Anesth Analg 2007;104:435-436
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000252462.70451.0e
GENERAL ARTICLES
The Anesthetic Implications of Crigler-Najjar Syndrome
Christopher Robards, MD, and
Sorin J. Brull, MD
From the Department of Anesthesiology, Mayo Clinic College of Medicine, Mayo Clinic, Jacksonville, Flourida.
Address correspondence and reprint requests to Sorin J. Brull, MD, Mayo Clinic, JAB 4035, 4500 San Pablo Rd., Jacksonville, FL 32224, (904) 296-5688. Address e-mail to brull.sorin{at}mayo.edu.
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Abstract
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Crigler-Najjar syndrome is a hereditary condition of unconjugated hyperbilirubinemia due to a deficiency of the enzyme, uridine diphosphate glucuronosyltransferase. Exacerbations of the disease can occur whenever there is either an increase in free serum bilirubin and/or a decrease in serum albumin. The exacerbations can lead to bilirubin encephalopathy and severe brain damage. The goal of anesthetic management in these patients is to prevent an imbalance in the serum bilirubin to serum albumin molar ratio, thereby avoiding neurologic sequelae.
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CASE REPORT
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A 20-year-old, 80-kg, 198-cm, man with a medical history of Crigler-Najjar Type II (Arias' syndrome) presented for mandibular reconstruction. He was otherwise healthy with no known drug allergies. His preoperative medication therapy included rifampin 300 mg by mouth (PO) daily, ursodiol 500 mg PO four times daily (for prophylaxis of gallstone formation), and vitamins C and E. He was not receiving oral phenobarbital therapy. On preoperative examination, the patient was awake and alert and had no stigmata of hyperbilirubinemia, except for mild scleral icterus. His preoperative laboratory data are shown in Table 1, and included a high level of total serum bilirubin with normal liver function tests and serum electrolytes. Anesthesia was induced with sevoflurane 4% in 100% oxygen, and nasal intubation of the trachea was facilitated with succinylcholine 120 mg, fentanyl 150 mcg, and direct laryngoscopy using a Macintosh #4 blade. Anesthesia was maintained with 2.3% sevoflurane for the remainder of the operation. The patient received 900 cc of lactated Ringer's solution. Ondansetron 4 mg was administered before emergence from anesthesia. Postoperative analgesia was provided with 100 mcg fentanyl. The patient was discharged from the postanesthesia care unit to home later that day in stable condition. Laboratory data obtained 1 wk postoperatively (Table 1) showed increased serum bilirubin levels, and normal renal and liver function tests.
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DISCUSSION
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Crigler-Najjar syndrome results from a mutation in one of the five exons of the gene coding for the enzyme uridine diphosphate glucuronosyltransferase (UDPGT) (1). The disease exists in two forms: Type I is the more severe disease form in which there is a complete absence of enzyme activity; Type II, also known as Arias' syndrome, is autosomal dominant with variable penetrance, characterized by a partial enzyme deficiency. Affected individuals have approximately 10% of UDPGT activity, and jaundice typically becomes apparent by one year of age (1). The total serum bilirubin range is typically 250–500 µmol/L (15–30 mg/dL). Total serum albumin is typically 550–650 µmol/L (3.6–4.4 g/dL).
The mainstay of treatment for these patients is oral administration of drugs known to induce the UDPGT enzyme, thereby increasing bilirubin conjugation and conversion to the water-soluble, easily excreted form. Drugs that induce glucuronosyl transferase activity include phenobarbital, phenytoin, dexamethasone, hydrocortisone, para-aminosalicylic acid, omeprazole, clotrimazole, and rifampin (rifampicin) (2–6). Of these, rifampin and phenobarbital are used most commonly. Phototherapy has recently been reported to be beneficial during pregnancy in a patient with Crigler-Najjar Type II syndrome (7), by decreasing the maternal serum levels of bilirubin.
During states of physiological stress, the patient's serum bilirubin-to-albumin ratio can increase to more than unity, and the patient becomes at increased risk for developing bilirubin encephalopathy, or kernicterus. Kernicterus can lead to central deafness, ocular motor palsy, ataxia, choreoathetosis, mental retardation, seizures, and even death.
Avoidance of hyperbilirubinemia can be accomplished by avoiding drugs and physiologic states that displace bilirubin from albumin. Brodersen et al. (8) performed laboratory testing on a series of drugs and metabolites to measure the amount of bilirubin displacement from albumin due to competition for albumin binding sites. The authors found that sulfonamides, ceftriaxone, ampicillin, salicylates, and furosemide, all displace bilirubin from albumin (8). Dehydration, hypercarbia, and acidosis also displace bilirubin, resulting in hyperbilirubinemia.
The anesthetic goal in caring for patients with Crigler-Najjar disease is prevention of increased serum-free bilirubin. The ability of drugs used in anesthesia to displace bilirubin from albumin has not been well studied. Lacking specific data, albumin binding is a reasonable surrogate for risk of bilirubin displacement. For example, benzodiazepines bind albumin, but they do not displace bilirubin. Sodium thiopental is highly protein bound, but whether or not it displaces bilirubin from albumin has not been researched extensively. Etomidate is 75% protein bound (9). There are no specific data regarding the protein binding of propofol, but displacement of bilirubin from albumin induced by the fatty acid components of propofol is known to occur, resulting in increased free bilirubin. Morphine (20%–40% protein bound) and meperidine (39% protein bound) are reasonable opioids, in terms of binding, but a more logical selection may be an opioid that is highly potent. Because a drug can displace no more than an equivalent number of molecules of bilirubin, drugs with high potency will displace far fewer bilirubin molecules from albumin than those with low potency. On this basis, fentanyl is a very good choice, and sufentanil is probably the best choice among opioids because of its high potency. Atracurium and cisatracurium undergo Hoffman elimination in the plasma, as well as ester hydrolysis, and may have minimal effects on plasma bilirubin levels (10,11).
Local anesthetics bind to two major proteins, 
-1-acid glycoprotein, and albumin. Although local anesthetics can bind albumin and can displace other molecules, the affinity of local anesthetics for albumin is 5–10,000 times lower than the affinity for -1-acid glycoprotein (12). Lidocaine is 55%–65% protein bound in adults, whereas mepivacaine, ropivacaine, and bupivacaine are 75%–80%, 94%, and 85%–95% protein bound, respectively (12).
Although inhaled anesthetics do not have a direct effect on the protein binding of bilirubin, mild postoperative increases in serum bilirubin have been reported in surgical patients receiving sevoflurane and isoflurane (13), but without evidence of hepatotoxicity (14). Interestingly, administration of either sevoflurane (15) or desflurane (16) to volunteers not undergoing surgery induced no abnormalities in liver function tests, suggesting that perhaps other perioperative, surgical factors may be responsible for the alterations in liver function tests. Based on these data, it would appear prudent that in patients with Crigler-Najjar syndrome, volatile anesthetics that have been shown not to influence serum bilirubin levels or produce alterations in liver function (such as sevoflurane, desflurane, and isoflurane) should be selected.
Most patients with Crigler-Najjar Type II can be expected to do well with anesthesia and surgery, provided attention is given to avoiding displacement of bilirubin from albumin. Our patient is representative of this population. Acute kernicterus has been reported after surgical stress (17), if the patient is already compromised with additional metabolic abnormalities. Few patients with Type I disease reach adulthood, but such patients should be treated especially carefully, as they likely have far less tolerance for even modest changes in serum-free bilirubin.
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Footnotes
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Accepted for publication October 13, 2006.
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REFERENCES
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Abstract
CASE REPORT
