Hyperbilirubinemia in Term and Near-Term Infants: Kernicterus on the Rise?

Shari Steffensrud, MS, RNC, NNP

NAINR. 2004;4(4) 

In This Article

Treatment

Severe hyperbilirubinemia is a medical emergency requiring immediate treatment. Common treatment strategies to lower serum bilirubin levels include hydration, cessation of breastfeeding for a short period of time, drug therapy, phototherapy, and exchange transfusion.

Hydration of hyperbilirubinemic infants with supplemental intravenous (IV) fluids has been thought to decrease serum bilirubin via dilution. Unless an infant is dehydrated, giving IV fluids has not been shown to significantly impact serum bilirubin levels.[39] Mild dehydration may be present in exclusively breastfed infants; however, supplementing with formula, as opposed to IV fluids, would appear to be more logical. Milk-based formula inhibits enterohepatic circulation and may help lower serum bilirubin levels in breastfed infants. Supplementing these infants with water/glucose water is not advised as disruption in the mother's milk production may occur and neither solution supplies the calories of breastmilk.[29]

In the face of high serum bilirubin levels, many health care providers advocate cessation of breastfeeding with substitution of formula for 24 to 48 hours. Generally, if the hyperbilirubinemia is related to breastmilk jaundice, serum bilirubin will rapidly fall during the formula-fed period. Once breastmilk is restarted, serum bilirubin levels again rise, but rarely to the previous high level. Full-term infants with breastmilk jaundice whose bilirubin levels are <20 mg/dL may require no intervention. Those infants with serum bilirubin levels ranging 20 to 25 mg/dL require close monitoring and may require supplementation with formula.[40]

Various drugs have been used in infants with severe hyperbilirubinemia, especially if hemolysis is present. Phenobarbital has probably been the most widely used drug and exerts its effect by enhancing enzyme activity in the hepatocytes, resulting in increased bilirubin conjugation.[41] Phenobarbital is not benign, however, and may alter oxidation of bilirubin in the brain and increase the risk of bilirubin encephalopathy.[29,42] Phenobarbital requires several days to show any effect on serum bilirubin level and thus has limited value in the acute setting.

Cholestyramine and agar have some effect on decreasing serum bilirubin by binding bile acids and bilirubin in the intestine. Clofibrate, an antilipidemic agent, enhances hepatocyte enzyme activity potentially aiding in bilirubin conjugation. All three drugs have had limited studies in neonates, mostly in the 1970s to early 1990s.[42,43,44]

One potentially useful drug therapy to lower serum bilirubin levels in ABO and Rh hemolysis is intravenous immunoglobulin (IVIG). Studies show that, when successful, IVIG can inhibit hemolysis in affected infants.[45,46] The mechanism of effect is unclear; proposed theories include inhibition of antibody-coated erythrocytes by receptor blocking or possible acceleration of IgG catabolism resulting in reduction of circulating autoantibodies.[46,47] Cochrane Neonatal Reviews examined published studies on IVIG and concluded that, while IVIG appears effective in some cases, more studies are needed before widespread use should be instituted.[48]

Metalloporphyrins, primarily tin-mesoporphyrin (SnMP), prevent bilirubin formation. Heme oxygenase breaks down heme resulting in release of iron, CO, and bilverdin that in turn is converted into bilirubin, as previously noted. SnMP is a heme analog with tin, instead of iron, as its central metal atom. SnMP is specific for heme oxygenenase and binds the enzyme, thus preventing heme degradation; the end result is decreased bilirubin formation.[49,50] SnMP doesn't affect excretion of bilirubin previously formed and the drug is excreted in the bile, as is the undegraded heme. In addition, SnMP doesn't enter the brain or appear to compete with bilirubin for albumin-binding sites.[50]

Studies utilizing SnMP in treatment of high-risk neonates have shown SnMP to be an extremely effective agent.[51,52,53,54,55] One study comparing the use of SnMP with phototherapy in healthy term and near-term infants concluded SnMP was the superior treatment.[56]

SnMP had one adverse effect, a transient rash in some treated infants exposed to direct sunlight. Concern has been raised that, as SnMP has photosensitizer activity, treated infants may be predisposed to the formation of singlet oxygen. Singlet oxygen, via oxidation, may alter and/or damage cells and impact body functions.[57] Whether this is a potential or actual problem has yet to be determined.

SnMP is approved by the FDA for clinical use; treated infants have been followed up to 5 years with no significant early or late side effects reported.[49] Cochrane Neonatal Reviews concluded that more studies were needed to compare the cost/efficacy of SnMP with phototherapy and further studies in neonates were needed before widespread use could be recommended.[58]

In the mid-1950s, Sister Jean at Rochford General Hospital in England noted that infants exposed to sunlight were less jaundiced in the uncovered skin areas than their nonexposed counterparts.[7] Cremer and coworkers[59] subsequently established that blue fluorescent light decreased jaundice and serum bilirubin levels in neonates.

Phototherapy alters bilirubin in three different ways. The first is photooxidation, which results in formation of a number of water-soluble products; however, the process is slow and likely plays only a minor role in bilirubin elimination. Configurational isomerization is the second method by which phototherapy changes bilirubin. Some of bilirubin's chemical groups are rearranged, making the molecule more water soluble. Configurational isomerization is a reversible reaction, however, and bilirubin may revert to its native form under various conditions, especially if light is removed. The third change in bilirubin by phototherapy involves structural isomerization, which alters bilirubin atoms in an irreversible reaction to form a new molecule termed lumirubin. Lumirubin is believed to be the primary bilirubin photoproduct excreted in the neonate.[60,61]

Lumirubin formation is the rate-limiting step in bilirubin elimination, rather than excretion, and is influenced by light spectrum, light intensity, and surface area of exposed skin.[62] Only certain wavelengths (colors) of light are absorbed by bilirubin; as bilirubin is a yellow pigment, blue light is absorbed most effectively, however, green light is more deeply absorbed into the skin. Broad-spectrum fluorescent white light, a commonly used form of phototherapy, is much less effective in reaching bilirubin and decreasing serum levels.[60,62] A more effective configuration is four Special Blue Bulbs (F20T12/B) flanked on either side by two daylight fluorescent tubes.[13]

Effectiveness of phototherapy is also related to light intensity (irradiance), which is most effective in the 400 to 550 nm light range. Success of phototherapy in decreasing serum bilirubin is also influenced by amount of exposed body surface and distance of light source from the infant.[39,61,62]

Conflicting results have been noted in studies looking at continuous versus intermittent phototherapy and it appears that turning infants under phototherapy doesn't increase the effectiveness of the treatment.[63] Phototherapy may not be as successful in decreasing serum bilirubin levels in breastfed infants due to increased enterohepatic circulation; supplementing with formula in addition to phototherapy may be more efficacious in these infants.[64]

Phototherapy is not without disadvantages ( Table 2 ). Phototherapy is generally started only after the serum bilirubin has reached a specific level of concern to the health care provider and there is no consensus on what that level should be. Under fluorescent tubes infants must wear eye protection and are usually separated from the mother in the nursery. Phototherapy may take days to exert the desired effect and, once the phototherapy lights are stopped, rebound hyperbilirubinemia may occur as bilirubin moves from the tissue into the blood. Risk of photooxidative damage to lipoprotein and red blood cell membranes is possible and data suggest that conventional phototherapy (with fluorescent tubes) may decrease postprandial mesenteric blood flow response that may adversely impact the neonatal GI tract.[65]

Despite potential problems, the only real contradiction to phototherapy is elevated direct (conjugated) serum bilirubin; phototherapy in these infants may cause the skin to turn grayish-brown, a phenomenon termed bronze baby syndrome. If skin discoloration does occur, it will fade with time.

Fiberoptic pads have developed popularity over recent years as an alternative to conventional fluorescent tubes. Fiberoptic light-emitting cables are woven together and enclosed in a pad on which the infant lies. Advantages are that one may use more than one pad (double phototherapy), eye patches are not needed, and infants can be swaddled while lying on the pad. The major disadvantage of fiberoptic pads is the limited ability to deliver high light intensity to large skin areas. Fiberoptic pads may be less optimal in term infants and these infants may be more likely to require additional phototherapy than infants receiving conventional phototherapy alone.[66] Fiberoptic pads may be more effective in premature infants with their thinner skin, allowing light to penetrate deeper into the tissues.[67] Cochrane Neonatal Reviews looked at 24 studies and found fiberoptic pads less effective than conventional phototherapy but more effective than no treatment for hyperbilirubinemia and that both treatment therapies may be of equal efficacy to premature infants.[68]

High-intensity gallium nitride light emitting diodes (LEDs) are being explored as a new phototherapy light source. Initial reports are that blue LEDs may be better absorbed by bilirubin; are small and lightweight; and produce significantly less ultraviolet light, infrared radiation, and heat than conventional phototherapy.[61] Studies comparing blue LEDs to conventional phototherapy in healthy term infants concluded that LED devices were as effective as conventional phototherapy when comparable light intensities were utilized; in addition no discomfort was reported by bedside nurses from the blue light.[69,70] The potential for LEDs to form unlimited sizes and shapes along with the ability to delivery higher light intensity over large skin areas is a promising prospect for infants requiring phototherapy.[61]

Exchange transfusion should be considered in any infant, with or without a hemolytic condition, if the serum bilirubin level fails to demonstrate a rapid, continued decline under intensive phototherapy (generally two to three phototherapy devices). The procedure consists of one or two catheters inserted into an umbilical artery and/or vein and withdrawal of small aliquots of blood with replacement of donor blood (red blood cells mixed with plasma). Most exchange transfusions are double-volume, meaning twice the infant's normal blood volume (85 to 100 mL/kg) is removed and replaced. This procedure not only removes bilirubin, but may have an added impact through removal of antibody-coated red blood cells and maternal antibodies. The amount of bilirubin removed depends on the amount of bilirubin in the tissues that reenters the circulation during the procedure and the rate of hemolysis. In some cases, rebound bilirubin requires the procedure to be repeated.

Significant morbidities may occur with exchange transfusion, including anemia, apnea, air embolism, infection bradycardia, NEC, thromboembolism, and death. One review found five clinically stable infants with significant complications related to exchange transfusions including death, anoxic encephalopathy, and AIDS.[28] In general, exchange transfusion should only be used in those infants for whom intensive phototherapy has failed to significantly lower the serum bilirubin level and the benefits of the procedure outweigh the potential risks.

Inherited disorders such as Crigler-Naijar Type 1, G-6-PD, and Gilbert's Syndrome may be tempered in the future by genomics. The potential for gene therapy for these and other inherited conditions may be on the horizon.[24,71]

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