Kernicterus Treatment & Management

The cornerstone of management of hyperbilirubinemia is prevention of neurotoxicity. 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.^[23] 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%).^[27]

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.^[28] 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.^[29]

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, most recently 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^[29] ), 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.^[23] 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.^[14]

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, more recently, in preterm infants with peak total serum bilirubin as low as 13.1 mg/dL.^[19] 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.^[30] 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.

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. Recent investigation has 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).^[31]

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.^[32] 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.^[33] Although more extensively studied in other countries, the safety and possible long-term sequelae of this therapeutic modality remain to be elucidated.

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.

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.

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.