severe hyperbilirubinemia, and all nurseries should establish protocols for assessing this risk. Such assessment is particularly important in infants who are discharged before the age of 72 hours (evidence quality C: benefits exceed harms).
RECOMMENDATION 5.1.1: The AAP recommends 2 clinical options used individually or in combination for the systematic assessment of risk: pre-discharge measurement of the bilirubin level using TSB or TCB and/or assessment of clinical risk factors. Whether either or both options are used, appropriate follow-up after discharge is essential (evidence quality C: benefits exceed harms).
The best documented method for assessing the risk of subsequent hyperbilirubinemia is to measure the TSB or TcB level( Bhutani et al.,2000) and plot the results on a nomogram . A TSB level can be obtained at the time of the routine metabolic screen, thus obviating the need for an additional blood sample. Some authors have suggested that a TSB measurement should be part of the routine screening of all newborns( Bhutani et al.,1999). An infant whose predischarge TSB is in the low-risk zone is at very low risk of developing severe hyperbilirubinemia(Stevenson et al.,2001).
- But, because these risk factors are common and the risk of hyperbilirubinemia is small, individually the factors are of limited use as predictors of significant hyperbilirubinemia( Newman et al.,2000). Nevertheless, if no risk factors are present, the risk of severe hyperbilirubinemia is extremely low, and the more risk factors present, the greater the risk of severe hyperbilirubinemia( Newman et al.,2000). The important risk factors most frequently associated with severe hyperbilirubinemia are breastfeeding, gestation below 38 weeks, significant jaundice in a previous sibling, and jaundice noted before discharge( Maisels and Kring,1998). A formula-fed infant of 40 or more weeks’ gestation is at very low risk of developing severe hyperbilirubinemia (Newman et al.,2000).
2.8 HOSPITAL POLICIES AND PROCEDURES
RECOMMENDATION 6.1: All hospitals should provide written and verbal information for parents at the time of discharge, which should include an explanation of jaundice, the need to monitor infants for jaundice, and advice on how monitoring should be done (evidence quality D: benefits versus harms exceptional).
2.9 FOLLOW-UP
RECOMMENDATION 6.1.1: All infants should be examined by a qualified health care professional in the first few days after discharge to assess infant well-being and the presence or absence of jaundice. The timing and location of this assessment will be determined by the length of stay in the nursery, presence or absence of risk factors for hyperbilirubinemia and risk of other neonatal problems (evidence quality C: benefits exceed harms).
2.9.1 Timing of Follow-up
RECOMMENDATION 6.1.2: Follow-up should be provided as follows:
For some newborns discharged before 48 hours, 2 follow-up visits may be required, the first visit between 24 and 72 hours and the second between 72 and 120 hours. Clinical judgment should be used in determining follow-up. Earlier or more frequent follow-up should be provided for those who have risk factors for hyperbilirubinemia. Whereas those discharged with few or no risk factors can be seen after longer intervals (evidence quality C: benefits exceed harms).
RECOMMENDATION 6.1.3: If appropriate follow-up cannot be ensured in the presence of elevated risk for developing severe hyperbilirubinemia, it may be necessary to delay discharge either until appropriate follow-up can be ensured or the period of greatest risk has passed (72-96 hours) (evidence quality D: benefits versus harms exceptional).
2.9.2 Follow-up Assessment
RECOMMENDATION 6.1.4: The follow-up assessment should include the infant’s weight and percent change from birth weight, adequacy of intake, the pattern of voiding and stooling, and the presence or absence of jaundice (evidence quality C: benefits exceed harms). Clinical judgment should be used to determine the need for a bilirubin measurement. If there is any doubt about the degree of jaundice, the TSB or TcB level should be measured. Visual estimation of bilirubin levels can lead to errors, particularly in darkly pigmented infants (evidence quality C: benefits exceed harms).
2.10 MEDICATION
Phototherapy, intravenous immune globulin (IVIG), and exchange transfusion are the most widely used therapeutic modalities in infants with neonatal jaundice. Although medications that impact bilirubin metabolism have been used in studies, drugs are not ordinarily used in unconjugated neonatal hyperbilirubinemia.
2.11 PHOTOTHERAPY
Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia (Bhutani et al.,1999). This therapeutic principle was discovered rather serendipitously in England in the 1950s and is now arguably the most widespread therapy of any kind (excluding prophylactic treatments) used in newborns. Phototherapy is effective because 3 reactions can occur when bilirubin is exposed to light, as follows:
* Initially, photooxidation was believed to be responsible for the beneficial effect of phototherapy. However, although bilirubin is bleached through the action of light, the process is slow and is now believed to contribute only minimally to the therapeutic effect of phototherapy.
* Configurational isomerization is a very rapid process that changes some of the predominant 4Z,15Z bilirubin isomers to water-soluble isomers in which one or both of the intramolecular bonds are opened (E,Z; Z,E; or E,E). In human infants, the 4Z,15E isomer predominates, and, at equilibrium conditions, the isomer constitutes about 20-25% of circulating bilirubin after a few hours of phototherapy(Garcia and Nager,2002). This proportion is not significantly influenced by the intensity of light, nor by the character of the light source or use of "double phototherapy(Garcia and Nager,2002). Data have shown that formation of photoisomers is significant after as little as 15 minutes of phototherapy(Garcia and Nager,2002) More recent studies suggest that the initial rate of isomerization is inversely related to the hemoglobin level.
* Structural isomerization consists of intramolecular cyclization, resulting in the formation of lumirubin. This process is enhanced by increasing the intensity of light. During phototherapy, lumirubin may constitute 2-6% of the total serum bilirubin concentration.
The photoisomers of bilirubin are excreted in bile and, to some extent, in urine. The half-life of lumirubin in serum is much shorter than that in E isomers, and lumirubin is the primary pigment found in bile during phototherapy.
Bear in mind when initiating phototherapy that lowering of the total serum bilirubin concentration may be only part of the therapeutic benefit. Because photoisomers, by virtue of their water-soluble nature, should not be able to cross the blood-brain barrier, phototherapy may reduce the risk of bilirubin-induced neurotoxicity as soon as the lights are turned on. At any given total serum bilirubin concentration, the presence of 20-25% of photoisomers means that only 75-80% of the total bilirubin may be present in a form that can enter the brain. Please note that although theoretically coherent, no experimental data support this speculation.
Phototherapy can be administered in a number of ways. To understand the benefits and limitations of the various approaches, some basic principles regarding wavelength and types of light are discussed below with comments and suggestions regarding each system.
First, wavelength must be considered. Bilirubin absorbs light primarily around 450-460 nm. However, the ability of light to penetrate skin is also important; longer wavelengths penetrate better. Thus, lamps with output predominantly in the blue region of the spectrum (460-490 nm) are probably most effective. In practice, light is used in the white, blue, turquoise, and green wavelengths.
Second, previously a dose-response relationship was thought to exist between the amount of irradiation and reduction in serum bilirubin up to an irradiation level of 30-40 µW/cm2/nm. Many older phototherapy units deliver much less energy, some at or near the minimally effective level, which appears to be approximately 6 µW/cm2/nm. On the other hand, newer phototherapy units, when properly configured and with the use of reflecting blankets and curtains may deliver light energy above 40 µW/cm2/nm. Recent data do not confirm that there really is a saturation level( Kaplan et al.,1998). Thus, the relationship between irradiance and the 24-hour decrement in total serum bilirubin was linear up to 55 μW/cm2, and with no evidence of a saturation point.
Third, the energy delivered to the infant's skin decreases with increasing distance between the infant and the light source. This distance should not be greater than 50 cm (20 in) and can be less (down to 10 cm) provided the infant's temperature is monitored.
Fourth, the efficiency of phototherapy depends on the amount of bilirubin that is irradiated. Irradiating a large skin surface area is more efficient than irradiating a small area, and the efficiency of phototherapy increases with serum bilirubin concentration.
Fifth, the nature and character of the light source may affect energy delivery. Irradiation levels using quartz halide spotlights are maximal at the center of the circle of light and decrease sharply towards the perimeter of the circle. Large infants and infants who can move away from the circle's center may receive less efficient phototherapy.
Although green light theoretically penetrates the skin better, it has not been shown unequivocally to be more efficient in clinical use than blue or white light. Because green light makes babies look sick and is unpleasant to work in, green light has not gained widespread acceptance.
Blue fluorescent tubes are widely used for phototherapy. Narrow-spectrum blue lamps (special blue) appear to work best, while ordinary blue fluorescent lamps are probably equivalent to standard white daylight lamps. Blue lights may cause discomfort in hospital staff members, which can be ameliorated by mixing blue and white tubes in the phototherapy unit.
White (daylight) fluorescent tubes are less efficient than special blue lamps; however, decreasing the distance between infants and lamps can compensate for the lower efficiency. Use of reflecting materials also helps. Thus, in LMICs where the cost of special blue lamps may be prohibitive, efficient phototherapy is accomplished with white lamps.
White quartz lamps are an integral part of some radiant warmers and incubators. They have a significant blue component in the light spectrum. When used as spotlights, the energy field is strongly focused towards the center, with significantly less energy delivered at the perimeter, as discussed above.
Quartz lamps are also used in single or double banks of 3-4 bulbs attached to the overhead heat source of some radiant warmers. The energy field delivered by these is much more homogeneous than that of spotlights, and the energy output is reasonably high. However, because the lamps are fixed to the overhead heater unit, the ability to increase energy delivery by moving lights closer to infants is limited.
Fiberoptic lights are also used in phototherapy units. These units deliver high energy levels, but because spectral power (ie, irradiance multiplied by the size of the irradiated area) is related to the size of the lighted field, the smaller "pads" are less efficient than larger wrap-around blankets. Drawbacks of fiberoptic phototherapy units may include noise from the fan in the light source and a decrease of delivered energy with aging and/or breakage of the optic fibers. Some new fiberoptic units now incorporate photodiodes as a light source. Advantages of fiberoptic phototherapy include the following:
- Low risk of overheating the infant
- No need for eye shields
- Ability to deliver phototherapy with the infant in a bassinet next to the mother's bed
- Simple deployment for home phototherapy
- The possibility of irradiating a large surface area when combined with conventional overhead phototherapy units (double/triple phototherapy)
Light-emitting diode (LED) lights are found in most newer phototherapy units. Advantages include low power consumption, low heat production, and a much longer life span of the light-emitting units (20,000 hours) compared with older light sources. Blue LED lights have a narrow spectral band of high-intensity light that overlaps the absorption spectrum of bilirubin. Trials comparing LED phototherapy to other light sources were recently reviewed by the Cochrane Collaboration and by Tridente and DeLuca. The authors of these reviews conclude that the efficacy of LED lights in reducing total serum bilirubin levels is comparable to that of conventional light sources (fluorescent or halogen lamps)( Valaes,1994). Formation of bilirubin photoisomers also appears comparable between LEDs and blue fluorescent lamps(Garcia and Nager,2002) "Double" and "triple" phototherapy, which implies the concurrent use of 2 or 3 phototherapy units to treat the same patient, has often been used in the treatment of infants with very high levels of serum bilirubin. The studies that appeared to show a benefit with this approach were performed with old, relatively low-yield phototherapy units. Newer phototherapy units provide much higher levels of irradiance. Whether double or triple phototherapy also confers a benefit with the newer units, has not been tested in systematic trials. However, because recent studies appear to rule out the existence of a saturation point (see discussion above), the utility of double or triple phototherapy in extreme jaundice should not be discounted ( Garcia and Nager,2002).
The purpose of treating neonatal jaundice is to avoid neurotoxicity. Thus, indications for treatment have been based on clinical studies of infants who developed kernicterus. Historical data, much of which was derived from infants with hemolytic jaundice, appeared to suggest that total serum bilirubin levels greater than 350 µmol/L (20 mg/dL) were associated with increased risk of neurotoxicity, at least in full-term infants.
As treatment of premature infants became more widespread and increasingly successful during the last half of the 20th century, autopsy findings and follow-up data suggested that immature infants were at risk of bilirubin encephalopathy at lower total serum bilirubin levels than mature infants. Treatment was initiated at lower levels for these infants.
Until the 1940s, a truly effective treatment was not available. At that time, exchange transfusion was shown to be feasible and was subsequently used in the treatment of Rh-immunized infants with severe anemia, hyperbilirubinemia, or hydrops. However, exchange transfusion is not without risk for the infant, and only with the discovery of phototherapy did neonatal jaundice start to become an indication for treatment on a wider scale. Once phototherapy was shown to be an apparently innocuous treatment, lights were turned on at lower serum bilirubin values than those that had triggered exchange transfusion.
Exchange transfusion became the second-line treatment when phototherapy failed to control serum bilirubin levels. However, data have shown that treatment with IVIG in infants with Rh or ABO isoimmunization can significantly reduce the need for exchange transfusions( Carbonell et al.,2001). At the author's institution, a tertiary center where exchange transfusions used to be frequent, currently only 0-2 such procedures per year are performed, and IVIG has replaced exchange transfusion as the second-line treatment in infants with isoimmune jaundice( Stevenson et al.,2001). In a recent 1-year prospective national survey of NICU phototherapy practices in Norway, Mreihil and collaborators found that only 6 exchange transfusions had been performed in a birth population of 60.000 infants (Mreihil et al., 2000).
Clearly, the scientific data on which current therapeutic guidelines are based have very significant shortcomings. Unfortunately, because the endpoint of bilirubin neurotoxicity is permanent brain damage, a randomized study to reassess the guidelines is ethically unthinkable.
In most neonatal wards, total serum bilirubin levels are used as the primary measure of risk for bilirubin encephalopathy. Numerous people would prefer to add a test for serum albumin at higher bilirubin levels because bilirubin entry into the brain, a sine qua non for bilirubin encephalopathy, increases when the bilirubin-albumin ratio exceeds unity. Tests for bilirubin-albumin binding or unbound bilirubin levels are used by some but have failed to gain widespread acceptance. New analytical tools for measurement of unbound bilirubin have greatly simplified the process, but the effect on clinical practice remains to be seen.
Numerous guidelines for the management of neonatal jaundice have been published, and even more appear to be in local use without submission for critical review. In a survey published in 1996, the author analyzed clinical practices in this field based on responses from 108 neonatal intensive care units (NICUs) worldwide (Newman et al.,2000). The survey revealed a significant disparity in guidelines.
The image below shows a box-and-whisker plot of the range of serum bilirubin values that trigger phototherapy and exchange transfusion, respectively, in these NICUs. Evidently, an infant might receive an exchange transfusion in one NICU for a serum bilirubin level that would not trigger phototherapy in many other NICUs. This disparity illustrates how difficult it has been to translate clinical data into sensible treatment guidelines.
In 2004, the AAP published new guidelines for the management of hyperbilirubinemia in healthy full-term newborns (Maisels and Kring,1998).
The 2004 AAP guidelines represent a significant change from the 1994 guideline (Maisels and Kring,1998) Thus, the emphasis on preventive action and risk evaluation is much stronger. Clinicians in different ethnic or geographic regions should consider tailoring these guidelines as pertinent to their own populations and must consider factors that are unique to their medical practice settings. Such factors may include racial characteristics, prevalence of congenital hemolytic disorders, prevalence of genetic variants, and environmental concerns. Such adaptation of guidelines should also take into consideration how healthcare delivery systems are organized, as this is likely affect both in-hospital delivery of care as well as follow-up. At present, the wisest course of action may be to apply local guidelines, assuming that these have been successful in the prevention of kernicterus..
With this background and the clear understanding that this is meant only as an example, the image below shows the chart currently in use in all pediatric departments in Norway. These guidelines are the result of a 2006 consensus in the Neonatal Subgroup of the Norwegian Pediatric Society. The similarities between the Norwegian chart and the 2004 AAP guidelines are apparent.
Key points in the practical execution of phototherapy include maximizing energy delivery and the available surface area. Also consider the following:
* The infant should be naked except for diapers (use these only if deemed absolutely necessary and cut them to minimum workable size), and the eyes should be covered to reduce risk of retinal damage.
* Check the distance between the infant's skin and the light source. With fluorescent lamps, the distance should be no greater than 50 cm (20 in). This distance may be reduced down to 10-20 cm (4-8 in) if temperature homeostasis is monitored to reduce the risk of overheating. Note that this does not apply to quartz lamps.
* Cover the inside of the bassinet with reflecting material; white linen works well. Hang a white curtain around the phototherapy unit and bassinet. These simple expedients can multiply energy delivery by several fold.
* When using spotlights, ensure that the infant is placed at the center of the circle of light, since photo-energy drops off towards the circle's perimeter. Observe the infant closely to ensure that the infant doesn't move away from the high-energy area. Spotlights are probably more appropriate for small premature infants than for larger near-term infants.
* Older data suggested that phototherapy was associated with increased insensible water loss; therefore, many clinicians have routinely added a certain percentage to the infant's estimated basic fluid requirements. Newer data suggest that if temperature homeostasis is maintained, fluid loss is not significantly increased by phototherapy. At the author's institution, routine fluid supplementation for infants under phototherapy has not been used for more than a decade and is not recommended in national guidelines. Rather, the infant is monitored for weight loss, urine output, and urine specific gravity. Fluid intake is adjusted accordingly. In infants who are orally fed, the preferred fluid is milk because it serves as a vehicle to transport bilirubin out of the gut.
* Timing of follow-up serum bilirubin testing must be individualized. In infants admitted with extreme serum bilirubin values (>500 µmol/L or 30 mg/dL), monitoring should occur every hour or every other hour. Reductions in serum bilirubin values of 85 µmol/L/h (5 mg/dL/h) have been documented under such circumstances. In infants with more moderate elevations of serum bilirubin, monitoring every 6-12 hours is probably adequate.
* Expectations regarding efficacy of phototherapy must be tailored to the circumstances. In infants in whom serum bilirubin concentrations are still rising, a significant reduction of the rate of increase may be satisfactory. In infants in whom serum bilirubin concentrations are close to their peak, phototherapy should result in measurable reductions in serum bilirubin levels within a few hours. In general, the higher the starting serum bilirubin concentration, the more dramatic the initial rate of decline.
* Discontinuation of phototherapy is a matter of judgment, and individual circumstances must be taken into consideration. In practice, phototherapy is discontinued when serum bilirubin levels fall 25-50 µmol/L (1.5-3 mg/dL) below the level that triggered the initiation of phototherapy. Serum bilirubin levels may rebound after treatment has been discontinued, and follow-up tests should be obtained within 6-12 hours after discontinuation.
* Indications for prophylactic phototherapy are debatable. Phototherapy probably serves no purpose in an infant who is not clinically jaundiced. In general, the lower the serum bilirubin level, the less efficient the phototherapy. It seems more rational to apply truly effective phototherapy once serum (and skin) bilirubin has reached levels at which photons may do some good.
* Wherever phototherapy is offered as a therapeutic modality, a device for measuring the irradiance delivered by the equipment used should be readily at hand. This assists in configuring the phototherapy set-up to deliver optimal efficiency. Some recommend this routinely, every time phototherapy is initiated, and use this as a tool to focus staff attention on maximizing energy delivery.
Generally, phototherapy is very safe and may have no serious long-term effects in neonates; however, the following adverse effects and complications have been noted:
* Insensible water loss may occur, but data suggest that this issue is not as important as previously believed. Rather than instituting blanket increases of fluid supplements to all infants receiving phototherapy, the author recommends fluid supplementation tailored to the infant's individual needs, as measured through evaluation of weight curves, urine output, urine specific gravity, and fecal water loss.
2) As noted above, a reanalysis of the NRN trial of ”aggressive” versus ”conservative” phototherapy in premature infants of less than 1000 g birthweight showed that mortality was increased in the subgroup of sick 501- to 750-g birthweight infants receiving aggressive' phototherapy (Soskolne et al.,1996). In a recent recommendation for treatment of hyperbilirubinemia in premature infants younger than 35 weeks’ gestation, the authors propose that initial irradiance should be reduced in the most vulnerable infants(Gale et al.,1990). However, as pointed out in an editorial to this paper, extant data seem to be more compatible with the interpretation that duration of phototherapy is more dangerous than irradiance levels (Ebbesen and Brodersen,1982). Thus, it may be argued that phototherapy should be short and efficient rather than less efficient and of longer duration. This question is still open to interpretation and discussion.
* Phototherapy may be associated with loose stools. Increased fecal water loss may create a need for fluid supplementation.
* Retinal damage has been observed in some animal models during intense phototherapy. In an NICU environment, infants exposed to higher levels of ambient light were found to have an increased risk of retinopathy. Therefore, covering the eyes of infants undergoing phototherapy with eye patches is routine. Care must be taken lest the patches slip and leave the eyes uncovered or occlude one or both nares.
* The combination of hyperbilirubinemia and phototherapy can produce DNA-strand breakage and other effects on cellular genetic material. In vitro and animal data have not demonstrated any implication for treatment of human neonates. However, because most hospitals use (cut-down) diapers during phototherapy, the issue of gonad shielding may be moot.
* Skin blood flow is increased during phototherapy, but this effect is less pronounced in modern servocontrolled incubators. However, redistribution of blood flow may occur in small premature infants. An increased incidence of patent ductus arteriosus (PDA) has been reported in these circumstances. The appropriate treatment of PDA has been reviewed( Cashore et al.,1983)
* Hypocalcemia appears to be more common in premature infants under phototherapy lights. This has been suggested to be mediated by altered melatonin metabolism. Concentrations of certain amino acids in total parenteral nutrition solutions subjected to phototherapy may deteriorate. Shield total parenteral nutrition solutions from light as much as possible.
* Regular maintenance of the equipment is required because accidents have been reported, including burns resulting from a failure to replace UV filters.
2.12 INTRAVENOUS IMMUNE GLOBULIN
In relatively recent years, IVIG has been used for numerous immunologically mediated conditions. In the presence of Rh, ABO, or other blood group incompatibilities that cause significant neonatal jaundice, IVIG has been shown to significantly reduce the need for exchange transfusions. However, it must be recognized that some studies have failed to show efficacy. The reasons for this discrepancy have not been explained, but it should be noted that in the studies that failed to show significant effects, IVIG was used more or less prophylactically for all apparently immunized infants, whereas in the studies that reported benefits IVIG was used exclusively as a rescue therapy in infants headed for exchange transfusion. Also, one can speculate whether differences in the origin and characteristics of the IVIG preparation might play a role. If one particular IVIG preparation appears not to work, it may be worthwhile to try IVIG from a different source/manufacturer.
2.13 EXCHANGE TRANSFUSION
Exchange transfusion is indicated for avoiding bilirubin neurotoxicity when other therapeutic modalities have failed or are not sufficient. In addition, the procedure may be indicated in infants with erythroblastosis who present with severe anemia, hydrops, or both, even in the absence of high serum bilirubin levels.
Exchange transfusion was once a common procedure. A significant proportion was performed in infants with Rh isoimmunization. Immunotherapy in Rh-negative women at risk for sensitization has significantly reduced the incidence of severe Rh erythroblastosis. Therefore, the number of infants requiring exchange transfusion is now much smaller, and even large NICUs may perform only a few procedures per year. As mentioned previously, the incidence of infants requiring exchange transfusion in Norway was in a prospective survey shown to be only 0.01%. ABO incompatibility has become the most frequent cause of hemolytic disease in industrialized countries.
Early exchange transfusion has usually been performed because of anemia (cord hemoglobin < 11 g/dL), elevated cord bilirubin level (>70 µmol/L or 4.5 mg/dL), or both. A rapid rate of increase in the serum bilirubin level (>15-20 µmol/L /h or 1 mg/dL/h) was an indication for exchange transfusion, as was a more moderate rate of increase (>8-10 µmol/L/h or 0.5 mg/dL/h) in the presence of moderate anemia (11-13 g/dL).
The serum bilirubin level that triggered an exchange transfusion in infants with hemolytic jaundice was 350 µmol/L (20 mg/dL) or a rate of increase that predicted this level or higher. Strict adherence to the level of 20 mg/dL has been jocularly referred to as vigintiphobia (fear of 20).
Currently, most experts encourage an individualized approach, recognizing that exchange transfusion is not a risk-free procedure, that effective phototherapy converts 15-25% of bilirubin to nontoxic isomers, and that transfusion of a small volume of packed red cells may correct anemia. Administration of IVIG (500 mg/kg) has been shown to reduce red cell destruction and to limit the rate of increase of serum bilirubin levels in infants with Rh and ABO isoimmunization (see above).
Current AAP guidelines distinguish between 3 risk categories: low, intermediate, and high (Maisels and Kring,1998). These correspond to 3 levels of suggested intervention, which increase from birth and plateau at age 4 days. Naturally, intervention levels associated with exchange transfusion are higher than those for phototherapy. Intensive phototherapy is strongly recommended in preparation for an exchange transfusion. In fact, intensive phototherapy should be performed on an emergency basis in any infant admitted for pronounced jaundice; do not await laboratory test results in these cases. Phototherapy has minimal side effects in this scenario, whereas the waiting period for laboratory test results and blood for exchange can take hours and could constitute the difference between intact survival and survival with kernicterus. If phototherapy does not significantly lower serum bilirubin levels, exchange transfusion should be performed.
Many believe that hemolytic jaundice represents a greater risk for neurotoxicity than nonhemolytic jaundice, although the reasons for this belief are not intuitively obvious, assuming that total serum bilirubin levels are equal. In animal studies, bilirubin entry into or clearance from the brain was not affected by the presence of hemolytic anemia.
2.14 MANAGEMENT OF INFANTS WITH EXTREME JAUNDICE
Numerous cases have been reported in which infants have been readmitted to hospitals with extreme jaundice. In some cases, significant delays have occurred between the time the infant was first seen by medical personnel and the actual commencement of effective therapy( Cashore,1980).
Any infant who returns to the hospital with significant jaundice within the first 1-2 weeks of birth should be immediately triaged with measurement of transcutaneous bilirubin. High values should result in immediate initiation of treatment. If such a measuring device is not available, or if the infant presents with any kind of neurological symptoms, the infant should be put in maximally efficient phototherapy as an emergency procedure, preferably by fast-tracking the infant to a NICU. Waiting for laboratory results is not necessary before instituting such therapy because no valid contraindications to phototherapy are possible in this scenario. Plans for an exchange transfusion do not constitute an argument for delaying or not performing phototherapy. Immediate benefit may be obtained within minutes, as soon as conversion of bilirubin into water-soluble photoisomers is measurable. The need for intravenous hydration in such infants has been discussed. In the absence of clinical signs of dehydration, no evidence suggests that overhydration is helpful. If the infant is dehydrated, hydration should be given as clinically indicated. However, if the infant is able to tolerate oral feeding, oral hydration with a breast milk substitute is likely to be superior to intravenous hydration because it reduces enterohepatic circulation of bilirubin and helps "wash" bilirubin out of the bowel.
Every hospital in which babies are delivered, or which has an emergency department in which infants may be seen, should develop a protocol and triage algorithm for rapid evaluation and management of jaundiced infants. The objective of such a protocol should be rapid recognition of risk severity and reduction in the time to initiate appropriate treatment.
Infants admitted with signs of intermediate to advanced acute bilirubin encephalopathy (ABE) are in urgent need of treatment because reversibility may be possible, even in such cases. The term "crash-cart approach" has been used as a recommendation in such cases. The author, together with other European colleagues, has published a series that included 6 patients with signs of ABE who were urgently managed and appear to have escaped neurologic sequelae( Bratlid,1990).
In a review of the Kernicterus Registry, full recovery was noted in 8 of 11 cases treated with a crash-cart approach, which included effective phototherapy plus exchange transfusion; full recovery was not noted in cases in which delays had occurred( Cashore,1980). In the Kernicterus Registry, reversal was not observed in cases treated with only phototherapy; the authors strongly recommend that exchange transfusion be performed in such cases( Cashore,1980).In the European study, reversal was also seen in 2 patients who did not receive exchange transfusion(Bratlid,1990). In one of these cases, IVIG was used in lieu of exchange transfusion; in the other case, intensive phototherapy and intravenous albumin were used.
2.15 CLINICAL EVALUATION OF JAUNDICE AND TCB MEASUREMENTS
Jaundice is usually seen in the face first and progresses caudally to the trunk and extremities (MacDonald,1995), but because visual estimation of bilirubin levels from the degree of jaundice can lead to errors,( Penn et al.,1994),a low threshold should be used for measuring the TSB. Devices that provide a noninvasive TcB measurement have proven very useful as screening tools( Institue of Medicine,2001) and newer instruments give measurements that provide a valid estimate of the TSB level( Bertini,2001). Studies using the new TcB-measurement instruments are limited, but the data published thus far suggest that in most newborn populations, these instruments generally provide measurements within 2 to 3 mg/dL (34–51 μmol/L) of the TSB and can replace a measurement of serum bilirubin in many circumstances, particularly for TSB levels less than 15 mg/dL (257 μmol/L)(American Academy of Pediatrics ,2002). Because phototherapy “bleaches” the skin, both visual assessment of jaundice and TcB measurements in infants undergoing phototherapy are not reliable. In addition, the ability of transcutaneous instruments to provide accurate measurements in different racial groups requires additional study(Carvalho et al.,1981). The limitations of the accuracy and reproducibility of TSB measurements in the clinical laboratory(Madlon-Kay,1992) must also be recognized and are discussed in the technical report (Davidson et al.,1980)
2.16 CAPILLARY VERSUS VENOUS SERUM BILIRUBIN MEASUREMENT
Almost all published data regarding the relationship of TSB levels to kernicterus or developmental outcome are based on capillary blood TSB levels. Data regarding the differences between capillary and venous TSB levels are conflicting (Tayaba et al.,1998). In 1 study the capillary TSB levels were higher, but in another they were lower than venous TSB levels. Thus, obtaining a venous sample to “confirm” an elevated capillary TSB level is not recommended, because it will delay the initiation of treatment.
2.17 DIRECT-REACTING AND CONJUGATED BILIRUBIN
Although commonly used interchangeably, direct-reacting bilirubin is not the same as conjugated bilirubin. Direct-reacting bilirubin is the bilirubin that reacts directly (without the addition of an accelerating agent) with diazotized sulfanilic acid. Conjugated bilirubin is bilirubin made water soluble by binding with glucuronic acid in the liver. Depending on the technique used, the clinical laboratory will report total and direct-reacting or unconjugated and conjugated bilirubin levels. In this guideline and for clinical purposes, the terms may be used interchangeably.
2.18 ABNORMAL DIRECT AND CONJUGATED BILIRUBIN LEVELS
Laboratory measurement of direct bilirubin is not precise( Yasuda et al.,2003) and values between laboratories can vary widely. If the TSB is at or below 5 mg/dL (85 μmol/L), a direct or conjugated bilirubin of more than 1.0 mg/dL (17.1 μmol/L) is generally considered abnormal. For TSB values higher than 5 mg/dL (85 μmol/L), a direct bilirubin of more than 20% of the TSB is considered abnormal. If the hospital laboratory measures conjugated bilirubin using the Vitros (formerly Ektachem) system (Ortho-Clinical Diagnostics, Raritan, NJ), any value higher than 1 mg/dL is considered abnormal.
2.19 ASSESSMENT OF ADEQUACY OF INTAKE IN BREASTFEEDING INFANTS
The data from a number of studies (Maisels et al.,2004) indicate that unsupplemented, breastfed infants experience their maximum weight loss by day 3 and, on average, lose 6.1% ± 2.5% (SD) of their birth weight. Thus, ∼5% to 10% of fully breastfed infants lose 10% or more of their birth weight by day 3, suggesting that adequacy of intake should be evaluated and the infant monitored if weight loss is more than 10%(Alpay et al.,2000). Evidence of adequate intake in breastfed infants also includes 4 to 6 thoroughly wet diapers in 24 hours and the passage of 3 to 4 stools per day by the fourth day. By the third to fourth day, the stools in adequately breastfed infants should have changed from meconium to a mustard yellow, mushy stool( Carbonell et al.,2001). The above assessment will also help to identify breastfed infants who are at risk for dehydration because of inadequate intake.
2.20 NOMOGRAM FOR DESIGNATION OF RISK
Note that this nomogram does not describe the natural history of neonatal hyperbilirubinemia, particularly after 48 to 72 hours, for which, because of sampling bias, the lower zones are spuriously elevated( Kaplan et al.,2000). This bias, however, will have much less effect on the high-risk zone (95th percentile in the study) (Stevenson et al.,2001).
2.21 G6PD DEHYDROGENASE DEFICIENCY
It is important to look for G6PD deficiency in infants with significant hyperbilirubinemia, because some may develop a sudden increase in the TSB. In addition, G6PD-deficient infants require intervention at lower TSB levels . It should be noted also that in the presence of hemolysis, G6PD levels can be elevated, which may obscure the diagnosis in the newborn period so that a normal level in a hemolyzing neonate does not rule out G6PD deficiency( Newman et al.,2000). If G6PD deficiency is strongly suspected, a repeat level should be measured when the infant is 3 months old. It is also recognized that immediate laboratory determination of G6PD is generally not available in most US hospitals, and thus translating the above information into clinical practice is currently difficult. Nevertheless, practitioners are reminded to consider the diagnosis of G6PD deficiency in infants with severe hyperbilirubinemia, particularly if they belong to the population groups in which this condition is prevalent. This is important in the African American population, because these infants, as a group, have much lower TSB levels than white or Asian infants( Gale et al.,1990). Thus, severe hyperbilirubinemia in an African American infant should always raise the possibility of G6PD deficiency.
2.22 BASIS FOR THE RECOMMENDATIONS
Ideally, recommendations for when to implement phototherapy and exchange transfusions should be based on estimates of when the benefits of these interventions exceed their risks and cost. The evidence for these estimates should come from randomized trials or systematic observational studies. Unfortunately, there is little such evidence on which to base these recommendations. As a result, treatment guidelines must necessarily rely on more uncertain estimates and extrapolations. For a detailed discussion of this question, please see “An Evidence-Based Review of Important Issues Concerning Neonatal Hyperbilirubinemia(Davidson et al.,1980).
The recommendations for phototherapy and exchange transfusion are based on the following principles:
* The main demonstrated value of phototherapy is that it reduces the risk that TSB levels will reach a level at which exchange transfusion is recommended (Berk et al.,1989).Approximately 5 to 10 infants with TSB levels between 15 and 20 mg/dL (257–342 μmol/L) will receive phototherapy to prevent the TSB in 1 infant from reaching 20 mg/dL (the number needed to treat)( American Academy of Pediatrics ,2002). Thus, 8 to 9 of every 10 infants with these TSB levels will not reach 20 mg/dL (342 μmol/L) even if they are not treated. Phototherapy has proven to be a generally safe procedure, although rare complications can occur.
* Recommended TSB levels for exchange transfusion are based largely on the goal of keeping TSB levels below those at which kernicterus has been reported (Bratlid ,1990). In almost all cases, exchange transfusion is recommended only after phototherapy has failed to keep the TSB level below the exchange transfusion level.
* The recommendations to use phototherapy and exchange transfusion at lower TSB levels for infants of lower gestation and those who are sick are based on limited observations suggesting that sick infants (particularly those with the risk factors and those of lower gestation (Egger et al.,1984) are at greater risk for developing kernicterus at lower bilirubin levels than are well infants of more than 38 6/7 weeks’ gestation. Nevertheless, other studies have not confirmed all of these associations (Egger et al.,1984). There is no doubt, however, that infants at 35 to 37 6/7 weeks’ gestation are at a much greater risk of developing very high TSB levels. Intervention for these infants is based on this risk as well as extrapolations from more premature, lower birth-weight infants who do have a higher risk of bilirubin toxicity ( Wennberg,1991).
* For all newborns, treatment is recommended at lower TSB levels at younger ages because one of the primary goals of treatment is to prevent additional increases in the TSB level.
2.23 ADVERSE EFFECT OT NEONATAL PHOTOTHERAPY
>Short-term Diarrhea
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>Interference with maternal–infant bonding
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>Intestinal hypermotility
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>Temperature instability
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>Long-term Increased risk of childhood asthma (odds ratio = 1.4)
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RECOMMENDATION
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Phototherapy decreases the incidence of severe hyperbilirubinemia in newborns.
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Phototherapy decreases the need for exchange transfusion in newborns with severe hyperbilirubinemia.
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Interrupting breastfeeding in an infant with jaundice decreases the chances of successful breastfeeding.
A= Consistent, good quality- oriented evidence.
B= Inconsistent or limited quality patient- oriented evidence.
C= Consensus, disease oriented evidence, usual practice, expert opinion, or case series.
Acute bilirubin enceohalopathy develops in 10,000 infants and presents with hypertonia, arching, retrocolis, opisthotones, fever, and high pitched cry. 2 data of acute bilirubin encephalopathy to Kermictus are limited, but one study found that 95% of infants with acute bilirubin encephalopathy had full resolution of symptoms ,and 5% develops in had evidence of kericterus by the time of discharge. 3 kericteris develops in one in 100,000 infants and manifests as athetoid cerebral palsy, auditory dysfunction, dental dysplasia, paralysis of upward gaze, and variable intellectually disability.
Risks factors for the development of severe hyperbilirubinemia include cephalhematoma or significant bruising, early gestation al age, exclusive breastfeeding ( especially unsuccessful breastfeeding and / or weight loss of 8% to 10%). Isoimmune or other hemolytic addition to hyperbilirubinemia, early gestational age, hemolysis, sepsis, and low birth weight are associated with the development of bilirubin encephalopathy. One study found that less than 5% of healthy term infants with TSB level greater than 30mg per dL (513.1 µmol per L) developed acute builirubin encephalopathy or Kermicterus.
RISKS SCORE FOR NEONATAL HYPERBILIRUBINEMIA
VARIABLE SCORE
BIRTH WEIGHT:
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