Kernicterus: a re-emerging problem?

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Kernicterus a re-emerging problem?

• N. Ambalavanan MD
• Division of Neonatology
• University of Alabama at Birmingham
• May 2003

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Overview

• What is kernicterus?
• Is it a problem?
• Why is it a problem?
• What can we do about it?

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Kernicterus

• Kernicterus Schmorl (1904) described yellow
  staining of the basal ganglia in the brain of
  infants who died with severe jaundice and called
  it kernikterus. Also noted by Orth in 1875.
• Extreme hyperbilirubinemia causes bilirubin
  encephalopathy and toxicity to basal ganglia and
  brainstem nuclei.
• Rare but preventable cause of severe morbidity in
  otherwise normal infants.

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Stages of kernicterus

• Acute bilirubin encephalopathy 3 distinct
  clinical phases
• First phase (first few days) Stupor, hypotonia,
  and poor sucking.
• Second phase Hypertonia (retrocollis backward
  arching of neck, opisthotonus arching of trunk)
  and fever. All infants who develop this will
  develop chronic encephalopathy.
• Third phase (after first week) Disappearance of
  hypertonia.
• Muscle rigidity, paralysis of upward gaze,
  periodic oculogyric crisis, and irregular
  respirations are present in the terminal phase.
  4 die in acute phase (data from USA)

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Stages of kernicterus

• Chronic bilirubin encephalopathy
• First year Poor feeding, high pitched cry.
  Hypotonia but good deep tendon reflexes. Tonic
  neck reflex, righting reflex persist. Slow motor
  skills (up to 5 years to walk).
• After first year Main clinical features are
• extrapyramidal disorder (athetosis, ballismus,
  tremor, dysarthria)
• hearing loss (damage to cochlear nuclei in
  brainstem)
• gaze abnormalities (limitation of upward gaze)
• Athetosis normally develops 18 months- 8 years
  of age. Hearing loss may be the only symptom in
  some children.

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Investigations (Volpe JJ. 3rd Ed., 1995)

• Clinical features
• Bilirubin (unconjugated) level
• Magnetic Resonance Imaging (MRI)
• Increased signal intensity in the globus pallidus
  ( putamen thalamus) on T2-weighted images

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Is kernicterus a problem?

• Major problem in the 1950s -1970s
• Rh-hemolytic disease was common, and kernicterus
  had a high incidence
• Exchange transfusion, Rh-immunoglobulin, and
  phototherapy markedly reduced kernicterus by
  1980s.
• Less emphasis on jaundice in 1990s
• An increase in kernicterus recently

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What is the incidence?

• Kernicterus registry in the United States 90
  cases from 1984 to 2001
• True incidence unknown, as not all cases are
  identified or reported
• JCAHO (Joint Commission on Accreditation of
  Healthcare Organizations) issued a Sentinel
  Event Alert on kernicterus recently (Apr 2001)

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www.pickonline.org

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Why is kernicterus a problem?

• Jaundice in the newborn is common
• Extreme hyperbilirubinemia that can cause
  kernicterus is rare
• Assessment of risk of extreme hyperbilirubinemia
  has been inadequate or unreliable, and bilirubin
  levels have not always been measured, or measured
  in time

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Risk factors for hyperbilirubinemia in full-term
newborns

• Jaundice within first 24 hours of birth
• A sibling who was jaundiced as a neonate
• Unrecognized hemolysis (ABO- or Rh-
  incompatibility)
• Non-optimal sucking/nursing
• Deficiency in G6PD
• Infection
• Cephalhematomas/bruising
• East Asian or Mediterranean descent
• MMWR Vol 50, No. 23, 491-4, June 15, 2001

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Pathophysiology

• Physiologic hyperbilirubinemia
• Increased bilirubin production
• Decreased bilirubin conjugation
• Decreased excretion
• Average peak in full term 5-6 mg/dL
• Exaggerated physiological 7-17 mg/dL
• Pathologic hyperbilirubinemiagt17 mg/dL
• Dennery et al. NEJM 344581, 2001

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Pathophysiology
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Pathophysiology

• Factors affecting neurotoxicity
• Concentration of bilirubin in the brain
• Duration of exposure to bilirubin
• Correlation between serum bilirubin and
  neurotoxicity is weak, except in infants with
  hemolysis
• Dennery et al. NEJM 344581, 2001

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Problems with serum bilirubin

• No estimate of duration
• Not a good estimate of
• tissue concentration
• bilirubin production
• albumin-bound bilirubin in serum
• Phototherapy creates photo-isomer that is excreted

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Serum Bilirubin and Kernicterus

• Kernicterus in Rh-isoimmunization
• Serum level Incidence
• 10-18 mg/dL 0
• 19-24 mg/dL 8
• 25-29 mg/dL 33
• 30-40 mg/dL 73
• Volpe JJ Neurology of the Newborn. 3rd Ed. pp
  490-514, 1995

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Is there a safe serum bilirubin level in the
absence of hemolysis?
Management of Hyperbilirubinemia in the Healthy
Term Newborn. Pediatrics 94 558, 1994
Age,hours TSB Level, mg/dL (pmol/L) TSB Level, mg/dL (pmol/L) TSB Level, mg/dL (pmol/L) TSB Level, mg/dL (pmol/L)
  Consider Photo-therapy Phototherapy Exchange Transf. if Intensive Photo therapy Fails Exchange Transf. and Intensive Phototherapy
lt24 ... ... ... ...
25-48 gt12 (210) gt15 (260) gt20 (340) gt25 (430)
49-72 gt15 (260) gt18 (310) gt25 (430) gt30 (510)
gt72 gt17 (290) gt20 (340) gt25 (430) gt30 (510)
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Is a serum bilirubin of 20-25 mg/dL safe?

• 9.8 of babies with serum bilirubin between 20-25
  mg/dl had kernicterus
• Dhaded et al. Indian Pediatr 33 1059, 1996
• Prospective observational study of 94 infants
  admitted with bilirubin gt18 mg/dL
• Exchange transfusion done at level gt20 mg/dL
• 28 excluded as 24 had hemolysis and 4 had
  malformations
• 14 (22) of remaining 64 developed kernicterus (gt
  stage II)
• Total bilirubin 18-25 mg/dL 14 incidence
• 25-29 mg/dL 18
  incidence
• gt30 mg/dL 43
  incidence
• Problem Admitted in declining phase, after
  damage is done?
• Murki et al. Indian Pediatr 38 757, 2001

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Root cause analysis

• Four patient care processes
• Patient assessment
• Continuum of care
• Patient and family education
• Treatment
• JCAHO Sentinel Event Alert April 2001

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Root cause Patient assessment

• The unreliability of visual assessment of
  jaundice in newborns with dark skin
• Failure to recognize jaundice- or its severity-
  based on visual assessment, and measure a
  bilirubin level before the infants discharge
  from the hospital or during a follow-up visit
• Failure to measure the bilirubin level in an
  infant who is jaundiced within the first 24 hours

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Root cause Continuum of care

• Early discharge (before 48 hours) with no
  follow-up within 1 or 2 days of discharge
  (particularly important for infants lt38 wks
  gestation)
• Failure to provide early follow-up with physical
  assessment for infants who are jaundiced before
  discharge
• Failure to provide ongoing lactation support to
  ensure adequacy of intake for breast-fed newborns

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Root cause Patient and Family education

• Failure to provide appropriate information to
  parents about jaundice and failure to respond
  appropriately to parental concerns about a
  jaundiced newborn, poor feeding, lactation
  difficulties, and change in newborn behavior and
  activity.

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Root cause Treatment

• Failure to recognize, address, or treat rapidly
  rising bilirubin
• Failure to aggressively treat severe
  hyperbilirubinemia in a timely manner with
  intensive phototherapy or exchange transfusion

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Early identification Nomograms

• Bhutani et al. Pediatrics 1036, 1999

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How good is the nomogram?
() predictive value (-) predictive value Sensitivity Specificity
Above 95th ile 40 98 54 96
Above 75th -ile 22 99.5 91 85
Above 40th -ile 12 100 100 65

• For predicting values gt95th percentile
• Bhutani et al. Pediatrics 1036, 1999

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Transcutaneous measurement

• New multiwavelength spectral analysis devices
  (e.g. Bilicheck)
• Infants with predischarge BiliCheck values above
  the 75th percentile on the bilirubin nomogram at
  high risk for hyperbilirubinemia
• -gt Negative predictive value 100 positive
  predictive value 33 sensitivity 100
  specificity 88
• Bhutani et al. Pediatrics 106E17, 2000

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Transcutaneous measurement

• A recent study in a predominantly hispanic
  population showed that skin measurement
  underestimated serum levels, especially for
  levels gt10 mg/dL
• Engle et al. Pediatrics 11061, 2002

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Early identification CO

• COStat End-tidal breath analyzer (Natus Medical)

• Carbon monoxide production is an index of
  bilirubin production
• Devices available to measure CO production in
  exhaled air (ETCOc)
• Does not add much predictive ability to serum
  bilirubin measurements
• Stevenson et al. Pediatrics 108175, 2001

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Newer methods of prevention

• Metalloporphyrins inhibit bilirubin production
• Tin-mesoporphyrin (SnMP 6 mM/kg) within 24 h of
  birth in 517 preterm infants decreased peak
  bilirubin by 41 and need for phototherapy by 76
  (Valaes et al. Pediatrics 931, 1994)
• SnMP reduced need for phototherapy (Biligt19.5) in
  term infants with levels 15-18 mg/dL at 24-48 hrs
  of age (0 of 40 in SnMP gp vs. 12 of 44 in
  controls) (Martinez et al. Pediatrics 1031,
  1999)
• Other trials also show efficacy in term infants
  (Dennery et al. NEJM 344581, 2001)
• Not yet approved for use in newborn no oral
  formulation yet

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Early treatment is required!

• Phototherapy (gt12 mW/cm2/nm)
• Blue light/White light fluorescent bulbs
• Bili-blanket
• High intensity LED (blue, blue-green) gallium
  nitride
• Exchange transfusion
• Only after trial of optimal phototherapy, if
  bilirubin gt20-25 mg/dL
• About 2 mortality, 12 complications

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Summary

• Kernicterus still occurs, and is preventable
• Prevention is important
• Evaluate risk factors (JAUNDICE)
• Evaluate serum bilirubin (low threshold)
• Adequate feeding (especially breast fed)
• Early follow-up (1-2 days after discharge if lt48
  hours of age)
• Instructions to parents
• Aggressive treatment (early phototherapy)