882
PEDIATRICS
Vol. 81 No.
6 June 1988 inorganic metal should also be determined for an appropriate model such as the nonhuman primate to assess whether any tissue can metabolize thecompound and accumulate the inorganic metal to
an extent that metabolic processes are affected in vivo. Finally, the long-term action of unmetabol-ized Sn-protoporphyrin, itself, on heme and iron metabolism should receive further consideration and study.
The fate of heme reaching the intestine after
Sn-protoporphyrin treatment is another
interest-ing subject of investigation.’4”5 Heme oxygenase activity has been shown to be present in intestinal mucosa tissue in vitro,’6 and metabolism of heme
in CO by bacterial activity can also occur.’7 Heme
degradation mediated by heme oxygenase results in the formation of bilirubin. The products of the bacterial reactions have not been completely elu-cidated, but, include, at minimum, CO. Although
the enterohepatic circulation of bilirubin may
contribute to jaundice (eg, breast milk jaundice) and is a theoretical concern, it does not seem to have affected the clinical efficacy of Sn-protopor-phyrin in human neonates.
In conclusion, although the data presented from
animal studies and now human neonates prove
that Sn-protoporphyrin is effective in decreasing serum bilirubin levels, the mechanism of action
needs further study in the human neonate, and
various issues concerning toxicity, especially pho-totoxicity, still need to be studied. Although these concerns yet remain, they are not unresolvable. And, if they are resolved so that the safety of
Sn-protoporphyrin, other analogs of heme,’8 or their
derivatives is fully ascertained, this chemoprev-entive therapy may be a substantial and desirable
alternative treatment to phototherapy and
ex-change transfusion. Moreover, the identification of high producers of bilirubin before severe
hy-perbilirubinemia develops might provide the
op-portunity for selective treatment ofinfants among populations at generally low risk for severe jaun-dice,’9 thus avoiding unnecessary taking of even minor risks for many babies.
REFERENCES
DAVID K. STEVENSON, MD
HENDRIK J. VREMAN, MD Department of Pediatrics
Stanford University School of Medicine
Stanford, CA
1. Silverman WA: Medical inflation, in Oliver TK (ed): Re-trolental Fibroplasia: A Modern Parable. New York, Grune & Stratton, 1980, pp 69-89
2. Kappas A, Drummond GS, Manola T, et al: Sn-protopor-phyrin use in the management of hyperbilirubinemia in
term newborns with direct Coombs-positive ABO-incom-patibility. Pediatrics 1988;81:485-497
3. Drummond GS, Kappas A: Chemoprevention of neonatal jaundice: Potency of tin-protoporphyrin in an animal
model. Science 1982;217:1250-1252
4. McDonagh AF, Palma LA: Tin-protoporphyrin: A potent photosensitizer of bilirubin destruction. Photochem Pho-tobiol 1985;42:261-264
5. Kappas A, Drummond GS, Simionatto CS, et al: Control ofheme oxygenase and plasma levels ofbilirubin by a syn-thetic heme analogue, tin-protoporphyrin. Hepatology
1984;4:336-341
6. Anderson KE, Simionatto CS, Drummond GS, et al: Tissue distribution and disposition oftin-protoporphyrin, a potent competitive inhibitor ofheme oxygenase. JPharmacolExp Ther 1984;228:327-333
7. Drummond GS, Gaibraith R, Sardana MK, et al: Reduction ofthe C2 and C4 vinyl groups ofSn-protoporphyrin to form Sn-mesoprotoporphyrin markedly enhances the ability of the metalloporphyrin to inhibit in vivo heme catabolism.
Arch Biochem Biophys 1987;255:64-74
8. Anderson KE, Simionatto CS, Drummond GS, et al: Dis-position of tin-protoporphyrin and suppression of hyper-bilirubinemia in humans. Clin Pharrnacol Ther
1986;39:510-520
9. Whitington PF, Moscioni AD, Gartner LM: The effect of tin (W)-prothporphyrin-IX on bilirubin production and ex-cretion in the rat. Pediatr Res 1987;21:487-491
10. Tenhunen R, Marver HS, Schmid R: The enzymatic con-version of heme to bilirubin by microsomal heme oxygen-ase. Proc Natl Acad Sci USA 1968;61:748-755
11. Vreman HJ, Stevenson DK: Heme oxygenase activity as measured by CO production. Anal Biochem 1988;168:
31-38
12. Vreman HJ, Stevenson DK: Carbon monoxide generation from tin- and zinc-protoporphyrin by tissue homogenates.
Biochem Biophys Res Commun 1987;148:417-421
13. Schafer SG, Femfert U: Tin-A toxic heavy metal? A re-view of the literature. Regul Toxicol Pharmacol
1984;4:57-69
14. Kappas A, Simionatto CS, Drummond GS, et al: The liver excretes large amounts of heme into bile when heme ox-ygenase is inhibited competitively by Sn-protoporphyrin.
Proc Natl Acad Sci USA 1985;82:896-900
15. Hintz SR, Kwong LK, Vreman HJ, et al: Recovery of ex-ogenous heme as carbon monoxide and biliary heme in adult Wistar rats after tin protoporphyrin treatment. J Pediatr Ga.stroenterol Nutr 1987;6:302-306
16. Correia MA, Schmid R: Effect of cobalt on microsomal cy-tochrome P-450: Differences between liver and intestinal mucosa. Biochem Biophys Res Commun
1975;65:1378-1384
17. Engel RB, Matsen JM, Chapman 55, et al: Carbon mon-oxide production from heme compounds by bacteria. JBac-teriol 1972;112:1310-1315
18. Qato MK, Maines MD: Prevention of neonatal hyperbil-rubinemia in non-human primates by Zn-protoporphyrin.
Biochem J 1985;226:51-57
19. Smith DW, Inguillo D, Martin D, et al: Use of noninvasive tests to predict significant jaundice in full-term infants: Preliminary studies. Pediatrics 1985;75:278-280
Light Versus
Tin?
One of the first steps in the formation of bili-rubin from hemoglobin is an oxidative process in
PEDIATRICS (ISSN 0031 4005). Copyright © 1988 by the American Academy of Pediatrics.
at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news
COMMENTARIES 883
which the a-methene bridge of the heme
por-phyrin ring is opened and carbon monoxide and
bilirubin are formed. This oxidation is catalyzed
by the enzyme microsomal heme oxygenase.
Fol-lowing earlier observations from their laboratory,
Drummond and Kappas’ demonstrated that tin
protoporphyrin (Sn-protoporphyrin) was the most potent of several synthetic metalloporphyrins that competitively inhibited heme oxygenase. By competing with this enzyme, Sn-protoporphyrin
inhibits the conversion of heme to bilirubin and
is effective in preventing or ameliorating exper-imental and naturally occurring jaundice in the
neonatal animal and adult human. Their
impor-tant clinical trialla shows that Sn-protoporphyrin has similar effects in the human newborn.
Given the prevalence of jaundice in our
new-born population, it is exciting to contemplate the
use of a therapeutic modality that even hints at
the possibility ofeliminating this specter from our
nurseries. We must remember, however, that this
is the first clinical test of a powerful new therapy
and is, “. . . by definition, a step into the
unknown”2 that demands careful evaluation. In their discussion, the authors acknowledge some of the shortcomings in the design of their
study but argue that those shortcomings did not
influence the results.la Perhaps they did not, but their failure to use a placebo, to “blind” the care-takers, and to manage the infants using a prear-ranged, strict protocol for intervention with pho-totherapy must impair our ability to interpret the data.
In an attempt to eliminate the effect of photo-therapy on the measured response to
Sn-proto-porphyrin, the authors “dredged” the data and
separated out (post hoc) infants in the treatment and control groups who did not have “early jaun-dice.” Because the study was neither designed specifically to evaluate the efficacy of Sn-proto-porphyrin for these infants nor to compare
pho-totherapy with Sn-protoporphyrin, these data
must be treated with reserve. Thus, the claim that administration ofSn-protoporphyrin was superior
to phototherapy in moderating the course of hy-perbilirubinemia cannot be sustained, particu-larly as we have no idea of the dose of photother-apy used. (Most nurseries use levels of irradiance well below those necessary to produce the maxi-mum decrement in serum bilirubin levels.3
I must confess that I found the magnitude of the observed effect disappointing. The investigators offer two explanations for this modest effect: First, the doses used in this study were 25 to 200 times
lower (per kilogram of body weight) than those
given to newborn monkeys (an appropriately con-servative approach to the use of a compound that
had never been administered previously to human
newborns). Second, the Sn-protoporphyrin was
given an average of 12.8 to 15.5 hours after birth
at a time when the levels of heme oxygenase are
increasing rapidly. Administration directly after
birth would probably have been more effective.
There seems little doubt that the use of
Sn-pro-toporphyrin would decrease the need for
photo-therapy. Worldwide experience with thousands of
babies throughout the last two decades, however, suggests that phototherapy is probably as benign
an intervention as any ever inflicted on the
in-nocent newborn. Because Sn-protoporphyrin will
have to be administered prophylactically to most infants, we will need excellent documentation of its efficacy and (lack of) toxicity before
recom-mending that it replace phototherapy as the
treat-ment of choice for the jaundiced neonate.
In which populations might this synthetic heme
analogue be used? Sn-protoporphyrin might
de-crease the need for exchange transfusions in
new-borns with severe hemolytic disease. It would
probably be of greater benefit to nonhemolyzing infants. One could envisage giving a single dose (like vitamin K) in the delivery room. This might
spare pediatricians much of the tribulation they
must now endure with mild to moderately
jaun-diced babies, particularly those discharged within
24 to 48 hours of birth. In well-baby nurseries,
however, fewer than 5% of the population have a
serum bilirubin concentration that exceeds 12.9
mg/dL and only 1.5% have levels 16 mg/dL.4
Large populations would have to be studied to de-termine the risk to benefit ratio, and in most west-em countries, prophylactic administration of
Sn-protoporphyrin to the majority ofinfants could not
be justified. Sn-protoporphyrin is less likely to be useful in the low birth weight population. These
infants respond so well to phototherapy (during
their enforced stay in the neonatal unit) that ex-change transfusions in the neonatal intensive
care unit are rapidly becoming an anachronism.
Sn-protoporphyrin might help to control bilirubin
levels in those few unfortunate children with the
Crigler-Najjar syndrome.
When we consider the controversy that has sur-rounded the administration of a simple nutrient
(vitamin E) in an attempt to prevent severe
re-tinopathy in some premature infants, we must be
skeptical about widespread acceptance ofthe
din-ical utility of this drug. This is a pity, because decreasing serum bilirubin by inhibiting its pro-duction is a novel and exciting concept. Perhaps
future studies with different dosage schedules will
produce more impressive results that will require reevaluation. As the authors suggest, the use of Sn-protoporphyrin will likely be most useful in
at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news
PEDIATRICS (ISSN 0031 4005). Copyright © 1988 by the American Academy of Pediatrics.
884 PEDIATRICS
Vol. 81
No. 6 June 1988 populations in which severe jaundice is prevalent and in which other treatment modalities are not readily available.Finally, we should be cautious before we get
carried away by our desire to stamp out neonatal jaundice completely. Bilirubin is a powerful
bio-logic antioxidant, particularly at the tissue level, and, in modest quantities, may actually be good for you.5
REFERENCES
M. JEFFREY MAI5EL5, MB, BCH
Department of Pediatrics William Beaumont Hospital
Royal Oak, MI
1. Drummond GS, Kappas A: Prevention of neonatal hyper-bilirubinemia by Sn-protoporphyrin IX, a potent compet-itive inhibitor ofheme oxidation. Proc NatlAcad Sci USA
1981;78:6466-6470
la. Kappas A, Drummond GS, Manola T, et al: Sn-protopor-phyrin use in the management of term newborns with di-rect Coombs-positive ABO-incompatability. Pediatrics
1988;81:485-497
2. Silverman WA: Human Experimentation: A guided Step Into the Unknown. New York, Oxford University Press,
1985, p 8
3. Tan KL: The pattern ofbilirubin response to phototherapy for neonatal hyperbilirubinemia. Pediatr Res
1982;16:670-674
4. Maisels MJ, Gifford K, Antle CE, et al: Normal serum bilirubin levels in the newborn and the effect of breast
feeding. Pediatrics 1986;78:837-843
5. Stocker R, Yamamoto Y, McDonagh AF, et al: Bilirubin as an antioxidant of possible physiological importance.
Science 1987;235:1043-1046
What
Does the Cryotherapy
Preliminary
Report
Mean?
The dispassionate numbers in the preliminary report of the Multicenter Trial of Cryotherapy for
Retinopathy of Prematurity (CRYO-ROP)’ fail to
convey the excitement I feel as a physician who now, for the first time, has a tested intervention to offer the infant with serious retinopathy of pre-maturity. Infants with retinopathy of prematur-ity at the study’s threshold of severity have a 43% incidence of an unfavorable outcome in that eye, eg, retinal detachment or a fold across the macula. Either of these outcomes means severely reduced vision for life. Cryotherapy reduces the chances
of an unfavorable outcome to 22%. The
prelimi-nary report, however, has left many questions
un-answered. Why did the research team choose
early termination ofthe study? Why did they offer
only an enigmatic recommendation about
treat-ing the second eye? What do these data mean in
the intensive care unit today?
WHY WAS THE STUDY
ENROLLMENT
STOPPED
EARLY?
A trial of this complexity and magnitude is
de-signed and conducted by a committee, some
mem-bers of whom believe in the proposed treatment
and some who think it may be worthless or
dan-gerous. Knowledgeable individuals of varied
backgrounds are recruited to participate in an in-dependent data and safety committee to monitor the accumulating results at predetermined
inter-vals. This permits early termination without
bias-ing the participating investigators should a
clearly demonstrated benefit or unacceptable side effect emerge. After the most recent consideration
of the data, the monitoring committee for the
CRYO-ROP study recommended that the execu-tive committee examine the outcome data to date, consider the termination of enrollment of new pa-tients, and proceed with the timely and orderly announcement of preliminary results.
They made this recommendation because the
results showed a clear potential for immediately decreasing the number of infants with severe
vi-sion loss by at least half. In reaching the choice
for early cessation of enrollment and rapid dis-semination of the preliminary results, the
com-mittee’s concern weighted heavily for those
in-fants outside of the study in whom threshold
retinopathy of prematurity was developing and
who without the release of these data faced a 43% chance of vision loss in each eye with retinopathy of prematurity at threshold.
WHY
DID THE INVESTIGATORS
NOT
RECOMMEND
TREATING
BOTH
EYES?
Both the design of a study such as this and in-terpretation of the results involve clinical and
ethical dilemmas. Complicating the decision in
this case was that cryotherapy, if it is to be effec-tive, must be performed before the retinopathy progresses too far, at a time when it is not possible to accurately predict whether the infant’s disease will progress or regress spontaneously. In this study, the design included treatment of only one eye. This served both a clinical purpose (the re-maining eye offered an excellent control) and re-solved an ethical concern: if the treatment proved
at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news
1988;81;882
Pediatrics
M. JEFFREY MAISELS
Light Versus Tin?
Services
Updated Information &
http://pediatrics.aappublications.org/content/81/6/882
including high resolution figures, can be found at:
Permissions & Licensing
http://www.aappublications.org/site/misc/Permissions.xhtml
entirety can be found online at:
Information about reproducing this article in parts (figures, tables) or in its
Reprints
http://www.aappublications.org/site/misc/reprints.xhtml
Information about ordering reprints can be found online:
at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news
1988;81;882
Pediatrics
M. JEFFREY MAISELS
Light Versus Tin?
http://pediatrics.aappublications.org/content/81/6/882
the World Wide Web at:
The online version of this article, along with updated information and services, is located on
American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1988 by the
been published continuously since 1948. Pediatrics is owned, published, and trademarked by the
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has
at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news
