Kernicterus Treatment & Management

Surgical intervention

Stable central venous access is required to successfully perform an exchange transfusion. Surgical placement of appropriate lines may be required to facilitate this procedure if a catheter cannot be placed into the umbilical vein.

Transfer

Reported cases of kernicterus have occurred in near-term or term infants who were discharged from the hospital fewer than 48 hours after birth.

Most infants discharged at fewer than 72 hours after birth have clearly not reached their physiologic peak bilirubin level prior to discharge.

Any infant at risk for significant hyperbilirubinemia and possible neurotoxicity should be cared for in a nursery capable of rendering appropriate care for the hyperbilirubinemia and any contributing diagnoses.

A published nomogram predicts which babies may be at risk for significant disease, based on hour-of-life–specific bilirubin levels (see image below). ^[20]  Infants whose levels fall in the high-intermediate and high-risk zones should be closely monitored in a nursery capable of caring for sick newborns; they may require transfer from the birth hospital to a regional perinatal center.

The cornerstone of management of hyperbilirubinemia is prevention of neurotoxicity. ^[1] The definitive method of removing bilirubin from the blood is via exchange transfusion. This is currently the indicated approach in the presence of clinical bilirubin-induced neurologic dysfunction (BIND) when the bilirubin level has reached dangerous levels despite preventive efforts. Phototherapy is the most common method aimed at prevention of bilirubin toxicity. Clinical research efforts evaluating the use of metalloporphyrins to block bilirubin formation by competing with the enzyme heme oxygenase have not yielded a clinically useful intervention to date.

Exchange transfusion

This definitive therapy is used to mechanically remove already-formed bilirubin from the blood. It is indicated whenever clinical signs of acute bilirubin encephalopathy are present in patients who present with critically high serum bilirubin levels that continue to rise despite attempts to reduce it.

This procedure is not without risk. Whereas exchange transfusion remains the definitive therapy, as recommended in the AAP's Clinical Practice Guideline “Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation” published in 2004, all babies should undergo a trial of phototherapy, if only while the blood is being prepared, prior to initiating exchange transfusion. ^[20] In the presence of Rh isoimmunization, a cord bilirubin level of more than 5 mg/dL or a rate of rise in serum bilirubin of more than 0.5-1 mg/dL/h is predictive of the ultimate need for exchange transfusion. This relationship has not been demonstrated in hyperbilirubinemia of other etiologies. A report of supplemental intravenous fluid administration in 74 term babies with nonhemolytic severe hyperbilirubinemia (total serum bilirubin level, 18-25 mg/dL) demonstrated a decreased rate of exchange transfusion in babies receiving the extra fluid (16%) compared with controls (54%). ^[33]

The procedure involves removing the baby's native blood and replacing it with citrate phosphate dextrose (CPD) banked blood that does not contain bilirubin. Obviously, this must be performed gradually. Using an estimate of 80-90 mL/kg total blood volume, double this amount is usually removed and replaced sequentially in aliquots (10-15 mL in term babies; 5-10 mL in smaller preterm babies) over several hours. This approach, called a double volume exchange transfusion, harvests the most efficient amount of bilirubin from the blood for the amount of intervention and results in a decrease in total serum bilirubin levels by about 40%.

Because of ongoing pathology and equilibrium between the intravascular and extravascular spaces, having to repeat the procedure at least once is not uncommon.

Using O negative blood rather than the baby's blood type is important because not all circulating antibodies may be removed. Packed RBCs resuspended in fresh frozen plasma must be used for this procedure. Irradiated RBCs are used to decrease the risk of graft-versus-host reaction.

This procedure carries both inherent risks and iatrogenic ones and should be carefully performed. The reported overall mortality rate is about 3:1000; the risk of significant morbidity has been reported at about 5:100. In babies who were very ill, the risks are higher. One series of 25 infants who were ill reported a mortality rate of 20%. As exchange transfusion is becoming an increasingly rare intervention, iatrogenic complications can be expected to increase.

A review of 183 exchange transfusions performed in 165 neonates in Bangkok, Thailand, from 1994-2003 reported an overall morbidity of 15.3%, of which 67% was attributed to infection associated with the procedure. ^[34] Infants who were sick at the time of the procedure (31.3%) were more likely to develop complications than were infants who were basically healthy but hyperbilirubinemic (6.8%). Preterm infants who required exchange transfusion also developed procedure-related complications of anemia, apnea, and cardiac arrest; overall, basically healthy preterm infants were more likely to develop some morbidity than were similarly treated full-term infants. Morbidities were identified in infants at the same rate regardless of gestational age (preterm vs term). No mortalities were reported. In Iran, exchange transfusions performed from 2001-2004 in 68 infants for hyperbilirubinemia resulted in one death directly related to complications from the procedure. ^[35]

Transfusing with banked blood products carries a risk of infection. Currently, the risk of infection with known pathogens is exceedingly small. However, a risk of infection with pathogens that have not yet been discovered (ie, hepatitis C) continues.

During the procedure, continually monitor for attendant physiologic aberrations, such as hypoglycemia, thrombocytopenia (reported in 6% of patients in the Iranian series ^[35] ), hyperkalemia (particularly if the banked blood is >5 d), and hypocalcemia (if ethylenediamine tetra-acetic acid [EDTA] preservative is used in the banked blood).

Mechanical issues can contribute to the overall mortality and morbidity of the procedure. The need for central access, catheter-related and infusion-related problems, and human error during infusion are all areas that can pose potentially significant risk. Since the advent of phototherapy and obstetric treatment of Rh disease, the need for exchange transfusion has diminished. As fewer contemporary clinicians are familiar with exchange transfusion, the risk of iatrogenic complications increases.

As mentioned above, no clear-cut level of bilirubin above which encephalopathy is assured and below which neurologic safety is assured has been determined. Birthweight, gestational age, and chronologic age are all important, as are a baby's systemic condition, fluid and nutritional status, acid-base status, and the presence or absence of known pathology.

In 2004, the AAP published revised practice parameters for the management of hyperbilirubinemia in healthy infants aged 35 weeks' gestation or older. ^[20] In this document, the AAP presented recommendations for exchange transfusion for serum bilirubin levels greater than 20-25 mg/dL, depending on the postconceptional age of the infant and the bilirubin-to-albumin ratio, a tool that is not widely incorporated into the decision algorithm. The series by Gamaleldin et al of 249 infants with severe hyperbilirubinemia (≥25 mg/dL) suggested that when neurotoxicity risk issues such as Rh incompatibility or sepsis were present, 90% of infants who developed BIND manifested total serum bilirubin levels of greater than 25.4 mg/dL. However, in the 111 infants without risk factors, neurotoxicity was first observed with total serum bilirubin levels greater than 31.5 mg/dL. ^[8]

Studies have reported neurologically normal outcomes in healthy term infants with histories of serum bilirubin levels as high as 46 mg/dL. However, kernicterus has been reported to occur in near-term infants with serum bilirubin levels as low as 20.7 mg/dL and in preterm infants with peak total serum bilirubin as low as 13.1 mg/dL. ^[10] The level at which to intervene is a clinical question that remains to be answered. A survey answered by 163 hospitals in the United Kingdom in 2009 yielded a range of 20-30 mg/dL as thresholds for exchange transfusion in otherwise healthy term infants. ^[24] The procedure should be strongly considered in babies with significant risk factors predisposing for kernicterus (eg, sepsis, acidosis, hemolytic disease) if the bilirubin level has approached the range of 20-25 mg/dL.

Phototherapy

Phototherapy induces a conformational change in the bilirubin molecule, rendering it water-soluble. Formation of lumirubin is irreversible, whereas the formation of other water-soluble isomers is reversible upon cessation of phototherapy. Protect the infant's eyes during phototherapy to prevent irreversible retinal damage. ^[1] Typically, phototherapy is initiated at the following total serum bilirubin levels in neonates aged ^[1] :

• 25-48 hours old: ≥15 mg/dL
• 49-72 hours old: ≥18 mg/dL
• Older than 72 hours: ≥20 mg/dL

Postphototherapy rebound is a well-recognized phenomenon that must be considered in all patients receiving phototherapy for hyperbilirubinemia due to a hemolytic process or prematurity. One series of 226 term and near-term neonates treated in Israel between January 2001 and September 2002 reported significant rebound hyperbilirubinemia in 13.3% of patients. ^[36]  Risk factors of excessive rebound included a positive direct Coombs test and a gestation less than 37 weeks.

Enteral interventions

Administration of agar has been tried in an attempt to decrease the enterohepatic recirculation of conjugated bilirubin. It has not proved to be clinically useful and may cause intestinal obstruction.

Parenteral administration of immunoglobulin G (IgG) has been shown in controlled clinical trials to reduce the need for exchange transfusion in both Rh and ABO immune-mediated hemolytic disease. Its mechanism of action is not entirely clear.

Administration in hyperbilirubinemia resulting from isoimmune hemolytic disease that is unresponsive to phototherapy and/or is approaching exchange level has been recommended by the AAP in its 2004 revised clinical practice guideline.

Accelerated meconium evacuation

Administration of glycerin suppositories to facilitate stooling has been evaluated as a potential method of ameliorating hyperbilirubinemia. Although a controlled trial demonstrated earlier passage of meconium, no effect was demonstrated on total serum bilirubin levels, except for a small statistically significant effect identified in males with blood type A positive. Whether this was a statistical aberration or a true treatment effect is unclear.

Enteral prebiotics

Enterohepatic recirculation and delayed stooling contribute to perpetuation of hyperbilirubinemia. Investigations have focused on the role of oligosaccharides (galactose and fructose) naturally occurring in breastmilk as a modulator of intestinal flora and function. As a result, major infant formula manufacturers are now adding these so-called prebiotics to their formulations. A randomized, double-blind trial of formula and prebiotics versus formula and maltodextrine placebo was examined the effect of the investigational formula on stooling frequency. For the first 28 days of life, 76 newborns were randomly assigned to receive one of the formulations. Transcutaneous bilirubin measurements and number of stools per day were recorded. Infants in the prebiotic group showed significantly more stools per day for the duration of the trial period, as well as lower transcutaneous bilirubin levels (p< 0.05). ^[37]

Beta-glucuronidase inhibition

L-aspartic acid and enzymatically hydrolyzed casein (EHC) are known inhibitors of beta glucuronidase, the enzyme that promotes enterohepatic recirculation of conjugated bilirubin in the neonatal intestine. A randomized controlled trial of enteral administration of these substances (2 treatment groups) compared with babies who received nothing (group 3) or enteral whey/casein (no known enzymatic activity, group 4) showed significantly lower transcutaneous bilirubin measurements in breastfed babies aged 3-7 days who received the enzyme inhibitors when compared with the controls. ^[38] However, a similar treatment effect observed in group 4 raises some questions regarding the value of these therapies.

Sn-mesoporphyrin

Experimental therapy with Sn-mesoporphyrin inhibits bilirubin production by interfering with heme-oxygenase, an essential enzyme in the catabolic pathway of hemoglobin. This therapy is in clinical trials but has not been approved for use by the Food and Drug Administration (FDA). A report of a single case of compassionate use in the United States in a very low birth weight infant with severe growth restriction who was not a candidate for exchange transfusion showed a more than 25% reduction in total serum bilirubin levels after administration of a single dose at 46 hours of life. ^[39] Although more extensively studied in other countries, the safety and possible long-term sequelae of this therapeutic modality remain to be elucidated.

Diet and activity

Depending on the degree of neurologic impairment, infants or children may have limitations in their ability to eat normally. Diet and nutrition must be individualized with the help of the neurodevelopmental team caring for the patient.

Some neurologic deficits typically appear during the phase of motor skill acquisition by the infant. Motor deficits should be identified early, and appropriate intervention should be initiated to maximize the infant's ability in this critical area. 

Obtaining input from a pediatric neurologist during the acute presentation of BIND may be useful. However, the history and clinical presentation may make the diagnosis apparent.

In the chronic phase, involving neurodevelopmental specialists in the care and evaluation of the infant is important. Developmental potential can be maximized by early identification of and intervention for neurologic deficits.

If the patient develops hydrocephalus, consultation with a neurosurgeon is recommended.

Prevention

Prevention of hyperbilirubinemia is the best way to minimize the incidence of kernicterus. However, because some babies develop kernicterus with relatively modest bilirubin levels, no known absolute level of bilirubin below which the infant is completely safe is recognized. Additionally, because other factors contribute to the ability of bilirubin to cross the blood-brain barrier, management of these components must be appropriately considered.

In 2009, Newman et al reported the numbers needed to treat with phototherapy to prevent kernicterus, based on the AAP 2004 guideline phototherapy threshold. Assessment of 22,547 infants from a cohort of 281,898 infants born in a California hospital system from 1995-2004 resulted in various NNTs for different subpopulations of infants. Averaging 222 for boys and 339 for girls, the subgroup NNTs ranged from 10 for less than 24-hour-old, 36–week-gestation boys to 3,041 for older than or 3-day-old, 41-week-gestation girls. ^[40]

Serum bilirubin

Total serum bilirubin comprises a conjugated fraction (loosely called direct bilirubin) and an unconjugated fraction (indirect bilirubin). They are additive. However, the indirect fraction is composed of bound bilirubin (bound to albumin), lumirubin and other isomers if the baby is under phototherapy (unbound but water-soluble and unlikely to cross the blood-brain barrier), and free bilirubin. The free component is potentially toxic, but its exact serum level cannot be readily measured.

Risk of reduction of serum bilirubin

The current level of knowledge does not recognize the physiologic benefits of bilirubin, despite the multiple mechanisms operant in the neonate to promote and preserve hyperbilirubinemia. In vitro experiments have demonstrated a potent antioxidant capability of bilirubin, more so than the currently identified mechanisms.

An emerging field of research in human medicine is the role of oxidative injury in the development of various pathologic processes, which may be contributory to many neonatal diseases, such as retinopathy of prematurity, periventricular leukomalacia, bronchopulmonary dysplasia, and necrotizing enterocolitis. Observational studies in the neonate have demonstrated an inverse correlation between peak serum bilirubin levels and the development of these various pathologies. Investigation into this line of research continues.

Phototherapy

Irradiance with light in the blue-green spectrum (440-480 nm) induces a photochemical reaction that changes the bilirubin molecule into other photoisomers that are water-soluble, readily excretable, and unlikely to cross the blood-brain barrier into the lipid-rich neuronal tissue. Such conversion begins immediately upon exposure of the skin surface to the light.

The most important photoreaction is an irreversible structural isomerization of bilirubin into a water-soluble substance called lumirubin, which is then excreted in the bile. Reversible configurational isomerization and photo-oxidation also contribute somewhat to the effectiveness of phototherapy to reduce free bilirubin in the baby.

To be effective, adequate skin surface must be exposed to the appropriate wavelength, with enough intensity (lux) to induce the desired reaction. The AAP included recommendations for wavelength (430-490 nm) and irradiance (>30 µW/cm²) in their 2004 clinical practice guideline. ^[20]

Serum bilirubin levels should be closely monitored during phototherapy. A 1-mg/dL to 2-mg/dL decrease of measured bilirubin levels over a period of 4-6 hours is an appropriate response to phototherapy. If an inadequate response has been observed, lining the baby's bedding with aluminum foil or white material can increase the surface area of exposure and may increase the effectiveness of phototherapy.

Various devices are commercially available to facilitate provision of phototherapy. Models include overhead lights, blankets, and swaddling devices; selection is based on abilities to cover a broad surface area, ease of administration, and personal preference. The assortment of commercially available phototherapy devices continues to expand, and each new market entry is advertised as superior to the previous entry. Head-to-head clinical trials repeatedly show that time, irradiance, and skin surface area are the most significant factors in efficacy of phototherapy. ^{[41, 42, 43]}

In 2004, the AAP revised its clinical practice guideline for the management of hyperbilirubinemia in the healthy infant older than 35 weeks' estimated gestational age. ^[20]  The guideline incorporates a nomogram that delineates serum bilirubin levels by hour of life with subsequent risk for significant disease (see following image).

An Internet-based tool, BiliTool, is now available to help clinicians assess and treat hyperbilirubinemia based on the hour-specific nomogram and published guidelines.

This reference should be used when deciding how closely to monitor babies being discharged home before their bilirubin levels have peaked. Since its development, some experts have recommended universal bilirubin screening (performed with the state metabolic screen to minimize blood draws) before discharge.

Although falling short of recommending universal bilirubin measurement, the AAP guideline does recommend assessment of risk of severe hyperbilirubinemia in every baby prior to hospital discharge. This assessment can include either a bilirubin measurement (serum or transcutaneous), a clinical assessment of risk factors, or a combination of these 2 approaches. Further prospective analysis of these strategies found that the hour-specific nomogram was a better predictor than a clinical risk factor approach and that predischarge bilirubin level combined with gestational age most accurately predicted an infant's risk of developing severe hyperbilirubinemia. ^{[44, 45]}

Current quantization of bilirubin has been limited to direct serum measurement. Transcutaneous measurement devices are commercially available and are slowly being integrated into clinical use. The manufacturers claim excellent reliability and validity in babies of all skin types and colors.

Risks of phototherapy

Phototherapy by itself is generally considered safe in babies, except in some rare genetic skin disorders and congenital porphyria. However, some risks are associated with its use.

Exposure to phototherapy can increase insensible fluid loss and lead to dehydration, especially in babies in open warmers if fluid intake and output are not closely monitored. This, in turn, potentiates hyperbilirubinemia.

Some extremely premature infants have reportedly experienced skin burns from fiberoptic blankets on which they were lying. Such devices should be used cautiously in infants with vulnerable skin.

Of potentially greater concern with respect to extremely premature infants is the report of increased mortality associated with phototherapy. A study conducted by the NICHD Neonatal Network as reported by Watchko evaluated the outcomes of aggressive versus conservative phototherapy in extremely low birth weight infants. Although aggressive phototherapy seemed to improve neurodevelopmental outcomes in the 751- to 1000-g cohort, aggressive phototherapy used in the group with birth weights of 501-750 g showed a 5% higher mortality rate, with a post-hoc Bayesian analysis estimating an 89% probability that aggressive phototherapy increased the rate of death in this cohort. The authors speculate that greater light penetration deeper into subcutaneous tissues and possible oxidative injury to cell membranes may be responsible. ^[10]

Concern exists about the risk of retinal damage in infants exposed to the extremely bright light of phototherapy. Accordingly, all infants should wear protective eye coverings while being treated.

An observed increase in the prevalence of patent ductus arteriosus (PDA) has been shown to occur in premature infants receiving phototherapy, and foil shields to the chest have been shown to ameliorate this increase. The operant mechanism has not been fully elucidated.

Bilirubin photosensitizes the skin, and skin damage is a theoretical risk. Bullous eruptions have been described in several infants with porphyrin abnormalities; congenital porphyria is a contraindication to the use of phototherapy. In 2011, Csoma et al from Hungary reported on 59 sets of twins, one of which received blue-light phototherapy and the other of which did not. Neonatal phototherapy was associated with a significantly higher prevalence of both cutaneous and uveal melanocytic lesions, after controlling for sun exposure and other confounders. ^[46]

Bronze baby syndrome occurs in infants with direct hyperbilirubinemia who are exposed to phototherapy. This seems likely to be the result of dermal accumulation of coproporphyrins. Measurement of the direct fraction of total bilirubin should be performed in every baby before starting phototherapy.

Phototherapy can interfere with maternal-child bonding at a critical time in the dyad's development. If a mother is breastfeeding, initiation of phototherapy introduces mechanical barriers to the breastfeeding process, which can be overwhelming at this critical time. Any comments about the role of breast milk in the development of hyperbilirubinemia may further sabotage this process. Altered parental perceptions of their infant from healthy to ill may further influence their short-term and long-term interactions with their infant. The pediatrician should address these issues with the family.

Phototherapy may be associated with ileus and/or feeding intolerance in premature infants treated with overhead (but not fiberoptic) devices. Doppler flow studies of splanchnic blood flow performed on babies receiving overhead phototherapy showed increased resistance to flow in the superior mesenteric artery (SMA) compared with prephototherapy measurements; no such effect was observed in babies being treated with fiberoptic devices. A retrospective review of 52 consecutive extremely low birth weight infants showed a higher incidence of ileus (abdominal distention, bilious aspirates) in babies receiving phototherapy (63.4%) compared with those who did not (9%). ^[47]  Outcomes between the 2 groups were comparable.

Breastfeeding

The link between hyperbilirubinemia and breastfeeding has long been recognized, and, until relatively recently, breastfeeding was typically interrupted in infants with jaundice. Randomized controlled trials have shown that offering formula or dextrose water to the breastfed infants with jaundice actually increases total serum bilirubin levels and, thus, should not be advocated. The AAP recommends against this practice, with evidence quality B and C in its 2004 clinical practice guideline. ^[20]  Furthermore, this practice has also been shown to result in a decrease in breast milk intake after breastfeeding is reestablished. Study of the effect of continuing breastfeeding versus its interruption has not shown any untoward effect of continued breastfeeding. Because of the clear short-term and long-term advantages to the infant of breast milk feeds, the evidence would indicate that breastfeeding should be continued in the infant who is well enough to have enteral feedings.

Infant massage

In 2011, Chen et al reported from Niigata, Japan the results of a randomized controlled trial of the benefits of infant massage on hyperbilirubinemia. Forty-two healthy term breastfed infants ranging in weight from 2800-3600 g were randomized to massage or no massage (control). Infants receiving massage had a significantly higher frequency of stooling on days 1 and 2 (P < .05) and a lower total serum bilirubin on day 4 compared with the control group. ^[48]

Clinical algorithms

A Journal of Pediatrics supplement devoted exclusively to hyperbilirubinemia and prevention of kernicterus advocated 2 models for public health policy aimed at eliminating kernicterus from the population. ^{[49, 50]}  To date, notwithstanding the efforts of some hospital systems and the American Academy of Pediatrics to standardize this aspect of newborn care, approaches to the surveillance and management of hyperbilirubinemia remain individualized, both throughout the United States and elsewhere. ^[24]

To help ensure that infants may reach their maximum neurodevelopmental potential, referring babies with bilirubin-induced neurologic dysfunction (BIND) to a neurodevelopmental pediatrician skilled in caring for these patients is important. Early identification of and intervention for neurodevelopmental deficits has been shown to positively impact an infant's long-term neurodevelopmental prognosis.

The numerous areas of uncertainty surrounding the diagnosis and treatment of hyperbilirubinemia in the infant, coupled with the infrequency of sequelae, make it easy to become cavalier about the evaluation of an infant with jaundice. However, remember that physiologic hyperbilirubinemia is a diagnosis of exclusion, and kernicterus, when it occurs, is a devastating and legally indefensible sequela.

Sepsis must always be excluded in the infant with jaundice. Uncommon, but treatable, metabolic causes of jaundice include hypothyroidism and galactosemia. The first sign of occult immune or nonimmune hemolytic disease may be hyperbilirubinemia.

In its 2004 clinical practice guideline, the AAP included recommendations regarding interval between hospital discharge and outpatient follow-up evaluation by a qualified health care professional. ^[20]  Recommendations are based on the infant's age (in hours of life) at discharge, presence or absence of risk factors for exaggerated hyperbilirubinemia, and the presence of other neonatal problems. Recommendations for follow-up range from as early as prior to 72 hours of life (if discharged before 24 h) to no later than 120 hours (5 d) if discharged before 72 hours.