signs, there may be no detrimental impact on infant development of prenatal SSRI exposure. Our study shows that neurobehavioral indices are sensitive to the conditions that differentiate SSRI-exposed and nonSSRI-exposed groups in the absence of atypical phys-ical signs. We believe that the addition of neurobehavioral mea-sures in future research may contribute meaningfully to the cost-benefit analysis in physician-patient discussions.
Philip Sanford Zeskind, PhD Laura E. Stephens
Carolinas Medical Center Charlotte, NC 28232
REFERENCES
1. Singer LT, Zeskind PS.Biobehavioral Assessment of the Infant. New York, NY: Guilford Press; 2001
2. Lester BM, Tronick E, Brazelton TB. The Neonatal Intensive Care Unit Network Neurobehavioral Scale procedures.Pediatrics.2004;113(3 pt 2): 641– 667
3. Schuetze P, Zeskind PS. Relations between women’s depressive symp-toms and perceptions of infant distress signals varying in pitch.Infancy. 2001;2:483– 499
doi:10.1542/peds.2004-1983
Hospital-Acquired Hyponatremia
To the Editor.—
The recent article and commentary1,2concerning
hospital-ac-quired hyponatremia have lost sight of the solid scientific evi-dence underlying the Holliday and Segar recommendations of 1957.3At the end of the 19th century and beginning of the 20th
century, meticulous and rigorous measurements were made of insensible water loss and urine production at basal conditions.4,5
These losses are a function of metabolic rate (heat production). Because patients are rarely found at a basal state and the variables of temperature, ventilation rate, muscular movement, and diet differ from patient to patient, clinician-investigators such as Dar-row6observed that the range, when the above-listed variables
were not extreme, is⬃1.5 times the basal for water losses. The obligatory sodium chloride losses are small, and thus the mainte-nance solutions (ie, 1.5 times basal for volume) must be hypotonic and the rate of intravenous administration should be spaced evenly over 24 hours. When maintenance fluid is combined with deficit replacement, no sodium chloride for maintenance is needed.
Holliday and Segar sought to simplify the calculation by pro-viding a formula for maintenance based on weight alone in 420-kJ increments derived from the forgoing rigorous data and with negligible variability and provided the pediatric community with a formula that is easy to use. The drawback of a simplified calcu-lation is that it does not allow the physician to derive the amount from basic physiology. Over the years, 1.5 times basal has been distorted to multiplying maintenance times 2 (which is 3 times basal, a high figure and suitable only for rare patients). There is no physiologic basis for multiplying the maintenance value by 2 or any other number.
The problem has been aggravated further by using this high-volume “maintenance” solution as an initial hydrating infusion for hypovolemic (albeit often mildly so) patients whose antidi-uretic hormone levels are high and giving it rapidly, thus flooding the central nervous system, in which capillaries delay sodium exchange while permitting instantaneous diffusion of water to equilibrate osmotic concentrations.
The answer to the problem is not the dangerous recommenda-tion for using isotonic sodium solurecommenda-tion for maintenance, which will lead to excessive salt load and hypernatremia. The isotonic sodium solutions should be used to restore circulation, initially given rapidly to dehydrated patients, and when needed to replace
losses more gradually.7The maintenance should always be spread
evenly over the whole day.
Laurence Finberg, MD
Department of Pediatrics University of California San Francisco, CA 94143
REFERENCES
1. Hoorn EJ, Geary D, Robb M, Halperin ML, Bohn D. Acute hyponatremia related to intravenous fluid administration in hospitalized children: an observational study.Pediatrics.2004;113:1279 –1284
2. Moritz MJ, Ayers JC. Hospital-acquired hyponatremia: why are there still deaths [commentary]?Pediatrics.2004;113:1395–1396
3. Holliday MA, Segar WE. The maintenance need for water in parenteral fluid therapy.Pediatrics.1957;19:823– 832
4. Rubner M, Heubner O. Natural heat production in infants [in German]. Z Biol.1898;36:1–55
5. Lusk G. Clinical calorimetry, paper 1. A respiration calorimeter for the study of disease.Arch Intern Med.1915:793– 802
6. Darrow DC. The physiologic basis for estimating requirements for par-enteral fluids.Pediatr Clin North Am.1959;6:29 – 41
7. Finberg L, Kravath RE, Hellerstein S.Water and Electrolytes in Pediatrics. Philadelphia, PA: W. B.Saunders;1993:141–147
doi:10.1542/peds.2004-1998
Bilirubin the Beneficent
To the Editor.—
I wish to add a few corrections and comments to the recent timely review by Sedlak and Snyder on bilirubin,1the born-again
benignant pigment.
1. It is not true that bilirubin formation is restricted to mammals. This is an obsolete, but frequently repeated, hypothesis that flies in the face of scientific evidence. Bilirubin and its conju-gates occur in many nonmammals, although they may not be the principle bile pigments excreted in bile.2For example,
con-jugates of bilirubin are excreted in bile in many fish species, and jaundice in fish is not unknown.3Bilirubin conjugates are also
present in bile of embryonic and adult chickens,4and the
ob-servation in 1886 by Minkowski and Naunyn5that arsine
poi-soning produced marked jaundice in normal but not hepatec-tomized geese was a key observation in the elucidation of the physiologic pathway of heme catabolism and the role of the reticuloendothelial system. Similarly, observations on the bio-synthesis of bilirubin in ducks were important in elucidating bilirubin-formation pathways in humans.6Bilirubin pigments
also occur in alligators, snakes, and turtles,2and a biliverdin
reductase with substantial sequence homology to the human enzyme is present even in the lowly unicellular cyanobacterium
Synechocystis.7Therefore, the hoary idea that bilirubin occurs
uniquely in mammals8is unfounded and should be laid to rest.
The puzzle is not so much why mammals make bilirubin but rather why biliverdin reductase evolved and why many ani-mals do without it.
2. Similarly, it is not true that the principle isomer of bilirubin formed in the fetus is bilirubin IXrather than the IX␣isomer produced postnatally.1,8 This notion seems to have evolved
from an incorrect interpretation of observations that the pre-dominant isomer of bilirubin in meconium and fetal bile is IX.9,10However, the IXisomer in fetal bile is probably but a
small residual fraction of the total amount of bile pigment produced, most of which is the IX␣ isomer. The IX␣isomer, being relatively lipophilic, does not accumulate because of its easy egress across the placenta.9,11 In contrast, the less
li-pophilic IXisomer is less likely to diffuse across the placenta but can be excreted relatively easily in bile without the need for hepatic conjugation.12Therefore, the fact that the IXisomer is
the principle isomer in fetal bile does not indicate that it is the major isomer made in the fetus. Similarly, the presence of an IX-specific reductase in the fetus does not mean that the IX␣-specific enzyme is not present or unimportant. Quite the contrary. The IX␣-specific reductase is probably essential, be-cause it facilitates transplacental excretion of bile pigment
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duced by heme cleavage during fetal life. There is no evidence that heme oxygenase is any less regioselective for the␣bridge of heme in the fetus than it is in adults, where small amounts of the IXisomer are also reportedly formed.13,14
3. Because biliverdin reduction occurs in nonmammals and non-placental mammals and a biliverdin reductase is present in
Synechocystis, it is reasonable to assume that biliverdin reduc-tases did not evolve solely to facilitate disposal of bilirubin across the placenta. However, that should not be interpreted to indicate that reduction is unimportant for fetal disposal of bile pigments in mammals. There is much experimental evidence in primates, guinea pigs, and rats that bilirubin IX␣ readily crosses the placenta and that reduction of biliverdin to uncon-jugated bilirubin really does facilitate fetal bile pigment dispos-al.11Striking evidence for bidirectional flux of bilirubin across
the placenta comes from the Gunn rat animal model, in which there is a recessive genetic defect in bilirubin conjugation. Het-erozygous pups born to homozygous jaundiced mothers are icteric at birth but quickly lose their yellow pigmentation. In contrast, homozygous pups born to heterozygous nonjaun-diced mothers are anicteric at birth but become jaunnonjaun-diced shortly thereafter. Early reports that bilirubin does not cross the placenta in the rat15are not reliable, because they depended on
the use of impure radioactive bilirubin prepared by a defective technique,16 which similarly has led to conflicting results in
more recent investigations.17,18
4. Although it is true that bilirubin is lipophilic, it is hardly correct to describe it as lipid soluble. Just try dissolving some in olive oil. As Brodersen19showed, bilirubin does not dissolve to any
significant extent in olive oil or classical lipids. Nevertheless, it does partition readily from aqueous solution to olive oil or octanol.20
5. Recycling of bilirubin by biliverdin reductase reduction of biliv-erdin is an old idea. It would be significant only if bilivbiliv-erdin is a major product of the reaction of bilirubin with reactive oxy-gen species. Although formation of some biliverdin has been noted under certain conditions,8there is much evidence that
biliverdin is not formed stoichiometrically and is generally not a major product of the reaction of bilirubin with oxyradicals, dioxygen, or singlet oxygen. The importance of the proposed mechanism in vivo, therefore, must remain speculative. Fur-thermore, there are other plausible chemical mechanisms for regenerating bilirubin after it intercepts radical reactions that do not require biliverdin reductase reduction. For example, bilirubin undergoes oxygen-dependent free-radical reactions in water at pH 7.4 to 9.0, in which the pigment is regenerated without the intermediacy of biliverdin or enzyme.21
6. As known for half a century, bilirubin is a potent antioxidant. However, evidence for its beneficial effects on human health,1
copious though it may be, remains fuzzy. It is surprising that so few studies have been done in Gunn rats. These animals permit comparative studies on icteric and anicteric littermates differ-ing only in their glucuronosyl transferase (UGT1A1) activities and burden of unconjugated bilirubin. Although rats may be unreliable models for humans, experiments in Gunn rats might provide decisive or quantitative answers to some of the cur-rently unresolved questions on the beneficial effects of biliru-bin. Anybody wishing to obtain breeder pairs for starting their own research colony can contact me.
7. Finally, although the antioxidant activity of bilirubin has been known for over half a century, credit for the first suggestion that bilirubin might be beneficial should perhaps go to Najib-Farah,22who postulated in 1937, albeit for curious reasons, that
the pigment forms part of a protective mechanism designed to overcome infection. Even by that date, however, the (probably ineffectual) use of bilirubin in traditional Asian medicines had become well established.23
Antony McDonagh, PhD
Division of Gastroenterology University of California San Francisco, CA 94143-0538
REFERENCES
1. Sedlak T, Snyder SH. Bilirubin benefits: cellular protection by a biliv-erdin reductase antioxidant cycle.Pediatrics.2004;113:1776 –1772
2. Cornelius CE. Comparative bile pigment metabolism in vertebrates. In: Ostrow JD, ed. Bile Pigments and Jaundice. New York, NY: Marcel Dekker; 1986:601– 647
3. Cornelius CE. Bile pigments in fishes: a review.Vet Clin Pathol.1991; 20:106 –115
4. Vajro P, Thaler MM, Blanckaert N. Bile pigment composition and bili-rubin esterification in the developing chick.Pediatr Res.1995;38:349 –355 5. Minkowski O, Naunyn B. Beitra¨ge zur Pathologie der Leber und des
Icterus.Arch Exp Path Pharmakol.1886;21:1–33
6. Israels LG, Novak W, Foerster J, Zipursky A. The early-appearing bilirubin in ducks.Can J Physiol Pharmacol.1966;44:864 – 866
7. Schluchter WM, Glazer AN. Characterization of cyanobacterial biliver-din reductase. Conversion of biliverbiliver-din to bilirubin is important for normal phycobiliprotein biosynthesis.J Biol Chem.1997;272:13562–13569 8. Baran˜ano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: a major physiologic cytoprotectant.Proc Natl Acad Sci USA 2002;99: 16093–16098
9. Aziz S, Kotal P, Leroy P, Servaes R, Eggermont E, Fevery J. Bilirubin-IXalpha and -IXbeta pigments, coproporphyrins and bile acids in meco-nium and stools from full-term and preterm neonates during the first month of life.Acta Paediatr.2001;90:81– 87
10. Yamaguchi T, Nakajima H. Changes in the composition of bilirubin-IX isomers during human prenatal development.Eur J Biochem.1995;233: 467– 472
11. McDonagh AF, Palma LA, Schmid R. Reduction of biliverdin and placental transfer of bilirubin and biliverdin in the pregnant guinea pig. Biochem J.1981;194:273–282
12. Blanckaert N, Heirwegh PM, Zaman Z. Comparison of the biliary excretion of the four isomers of bilirubin-IX in Wistar and homozygous Gunn rats.Biochem J.1977;164:229 –236
13. Hirota K. Urinary excretion of alpha- and beta-isomers of biliverdin-IX in humans.Biol Pharm Bull.1995;18:481– 484
14. Komuro A, Tobe T, Hashimoto K, et al. Molecular cloning and expres-sion of human liver biliverdin-IX beta reductase.Biol Pharm Bull.1996; 19:796 – 804
15. Grodsky GM, Contopoulos AN, Fanska R, Carbone JV. Distribution of bilirubin-H3 in the fetal and maternal rat. Am J Physiol. 1963;204: 837– 841
16. McDonagh AF. Binding of tritiated bilirubin to albumin and plasma membrane vesicles.Biochem J.1996;321:262–263
17. Pascolo L, Del Vecchio S, Koehler RK, et al. Albumin binding of uncon-jugated [3H]bilirubin and its uptake by rat liver basolateral plasma membrane vesicles.Biochem J.1996;316:999 –1004
18. Weisiger RA, Ostrow JD, Koehler RK, et al. Affinity of human serum albumin for bilirubin varies with albumin concentration and buffer composition: results of a novel ultrafiltration method.J Biol Chem. 2001;276:29953–29960
19. Brodersen R. Bilirubin. Solubility and interaction with albumin and phospholipid.J Biol Chem.1979;254:2364 –2369
20. McDonagh AF. Lyophilic properties of protoporphyrin and bilirubin. Hepatology.2002;36:1028 –1029
21. McDonagh AF, Assisi F. The ready isomerization of bilirubin IXa in aqueous solution.Biochem J.1972;129:797
22. Najib-Farah. Defensive role of bilirubinaemia in pneumococcal infec-tion.Lancet.1937;1:505–506
23. Keji C, ed.Imperial Medicaments—Medical Prescriptions Written for Em-press Dowager Cixi and Empero Guangxu With Commentary: Beijing, China: Foreign Languages Press; 1996
doi:10.1542/peds.2004-1426
In Reply.—
Dr McDonagh, an eminent authority on bilirubin, provides valuable historical insights regarding the chemistry and physiol-ogy of bilirubin in response to our essay on cellular protection by bilirubin conferred by a biliverdin reductase antioxidant cycle.1
He correctly points out that bilirubin formation is not restricted to mammals, a point with which we agree. We did not state that bilirubin existed only in mammals but rather that in some other species, biliverdin was predominant.
We agree with McDonagh’s comments that the relative forma-tion of the␣andisomers of bilirubin IX may impact placental transport of bilirubin. Our point was that bilirubin formation could not have evolved exclusively for transporting heme prod-ucts through the placenta, and species that lack placentas do generate bilirubin.
As McDonagh notes, although bilirubin partitions into li-pophilic solvents such as olive oil, it is difficult to dissolve biliru-bin directly in olive oil. Our comments about the lipophilicity of bilirubin were concerned with its disposition in living cells, in which it is established that bilirubin associates with lipid mem-branes and intracellular carrier proteins.
The main message of our article is that a bilirubin-biliverdin interconversion cycle amplifies the antioxidant actions of biliru-bin. McDonagh’s observations that oxidation of bilirubin may not provide complete, stoichiometric conversion to biliverdin and that biliverdin can revert to biliverdin nonenzymatically are excellent points. Enzymatic conversion of biliverdin to bilirubin by the enzyme biliverdin reductase is nonetheless a major protector from oxidative stress.
Thus, depletion of biliverdin reductase leads to the accumula-tion of cellular oxidants and to augmented cell death. Analo-gously, some DNA damage is not enzymatically repaired, but DNA-repair enzymes are still rather important in biology.
Gunn rats have elevated bilirubin levels because they lack the ability to glucuronidate bilirubin. McDonagh recommends them as tools for analyzing the physiologic importance of bilirubin as an antioxidant. We agree, and in our article we referred to publica-tions showing that Gunn rats are resistant to oxidative damage associated with hyperoxia.
In 1937, Najib-Farah2postulated protective actions of bilirubin
in bacterial infections, an interesting historical anecdote noted by McDonagh. Working at a time of major excitement in the medical community over the recently discovered antibacterial actions of sulfonamides, Najib-Farah treated pneumococci with elevated concentrations of bilirubin, which killed the bacteria. His research did not address antioxidant actions of bilirubin.
Thomas W. Sedlak, MD, PhD
Departments of Neuroscience and Psychiatry
Solomon H. Snyder, MD
Departments of Neuroscience, Psychiatry, and Pharmacology
Johns Hopkins School of Medicine Baltimore, MD 21205
REFERENCES
1. Sedlak TW, Snyder SH. Bilirubin benefits: cellular protection by a biliv-erdin reductase antioxidant cycle.Pediatrics.2004;113:1776 –1782 2. Najib-Farah. Defensive role of bilirubinemia in pneumococcal infection.
Lancet.1937;1:505–506
doi:10.1542/peds.2004-2015
Severe Extrapyramidal Symptoms in a 3-Year-Old
Boy After Accidental Ingestion of the New
Antipsychotic Drug Aripiprazole
To the Editor.—
Aripiprazole is a new type of antipsychotic medication exhib-iting high-affinity partial agonist activity at D2-dopamine recep-tors.1,2When used in adults for the treatment of schizophrenia and
schizoaffective disorder, aripiprazole has been associated with extrapyramidal symptoms (EPS) at a rate similar to that of place-bo.3Although it has been used in children, aripiprazole’s safety
profile in pediatric age groups is unknown.2,4We report a case of
severe EPS in a 3-year-old boy after accidental ingestion of a single dose of⬍15 mg of aripiprazole.
The patient was an otherwise healthy boy found by his mother holding an open bottle of his older sibling’s aripiprazole. After inspection, one half of a 15-mg pill was missing. The child pre-sented as a transfer to our hospital⬃48 hours after the suspected ingestion with extreme lethargy, flat affect, intention tremor, trun-cal ataxia, and a Parkinsonian gait. Extensive work-up was notable only for a serum aripiprazole concentration of 63 ng/ml, collected ⬃87 hours after ingestion. The patient’s hospital course was char-acterized by slow improvement in mental status, tremor, and Parkinsonian symptoms, which resolved completely 7 days after ingestion.
We approximated the patient’s initial dose and peak serum concentration of aripiprazole assuming the following
pharmaco-kinetic properties known for adults: volume of distribution⫽4.9 L/kg,4half-life⫽75 hours,4,5bioavailability⫽ 87%,4and peak
concentration 3 to 5 hours after ingestion.4,5The estimated
in-gested dose in this 15.5-kg patient was 11.9 mg. Given that aripi-prazole’s pharmacokinetic profile in children is poorly defined, the estimated ingested dose using adult pharmacokinetic values seemed reasonably consistent with the pill count showing one half of a 15-mg pill missing. The peak serum concentration was esti-mated at 136g/L. Adults taking therapeutic doses of aripipra-zole reached mean steady-state serum concentrations from 98 to 452 g/L.5 Even accounting for a wide range of half-lives of
aripiprazole secondary to variations in cytochrome P-450 isoen-zymes,2,4,5 our patient’s peak serum level was well within the
adult therapeutic range.
We found 2 references in the literature regarding aripiprazole ingestion in young children. An 18-month-old child ingested 15 mg of the drug without apparent incident, and a 2.5-year-old child exhibited central nervous system depression and mild tachycardia after ingesting 225 mg of the drug.4Severe EPS associated with
aripiprazole were reported in an adolescent with a previous his-tory of such symptoms.2 It is unknown whether our patient’s
adverse response represents an idiosyncratic sensitivity to the drug or whether it indicates a more general vulnerability to EPS in young children taking aripiprazole.2 This case underscores the
need for caution in treating young children with dopamine recep-tor partial agonists.
Robert B. Schonberger, MA
Yale University School of Medicine New Haven, CT 06510
Lindsey Douglas, MD
Carl R. Baum, MD, FAAP, FACMT
Department of Pediatrics
Yale University School of Medicine New Haven, CT 06510
REFERENCES
1. Burris KD, Molski TF, Xu C, et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors.J Phar-macol Exp Ther.2002;302:381–389
2. Lindsey RL, Kaplan D, Koliatsos V, Walters JK, Sandson NB. Aripipra-zole and extrapyramidal symptoms.J Am Acad Child Adolesc Psychiatry. 1268;42:1268 –1269
3. Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder.J Clin Psychiatry.2002;63:763–771
4. Levine M, Traub S, Burns MJ. The pharmacology and toxicology of aripiprazole.Internet J Med Toxicol.2004;7(1):5
5. Mallikaarjun S, Salazar DE, Bramer SL. Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers.J Clin Pharmacol.2004;44:179 –187
doi:10.1542/peds.2004-1268
Hospital-Acquired Hyponatremia Is Associated
With Excessive Administration of Intravenous
Maintenance Fluid
To the Editor.—
In their article about acute hyponatremia in hospitalized chil-dren, Hoorn et al1propose that hypotonic fluids not be
adminis-tered to children whose plasma sodium concentrations are⬍138 mmol/L. In their article, Moritz and Ayus go further and recom-mend 0.9% sodium chloride to provide for maintenance losses,2an
echo of their previous article.3I believe that these authors (and the
staff treating the patients in their report) are misinterpreting “maintenance.” Although all children have maintenance needs, those ill enough to be in the hospital generally have water and sodium needs that exceed maintenance from a deficit they have incurred, ongoing losses, or both. Hypotonic fluid, containing 5% dextrose and 0.2% to 0.3% saline, is appropriate for maintenance requirements from basal metabolism but is inappropriate to repair deficits or offset abnormal losses. I would like to call attention to 4 specific issues:
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DOI: 10.1542/peds.2004-1426
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Pediatrics
Antony McDonagh
Bilirubin the Beneficent
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