eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology
Kernicterus: Treatment & Medication
Updated: Sep 30, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
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. Current clinical research is evaluating the use of metalloporphyrins to block bilirubin formation by competing with the enzyme heme oxygenase.
- 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 (eg, >25 mg/dL) and dehydration or when the serum bilirubin level continues to rise despite attempts to reduce it. 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. This procedure is not without risk. 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%).8
- Technique
- 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.
- Risks
- 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%.
- 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.9 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.10
- 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 series10 ), 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.
- Indicated bilirubin levels
- 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.7 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.
- Studies have reported neurologically normal outcomes in healthy term infants with histories of serum bilirubin levels as high as 46 mg/dL. However, the recent resurgence in kernicterus has been reported to occur in near-term infants with serum bilirubin levels as low as 20.7 mg/dL. The level at which to intervene is a clinical question that remains to be answered. The procedure should be highly 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.
- Technique
- 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.
- 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.11 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.12 Although more extensively studied in other countries, the safety and possible long-term sequelae of this therapeutic modality remain to be elucidated.
Surgical Care
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.
Consultations
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.
Diet
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.
Activity
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.
Medication
No medications are available to treat the symptoms of acute or chronic bilirubin encephalopathy. Pharmacologic intervention is aimed at prevention. Current therapies are indicated as adjuncts to phototherapy when total bilirubin is approaching exchange level; experimental therapy continues with the use of bilirubin production inhibitors.
Blood product derivatives
These methods decrease the amount of free bilirubin in the intravascular space, thus theoretically reducing the risk of neurotoxicity. Bilirubin is produced via induction of its enzymatic pathway and by RBC degradation. Inhibition of either of those 2 mechanisms can decrease the amount of bilirubin in the blood.
Albumin (Albuminar, Albutein, Plasbumin)
Because bilirubin bound to albumin is not available to cross the blood-brain barrier, increasing the amount of serum albumin theoretically increases the amount of available binding sites and decreases free bilirubin. Efforts to quantify albumin-binding capability or serum levels of bound bilirubin have not proved to be clinically useful, although assessment of the bilirubin-to-albumin ratio has recently been incorporated into the decision-making algorithm for exchange transfusion. However, administration of albumin for the purpose of increasing bilirubin-binding capacity is not a recommended standard of care. It may be considered in cases of significant hypoalbuminemia. Measured albumin levels <3 g/dL may be considered an additional risk factor for BIND when considering therapeutic interventions.
Adult
Pediatric
0.5-1 g/kg IV of 5% albumin (ie, 5 g/100 mL)
None reported
Documented hypersensitivity; pulmonary edema; severe anemia; cardiac failure
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use 25% albumin with caution in premature neonates because of the increased risk of intraventricular hemorrhage; caution in renal or hepatic failure, may cause protein overload; rapid infusion may cause vascular overload or hypotension; monitor for volume overload; caution in sodium-restricted patients; common adverse effects include CHF, hypotension, tachycardia, fever, chills, and pulmonary edema; do not dilute albumin 25% with sterile water for injection (produces hypotonic solution and, if administered, may result in life-threatening hemolysis and acute renal failure)
Immune globulin intravenous (Gamimune, Gammagard S/D, Gammar-P, Polygam S/D)
Parenteral administration 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.
Adult
Pediatric
0.5-1 g/kg IV infused over 2 h; the dose can be repeated in 12 h, if needed
Globulin preparation may interfere with immune response to live virus vaccine (eg, MMR) and reduce efficacy (do not administer within 3 mo of vaccine)
Documented hypersensitivity; IgA deficiency
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Associated with other risks accompanying administration of other human blood products (eg, transmission of infection, allergic reaction); unknown if administration of IVIG places the neonate at a theoretically increased risk of susceptibility to infection; check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-30 d postinfusion)
Anticonvulsant agents
Phenobarbital may increase hepatic conjugation and excretion. Decreased hepatic conjugation caused by normal delay in enzyme induction increases the amount of unconjugated bilirubin in the blood stream. Conjugated bilirubin does not pose a threat of neurotoxicity. Once conjugated, this nontoxic form of bilirubin proceeds toward intestinal excretion.
Phenobarbital (Luminal, Solfoton)
Induces the hepatic enzymes involved in bilirubin conjugation and increases biliary excretion.
Do not administer intra-arterially. Dosing can be enteral or parenteral.
Adult
Pediatric
Hyperbilirubinemia: 3-8 mg/kg/d PO/IV initially; may increase up to 12 mg/kg/d
Not to exceed IV administration rate of 1 mg/kg/min or 30 mg/min for infants
May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may cause additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of PO contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities may also occur)
Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritis
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Use with caution in patients with renal impairment, hepatic impairment, or both; abrupt withdrawal may precipitate status epilepticus; high doses may cause respiratory depression or failure
More on Kernicterus |
| Overview: Kernicterus |
| Differential Diagnoses & Workup: Kernicterus |
 Treatment & Medication: Kernicterus |
| Follow-up: Kernicterus |
| Multimedia: Kernicterus |
| References |
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Further Reading
Keywords
kernicterus, acute bilirubin encephalopathy, chronic postkernicteric bilirubin encephalopathy, chronic bilirubin encephalopathy, profound pathologic hyperbilirubinemia, bilirubin-induced neurologic dysfunction, BIND, jaundice, hemolytic disease, glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis, retrocollis, opisthotonus, athetosis, chorea, hearing loss, delayed language acquisition, birth trauma, Crigler-Najjar syndrome, polycythemia, smoking, hemolytic disease of the newborn, pyruvate kinase deficiency, thalassemia, cephalohematoma, subgaleal hemorrhage, peripheral ecchymoses, hypoalbuminemia, liver transplantation, Arias syndrome, Gilbert syndrome, galactosemia, hypothyroidism, acidosis, breastfeeding jaundice, breast milk jaundice
