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Lethal Effect of a Single Dose of Rasburicase in a

Preterm Newborn Infant

abstract

This case report describes a preterm newborn infant who was treated with a single dose of rasburicase for an increase in uric acid level. He died on the third day as a result of complications of hemolysis, which appeared to be precipitated by rasburicase. The patient’s death was preceded by progressive respiratory insufficiency, lactic acidosis, and hyperbilirubinemia, culminating in refractory hypoxia and hypoten-sion. A postmortem assay for glucose-6-phosphate dehydrogenase showed deficiency and the glucose-6-phosphate dehydrogenase Med-iterranean genotype.Pediatrics2013;131:e309–e312

AUTHORS:Patrizia Zaramella, MD,aAlessandra De Salvia,

PhD, MD,bMartina Zaninotto, MD,cMaura Baraldi, MD,a

Giovanni Capovilla, MS-VI,dDomenico De Leo, MD,eand

Lino Chiandetti, MDa

aNICU, Womens and Childrens Health Department, anddMedical School, University of Padova, Padova, Italy;bForensic and Legal Medicine Department, andeDepartment of Public Health and Community Medicine, University of Verona, Verona, Italy; and cDepartment of Laboratory Medicine, Padova University Hospital, Padova, Italy

KEY WORDS

rasburicase, preterm newborn, hemolytic anemia

ABBREVIATIONS

G6PD—glucose-6-phosphate dehydrogenase Hb—hemoglobin

www.pediatrics.org/cgi/doi/10.1542/peds.2011-1580 doi:10.1542/peds.2011-1580

Accepted for publication Jul 31, 2012

Address correspondence to Patrizia Zaramella, MD, NICU, Women’s and Children’s Health Department, University of Padova, via Giustiniani, 3, 35128 Padova, Italy. E-mail: zaramella@pediatria. unipd.it

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2013 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE:Drs Zaramella and De Salvia served as paid expert witnesses in the case reported in this article; the other authors have indicated they have nofinancial relationships relevant to this article to disclose. FUNDING:No external funding.

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked disor-der and its most common clinical man-ifestations are neonatal jaundice and acute hemolytic anemia, triggered by an exogenous agent.1Most individuals re-main asymptomatic throughout their lives, but if they develop neonatal jaun-dice or hemolytic anemia, then death or permanent neurologic damage may oc-cur.2This report concerns the lethal ef-fect of an oxidative drug (rasburicase) administered to reduce the uric acid level in a preterm newborn with G6PD deficiency. This case report shows that caution is needed when considering the risk-benefit ratio of exposing patients to this drug.

PATIENT PRESENTATION

A newborn male infant was born at 30 weeks’ gestational age, 2012 g birth weight, by cesarean delivery because of placental abruption in a 29-year-old white female. Umbilical artery blood gas analysis showed normal values. The Apgar score was 3 at 1 minute and 7 at 5 minutes. The infant presented with hypotonia, cyanosis, apnea, and bradycardia. He was dried, his airway was suctioned, and he was stimulated and ventilated after 30 seconds with a laryngeal mask for∼3 minutes.

Free-flow O2was administered. Oxygen sat-uration was 95% to 96%, heart rate was 120 beats per minute, and grunt-ing and tachypnea were reported. He was moved to a tertiary-level NICU with a diagnosis of worsening respiratory distress in a preterm infant. Physical examination on admission to the NICU (first hour of life) revealed spontane-ous breathing with O2supplementation,

flaring of the ala nasi, thoraco-abdominal asynchrony, and poor perfusion. The in-fant was intubated, administered sur-factant intratracheally, and ventilated mechanically; antibiotics were started (gentamicin 10 mg every 24 hrs and ampicillin, 100 mg every 12 hrs

in-travenously), although blood culture remained negative.

Urine output was 0.9 mL/kg/h and a single dose of rasburicase (Fasturtec) was administered in the 33rd hour of life because of a uric acid level of 6.67 mg/dL and a brief period of oliguria. By the 64th hour, the boy’s bilirubin sud-denly increased, so phototherapy was begun and intravenous immunoglobu-lin was administered; nonetheless the bilirubin level remained at 18.3 mg% for 7 hours. Hematocrit dropped to 28% in the 79th hour, and 22% in the 83rd hour. Nurses reported 84% O2 transcutaneous saturation in the 77th hour, and capillary blood gases showed mixed acidosis and low O2saturation. In the 80th hour, vecuronium was ad-ministered and high-frequency venti-lation was started with a fraction of inspired oxygen of 1. On admission, fraction of inspired oxygen was 0.6 and it had stabilized at 0.3. Dopamine, which was stopped at 48 hours, was resumed and dobutamine was added. Blood electrolytes and gases were ur-gently conducted and a unit of packed red blood cells was ordered but the patient died before it could be admin-istered. The nursing diaries recorded a bronze skin color and dark urine, which may be a sign of urine hemo-globin (Hb) or bilirubin. In the last hour of life, the heart rate gradually de-creased (80 beats per minute) and transcutaneous O2saturation dropped to 0%, remaining so until death.

Blood drawn postmortem (intracardiac puncture) revealed G6PD: 1.5 IU/g Hb (normal value: 9.0–18.0). Molecular analysis of the G6PD gene on genomic DNA (National Center for Biotechnol-ogy Information reference sequence NC_000023.10) revealed hemizygosis for the G6PD Mediterranean variant. The mother’s G6PD level was 6.7 U/g Hb, and the father’s was 13.2 U/g Hb (normal value: 9.4–30.5). Autopsy re-vealed no evidence of bleeding or other

findings that informed the cause of death.

DISCUSSION

The main cause of the clinical picture described appears to be hemolytic anemia in conjunction with hyper-bilirubinemia, as bleeding and immune-mediated, maternal-fetal incompatibility were ruled out. Among the potential causes of hemolytic anemia, rasburicase was the drug administered to the child that is capable of causing hemolysis. Because hyperuricemia may exacerbate preexisting nephropathy,3 rasburicase has also been used as a novel treat-ment of hyperuricemia associated with acute kidney disease in infancy.4,5 Rasburicase is an enzyme that cataly-ses the conversion of uric acid into the more soluble allantoin,6 thereby decreasing the risk of renal damage. Ghirardello et al5concludedThe arti-cle by Hobbs and coworkers4provides scientific evidence for what we believe is a common clinical practice: the use of rasburicase in hyperuricemic new-borns with acute kidney injury (AKI).” This report prompted the administra-tion of rasburicase to our newborn infant. The article by Hobbs et al4also specifically mentions the main contra-indication to the use of rasburicase, however, which is G6PD deficiency. On day 1, the infant had a normal dieresis (0.9 mL/kg/h), followed by a brief period of oliguria that did not satisfy the criteria for acute kidney injury. The urineflow remained normal after rasburicase was administered. Hobbs et al4described a retrospective chart review on 7 infants, including 2 new-borns, with uric acid levels higher than 8 mg/dL, and Ghirardello et al5 con-sidered patients with a mean uric acid level of 14.563.6 mg/dL, that is, con-siderably higher than in our patient (6.67 mg/dL in the 33rd hour of life). Therefore, in our case, the administra-tion of rasburicase was not indicated.

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No controlled studies of rasburicase in newborn infants with decreased renal function are published, so the benefit and risk of this medicine remain un-defined in neonates.

G6PD deficiency is the most common inherited enzyme deficiency,7 causing acute and chronic hemolytic anemia, or severe jaundice associated with kernicterus, in response to the con-sumption of oxidant substances.8Blood transfusions9may be necessary in the acute hemolytic phase, as in the G6PD Mediterranean genetic variant.10More than 300 variants are known, but only a few cause chronic hemolysis even in the absence of any trigger.11Although some neonatal cases have been reported, most affected individuals exhibit no hemolysis12unless Hb oxi-dation is induced by oxidative drugs, fava beans, or infections. Sudden epi-sodes of hemolysis associated with G6PD deficiency may result in rapid increases in serum total bilirubin concentrations up to levels sufficient to cause neurologic damage.13Hemolysis induced by rasburicase usually begins 24 to 72 hours after the drug’s

admin-istration, and ends 4 to 7 days later.14,15 In G6PD deficiency, the drug prompts the formation of intracellular H2O2, resulting in cell death and oxidative membrane injury.2,8

Another reported adverse effect of rasburicase, when administered to a G6PD-deficient subject, is methemo-globinemia,16,17in which the heme iron changes from the ferrous to the ferric state, and the Hb is incapable of transporting O2. Methemoglobinemia is reported as a rare cause of persis-tently low oxygen saturation in new-borns18 and can be associated with G6PD deficiency. Tissue hypoxia and failure to eliminate CO2 lead to mixed acidosis.19 Concerning the causes of cyanosis and death in our patient, the pathology report ruled out a cardiac cause for cyanosis, ventilation prob-lems, or pulmonary embolism. Al-though it may not have changed the child’sfinal outcome, we feel it is im-portant to acknowledge that the sudden decrease in hematocrit and increase in oxygen dependence in the 77th hour should have prompted an urgent red blood cell transfusion.20,21

Our patient clearly died of anemia and the consequent progression of tissue hypoxia in spite of maximal support. Mixed metabolic and respiratory aci-dosis is considered a late finding in severe hemolytic anemia. Further-more, hemolysis has the effect of in-creasing the amount of free Hb in the plasma, with a consequent decline in the nitric oxide bioavailability and ho-meostasis, which produce endothelial dysfunction, platelet activation, and vasculopathy.22 Methemoglobin may have contributed to this infant’s in-effective tissue oxygenation, but post-mortem concentrations are not valid indicators of ante mortem levels.23,24

A single rasburicase dose can be fatal in the G6PD-deficient neonate. In the fu-ture, G6PD testing must be carefully considered before using rasburicase in any context, as its use is entertained only in unstable patients who already have organ compromise. With each decision to start a new medication, we should consider whether it may be better to refrain from certain therapies in compliance with the fundamental imperative: primum non nocere.

REFERENCES

1. Luzzatto L, Metha A, Vulliamy T. Glucose 6-phosphate dehydrogenase deficiency. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. Columbus, OH: McGraw-Hill; 2001:4517–4553

2. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371 (9606):64–74

3. Obermayr RP, Temml C, Gutjahr G, Knechtelsdorfer M, Oberbauer R, Klauser-Braun R. Elevated uric acid increases the risk for kidney disease.J Am Soc Nephrol. 2008;19(12):2407–2413

4. Hobbs DJ, Steinke JM, Chung JY, Barletta GM, Bunchman TE. Rasburicase improves hyperuricemia in infants with acute kidney injury.Pediatr Nephrol. 2010;25(2):305–309 5. Ghirardello S, Ardissino G, Mastrangelo A, Mosca F. Rasburicase in the treatment of hyperuricemia of newborns.Pediatr Neph-rol. 2010;25(9):1775–, author reply 1777

6. Teo WY, Loh TF, Tan AM. Avoiding dialysis in tumour lysis syndrome: is urate oxidase effective? A case report and review of lit-erature.Ann Acad Med Singapore. 2007;36 (8):679–683

7. Costa S, De Carolis MP, De Luca D, Savarese I, Romagnoli C. Severe hyperbilirubinemia in a glucose-6-phosphate dehydrogenase-deficient preterm neonate: could prema-turity be the main responsible factor?Fetal Diagn Ther. 2008;24(4):440–443

8. Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency: a potential source of severe neonatal hyperbilirubinaemia and kernicterus. Semin Neonatol. 2002;7 (2):121–128

9. Frank JE. Diagnosis and management of G6PD deficiency.Am Fam Physician. 2005;72 (7):1277–1282

10. Beutler E. G6PD deficiency.Blood. 1994;84 (11):3613–3636

11. Beutler E, Luzzatto L. Hemolytic anemia. Semin Hematol. 1999;36(4 suppl 7):38–47 12. Dhillon AS, Darbyshire PJ, Williams MD,

Bissenden JG. Massive acute haemolysis in neonates with glucose-6-phosphate de-hydrogenase deficiency.Arch Dis Child Fe-tal NeonaFe-tal Ed. 2003;88(6):F534–F536 13. Kaplan M, Hammerman C.

Glucose-6-phosphate dehydrogenase deficiency and severe neonatal hyperbilirubinemia: a complexity of interactions between genes and environment. Semin Fetal Neonatal Med. 2010;15(3):148–156

14. Dhaliwal G, Cornett PA, Tierney LM Jr. He-molytic anemia.Am Fam Physician. 2004;69 (11):2599–2606

15. Edwards CQ. Anemia and the liver. Hepatobiliary manifestations of anemia. Clin Liver Dis. 2002;6(4):891–907, viii 16. Browning LA, Kruse JA. Hemolysis and

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administration. Ann Pharmacother. 2005;39 (11):1932–1935

17. Góth L, Bigler NW. Catalase deficiency may complicate urate oxidase (rasburicase) therapy. Free Radic Res. 2007;41(9):953– 955

18. Titheradge H, Nolan K, Sivakumar S, Bandi S. Methaemoglobinaemia with G6PD deficiency: rare cause of persistently low saturations in neonates. Acta Paediatr. 2011;100(7):e47– e48

19. Greenough A, Milner AD. Mechanisms of re-spiratory failure. In: Donn SM, Shina SK, eds. Neonatal Respiratory Care. 2nd ed. Phila-delphia, PA: Mosby Elsevier; 2006:297–299 20. Bell EF. When to transfuse preterm babies.

Arch Dis Child Fetal Neonatal Ed. 2008;93 (6):F469–F473

21. El-Husseini A, Azarov N. Is threshold for treatment of methemoglobinemia the same for all? A case report and literature review. Am J Emerg Med. 2010;28:748.e5–e10

22. Donadee C, Raat NJH, Kanias T, et al. Nitric oxide scavenging by red blood cell micro-particles and cell-free hemoglobin as a mechanism for the red cell storage le-sion.Circulation. 2011;124(4):465–476 23. Reay DT, Insalaco SJ, Eisele JW. Postmortem

methemoglobin concentrations and their sig-nificance.J Forensic Sci. 1984;29(4):1160–1163 24. Wallace KL, Curry SC. Postcollection rise in methemoglobin level in frozen blood spec-imens.J Toxicol Clin Toxicol. 2002;40(1):91–94

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DOI: 10.1542/peds.2011-1580 originally published online December 3, 2012;

2013;131;e309

Pediatrics

Giovanni Capovilla, Domenico De Leo and Lino Chiandetti

Patrizia Zaramella, Alessandra De Salvia, Martina Zaninotto, Maura Baraldi,

Lethal Effect of a Single Dose of Rasburicase in a Preterm Newborn Infant

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DOI: 10.1542/peds.2011-1580 originally published online December 3, 2012;

2013;131;e309

Pediatrics

Giovanni Capovilla, Domenico De Leo and Lino Chiandetti

Patrizia Zaramella, Alessandra De Salvia, Martina Zaninotto, Maura Baraldi,

Lethal Effect of a Single Dose of Rasburicase in a Preterm Newborn Infant

http://pediatrics.aappublications.org/content/131/1/e309

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the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2013 has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

at Viet Nam:AAP Sponsored on August 28, 2020

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