Prophylactic ibuprofen for the prevention of intraventricular

Rubaltelli Carlo Dani, Giovanna Bertini, Marco Pezzati, Chiara Poggi, Pietro Guerrini, Claudio Among Preterm Infants: A Multicenter, Randomized Study Prophylactic Ibuprofen for the Preve

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DOI: 10.1542/peds.2004-1178

2005;115;1529

Pediatrics

Martano and Firmino F Rubaltelli Carlo Dani, Giovanna Bertini, Marco Pezzati, Chiara Poggi, Pietro Guerrini, Claudio

Among Preterm Infants: A Multicenter, Randomized Study

Prophylactic Ibuprofen for the Prevention of Intraventricular Hemorrhage

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Carlo Dani, MD*; Giovanna Bertini, MD*; Marco Pezzati, MD*; Chiara Poggi, MD*; Pietro Guerrini, MD‡; Claudio Martano, MD§; Firmino F Rubaltelli, MD*; and the IntraVentricular Ibuprofen Study Group

ABSTRACT. Objective. Ibuprofen enhances cerebral

blood flow autoregulation and was shown to protect

neurologic functions after oxidative stresses in an animal

model For these reasons, we hypothesized that the

pro-phylactic use of ibuprofen would reduce the occurrence

of intraventricular hemorrhage (IVH) and its worsening

toward grades 2 to 4 among preterm infants To confirm

this hypothesis, we planned the present prospective

study.

Methods. This was a double-blind, randomized,

con-trolled trial in which preterm infants with gestational

ages of <28 weeks received ibuprofen or placebo within

the first 6 hours of life The infants were assigned

ran-domly, at 7 neonatal care units, to receive ibuprofen (10

mg/kg, followed by 5 mg/kg after 24 and 48 hours) or

placebo Serial echoencephalography was performed 24

and 48 hours after the initial cerebral ultrasound study,

on postnatal days 7, 15, and 30, and at 40 weeks’

postcon-ceptional age Grade 1 IVH or no IVH was considered a

successful outcome, whereas grade 2 to 4 IVH

repre-sented failure The rates of ductal closure, side effects,

and complications were recorded.

Results. We studied 155 infants Grade 2 to 4 IVH

developed for 16% of the ibuprofen-treated infants and

13% of the infants in the placebo group The occurrence

of patent ductus arteriosus was less frequent only on day

3 of life in the ibuprofen group There were no

signifi-cant differences with respect to other complications or

adverse effects.

Conclusions. Our study demonstrated that

prophylac-tic ibuprofen is ineffective in preventing grade 2 to 4 IVH

and that its use for this indication cannot be recommended.

Pediatrics 2005;115:1529–1535; ibuprofen, intraventricular

hemorrhage, patent ductus arteriosus, infants.

ABBREVIATIONS IVH, intraventricular hemorrhage; PDA,

patent ductus arteriosus; CBF, cerebral blood flow; iRDS, infant

respiratory distress syndrome; ROP, retinopathy of prematurity;

OR, odds ratio; CI, confidence interval; PVL, periventricular

leukomalacia; PPHN, persistent pulmonary hypertension of the

newborn

D espite improvements in the assistance and

treatment of preterm infants, intraventricular hemorrhage (IVH) remains a frequent com-plication among these patients.1This point is crucial because the most severe IVH cases are related to a high risk of neurodevelopmental handicaps In fact, mental retardation, seizures, and cerebral palsy have been reported for 45% to 86% of preterm infants with parenchymal IVH involvement.2–5

Previous clinical trials demonstrated that indo-methacin, a cyclooxygenase inhibitor of prostaglan-din synthesis that is used commonly for the closure

of patent ductus arteriosus (PDA), decreased the cidence of IVH among very low birth weight in-fants.6–10Indomethacin was shown to decrease base-line cerebral blood flow (CBF), to modulate CBF changes in response to hypercarbic insults, to de-crease serum prostaglandin levels, and to promote germinal matrix maturation in animal models.11–14

However, indomethacin prophylaxis for IVH has never been used widely, because of the adverse ef-fects of indomethacin on renal function and the gas-trointestinal tract.10,15–19

In contrast, experimental20 and preliminary clini-cal21–24studies demonstrated that ibuprofen (another cyclooxygenase inhibitor of prostaglandin synthesis) was effective in closing PDA without reducing CBF25

or affecting cerebral vasoreactivity to arterial carbon dioxide tension26or intestinal27,28or renal29 hemody-namics Furthermore, ibuprofen enhances CBF auto-regulation30 and was shown to protect neurologic functions after oxidative stresses in an animal

mod-el.31

For these reasons, we hypothesized that the pro-phylactic use of ibuprofen would reduce the occur-rence of IVH and its worsening toward grades 2 to 4 among preterm infants To confirm this hypothesis,

we planned a double-blind, randomized, controlled trial in which preterm infants with gestational age of

⬍28 weeks received ibuprofen or placebo within the first 6 hours of life.

METHODS Patient Population

A multicenter, double-blind, prospective study, approved by local ethics committees, was conducted in 7 tertiary neonatal care units (Careggi University Hospital of Florence, Sant’Anna Univer-sity Hospital of Ferrara, Clinica Mangiagalli of Milan, Children’s Hospital “V Buzzi” of Milan, San Gerardo Hospital of Monza, Regional Hospital of Bolzano, and Sant’Anna Hospital of Turin, all in Italy) Inclusion criteria were gestational age of⬍28 weeks

From the *Department of Surgical and Medical Critical Care, Section of

Neonatology, Careggi University Hospital of Florence, Florence, Italy;

‡Di-vision of Neonatology, Sant’Anna University Hospital of Ferrara, Ferrara,

Italy; and §Division of Neonatology, Sant’Anna University Hospital of

Turin, Turin, Italy.

Accepted for publication Oct 4, 2004.

doi:10.1542/peds.2004-1178

No conflict of interest declared.

Reprint requests to (C.D.) Division of Neonatology, Careggi University

Hospital, University of Florence School of Medicine, Viale Morgagni, 85

Firenze, Italy E-mail: cdani@unifi.it

Acad-emy of Pediatrics.

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and postnatal age of⬍6 hours Exclusion criteria were the

pres-ence of major congenital malformations; hydrops fetalis; persistent

pulmonary hypertension of the newborn (PPHN); grade 2 to 4

IVH; platelet count of ⬍50 000 platelets per mm3; tendency to

bleed, as revealed by hematuria, blood in the endotracheal

aspi-rate, gastric aspiaspi-rate, or stools, or oozing from puncture sites; or

serum creatinine concentration of ⬎1.5 mg/dL Neonates were

enrolled after written informed consent was obtained from their

parents

Study Design

The infants in each unit were assigned randomly to a treatment

group with the sealed-envelope technique; envelopes were

pre-pared at Careggi University Hospital of Florence and then

distrib-uted to participating centers Each infant received 3 doses of

ibuprofen lysine (Arfen; Lisapharma, Erba, Italy; 10 mg/kg within

6 hours after birth, followed by 5 mg/kg after 24 and 48 hours) or

indistinguishable placebo The medications were infused

contin-uously in a period of 15 minutes The doses and dosing intervals

were the same as those used for newborn infants in previous

studies.21–23

When the ductus arteriosus was still patent after the randomly

assigned treatment for a patient of either group, ibuprofen was

administered as a nonrandomized rescue treatment If this

ther-apy also failed to promote ductal closure or if there was a

contra-indication to repeated pharmacologic treatment, then surgical

li-gation of the ductus arteriosus was performed

Echographic Study

All patients for whom study permission was requested

under-went cerebral ultrasonography within the first 6 hours of life, to

exclude grade 2 to 4 IVH Serial echoencephalography was

per-formed 24 and 48 hours after the first study, on postnatal days 7,

15, and 30, and at 40 weeks’ postconceptional age The images

were obtained with a high-resolution (7.5-MHz), real-time, sector

scanner, in both coronal and sagittal projections through the

an-terior fontanel

The grading system for hemorrhage was adapted from that

described by Papile et al,32 as follows: grade 1, blood in the

periventricular germinal matrix regions or germinal matrix

hem-orrhage; grade 2, blood within the lateral ventricular system

with-out ventricular dilation; grade 3, blood acutely distending the

lateral ventricles; grade 4, blood within the ventricular system and

parenchyma Hemorrhage was considered to have extended if an

intraventricular or parenchymal component developed from a

germinal matrix hemorrhage or a second hemorrhage was not in

the hemisphere opposite that with an existing hemorrhage The

echoencephalographic studies were also evaluated for the

pres-ence of periventricular leukomalacia (PVL) All infants identified

as having PVL had cystic areas on the 40-week cerebral ultrasound

scans; earlier scans of the same infants showed parenchymal

echodensities PVL was graded from grade 1 to grade 3 according

to the classification described by De Vries et al.33

Echocardiographic examinations were performed for all

pa-tients before enrollment and on postnatal days 2, 3, 5, 7, and 21 (or

more frequently, if indicated) The initial evaluation included

2-dimensional, M-mode, pulsed Doppler and color flow

evalua-tions of cardiac flow dynamics, performed to ascertain the

nor-mality of cardiac anatomic features and to rule out the possibility

of congenital heart disease with “ductus-dependent” pulmonary

or systemic blood flow or PPHN Two-dimensional studies were

performed for direct observation of the PDA, and left-to-right

shunts were documented with pulsed Doppler echocardiography

and color flow mapping A diagnosis of significant PDA was

made with echocardiographic demonstration of a ductal

left-to-right shunt, with a left atrium/aortic root ratio of⬎1.3 or a ductal

size of⬎1.5 mm.21All echographic studies were performed by

physicians who were unaware of the infants’ treatment

assign-ments

Concomitant Treatment

Daily clinical care was performed by attending physicians, in

accordance with common practices Fluid intake was based

essen-tially on changes in body weight, serum electrolyte

concentra-tions, and serum osmolality; we started with⬃70 mL/kg, which

was increased 10 to 20 mL each day to reach 150 mL/kg at the end

of the first week of life Infants could receive human milk from donors (and then from their own mothers) from the first day of life When dextrose infusion was indicated, its concentration was set to maintain appropriate plasma glucose levels Electrolytes were added after the first day of life, whereas intravenous admin-istration of amino acids and lipids was initiated generally by the second day of life

When hypotension was refractory to fluid-replacement therapy (with plasma, packed red cells, or more rarely saline), dopamine and/or dobutamine infusion was started For infant respiratory distress syndrome (iRDS), infants received oxygen therapy, respi-ratory support (nasal continuous positive pressure, synchronized mechanical ventilation, or high-frequency oscillatory ventilation), and early rescue surfactant treatment (Curosurf; Chiesi, Parma, Italy; 200 mg/kg plus 100 mg/kg after 12 hours) The objective of assisted ventilation was to maintain an arterial partial pressure of oxygen of 50 to 70 mm Hg, arterial partial pressure of carbon dioxide of⬍65 mm Hg, pH of ⬎7.20, and oxygen saturation of 90% to 95%

Infants who underwent mechanical ventilation, had signs of sepsis, or were predisposed to infection because of maternal fac-tors were given antibiotics after appropriate studies Antibiotic therapy was stopped after 3 or 4 days if the bacterial cultures (of blood, tracheal aspirate, and urine) remained negative Postnatal steroid treatment (12 days of tapering doses of dexamethasone34) was started for infants with severe respiratory failure who were receiving maximal ventilatory and oxygen support and for infants who, after 2 weeks of life, were still undergoing mechanical ven-tilation and were considered at high risk of developing chronic lung disease

Clinical Courses and Outcomes

For each newborn infant, gestational age, birth weight, gender, type of delivery, Apgar scores at 1 and 5 minutes, pH of umbilical artery blood, prenatal and postnatal steroid treatment, main ma-ternal pregnancy pathologic conditions, length of stay in the hos-pital, and death were recorded To evaluate the severity of iRDS, initial (at the first blood gas analysis) and highest values of the oxygenation index (mean airway pressure⫻ fraction of inspired oxygen⫻ 100/arterial partial pressure of oxygen) and the venti-latory index (oxygenation index ⫻ arterial partial pressure of carbon dioxide) were measured for patients undergoing mechan-ical ventilation

Serum creatinine levels and platelet counts were measured at 1,

3, and 5 days of life Urine output was measured every day during the first 5 days of life, by collecting urine in adhesive bags, and oliguria was defined as a urinary output of⬍1 mL/kg per hour during a 24-hour collection period; fluid intake was recorded every day during the first week of life To evaluate bleeding tendencies, hematuria, gastric bleeding, blood in the endotracheal aspirate or stools, and oozing from puncture sites were assessed Our patients were also monitored for complications such as sepsis, bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity (ROP) Diagnoses of sepsis were based on clinical and laboratory data (total neutrophil counts, immature/total neutrophil ratios, and C-reactive protein concen-trations) and confirmed with positive blood cultures.35Diagnosis

of bronchopulmonary dysplasia was based on the requirement for supplemental oxygen to maintain adequate oxygenation at

36 weeks’ postconceptional age.36Necrotizing enterocolitis was diagnosed in the presence of abdominal distension, gastric resid-uals with or without bile-stained vomiting and bloody diarrhea or stools, hypotension, and suggestive abdominal radiographs (showing dilated and thickened bowel loops, parietal pneumatosis with or without perforation, or portal or hepatic venous air).37The incidence of ROP, staged according to the international classifica-tion,38 was also recorded All clinical and biological data were reported on data sheets designed for this study

Statistical Analyses

In our study, we considered as successful outcomes grade 1 IVH or no IVH at 7 days of life, whereas grade 2 to 4 IVH represented failure We assumed a failure rate 20% higher in the placebo group than in the ibuprofen group Therefore, at a power

of 0.80 and␣ ⫽ 05, the estimated sample size was 74 infants in each group

Clinical characteristics of the 2 groups were described with

1530 IBUPROFEN AND IVH

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mean values and SDs or rates and percentages Statistical analyses

were performed with Student’s t test for parametric continuous

variables, the 2-sample Wilcoxon rank-sum test for nonparametric

continuous variables, and Fisher’s exact test for categorical

vari-ables such as frequencies P ⬍ 05 was considered statistically

significant

Multiple stepwise logistic regressions were conducted to

deter-mine which maternal, neonatal, or perinatal factors would

influ-ence the risk for development of grade 2 to 4 IVH Effect estimates

are expressed as odds ratios (ORs) with profile, likelihood-based,

95% confidence intervals (CIs)

RESULTS

Two hundred fifty patients were eligible for the

study, but 80 were excluded because of the presence

of cardiac malformations (n ⫽ 4), hydrops fetalis (n

⫽ 3), PPHN (n ⫽ 15), grade ⱖ2 IVH (n ⫽ 20), platelet

counts of ⬍50 000 platelets per mm3 or bleeding

tendency (n ⫽ 25), or serum creatinine

concentra-tions of ⬎1.5 mg/dL (n ⫽ 13) Among the remaining

170 infants, 10 were excluded because of a lack of

parental consent and 5 were excluded after

random-ization because of incomplete data collection (4 in the

ibuprofen group and 1 in the placebo group)

There-fore, we studied 155 infants, 77 of whom were

as-signed to the ibuprofen group and 78 to the placebo

group The initial dose of the drug was administered

at 5.2 ⫾ 0.6 hours and 5.4 ⫾ 0.5 hours in the

ibupro-fen and placebo groups, respectively The groups

had comparable proportions of maternal and

obstet-ric factors (Table 1); they were also comparable in

clinical characteristics except for gestational age

(Ta-ble 2).

The proportions of infants with grade 1 IVH at

enrollment were similar in the ibuprofen (n ⫽ 4, 5%)

and placebo (n ⫽ 5, 6%) groups Two of these infants

in each group experienced progression of

hemor-rhage; the 2 infants in the ibuprofen group

devel-oped grade 2 IVH, whereas 1 infant in the placebo

group developed grade 2 IVH and another

devel-oped grade 3 IVH Grade 2 to 4 IVH develdevel-oped for

21% of the ibuprofen-treated infants and for 17% in

the placebo group (Table 3) The incidences of grade

1, grade 2, grade 3, and grade 4 IVH were similar in

the ibuprofen and placebo groups We considered

the possibility that the occurrence of IVH could differ

between the groups at different times For this

rea-son, we compared the IVH rates at baseline and at 24

hours, 48 hours, and 7 days of life, but we did not

find any difference between the ibuprofen group and

the placebo group (Table 4).

The infant survival rates were similar in the 2

groups (Table 5) The most frequent causes of death

were refractory respiratory failure and sepsis There

was no significant difference between the groups in the occurrence of iRDS or its severity, the require-ment for or type of mechanical ventilation, or the need for surfactant treatment (Table 2) The rates of sepsis, bronchopulmonary dysplasia, necrotizing en-terocolitis, ROP (all grades), and PVL (all grades) and the lengths of stay in the hospital were similar in the ibuprofen and placebo groups (Table 5) The occurrence of PDA was less frequent on day 3 of life

in the ibuprofen group (Table 5) The incidences of serum creatinine levels of ⬎1.5 mg/dL, mean serum creatinine levels, urine outputs, rates of oliguria, bleeding tendency, and platelet counts of ⬍50 000/

mm3, and mean platelet counts did not differ be-tween the ibuprofen and placebo groups (Table 5) Logistic-regression analysis included all variables

in Tables 1 and 2 and also the occurrence of grade 1 IVH at enrollment, bleeding tendency, thrombocyto-penia, and PDA in the day 3 of life We found that the following factors had significant predictive val-ues for the development of grade 2 to 4 IVH: male gender (OR: 2.3; 95% CI: 1.76 –2.84) and prenatal steroid treatment (OR: 0.30; 95% CI: ⫺1.66 to ⫺0.71).

DISCUSSION

The anomalies of cerebral perfusion play an im-portant role in the development of cerebral injury among preterm infants Prostaglandins, especially prostaglandin E2 and F2␣, are determinants in the control of the upper range of CBF autoregulation; they exert a minimal vasoconstrictor activity, which could prevent an increase in CBF when systemic blood pressure increases.30 Ibuprofen was reported

to enhance CBF autoregulation among newborn pig-lets,30and Li et al39demonstrated that its effect was secondary to the up-regulation of prostaglandin E2 and F2␣receptors induced by inhibition of the isoen-zyme cyclooxygenase-2 Therefore, with stabilization

of cerebral perfusion, a reduction in the incidence of IVH among preterm infants might be expected Varvarigou et al21 reported a trend toward a de-crease in the incidence of IVH among preterm in-fants, although this was not statistically significant and was not confirmed in other studies.39

Unfortunately, our study demonstrated that ibu-profen was ineffective in preventing grade 2 to 4 IVH, confirming the results of a recent meta-analysis study of the prevention of PDA with ibuprofen pro-phylaxis.40 This result suggests that the action of ibuprofen in improving CBF autoregulation among preterm infants is insufficient to limit brain injuries.

We wondered why ibuprofen is ineffective in

reduc-TABLE 1. Comparison Between Ibuprofen and Placebo Groups in Obstetric and Maternal Factors

Ibuprofen

(n⫽ 77) (nPlacebo⫽ 78)

Preterm noninduced labor, rate (%) 46/77 (60) 58/78 (74)

Preterm premature rupture of membranes, rate (%) 6/77 (8) 6/78 (8) Gestational diabetes mellitus, rate (%) 3/77 (4) 5/78 (6)

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TABLE 2. Comparison Between Ibuprofen and Placebo Groups in Neonatal Factors

Ibuprofen

(n⫽ 77) (nPlacebo⫽ 78)

Apgar score, mean⫾ SD

pH of umbilical artery blood, mean⫾ SD 7.28⫾ 0.11 7.29⫾ 0.11

Respiratory diseases

Transient tachypnea of the newborn, rate (%) 5/75 (7) 4/75 (5)

Oxygen therapy

Mechanical ventilation

Surfactant

Oxygenation index

Ventilatory index

Total or partial parenteral nutrition, rate (%) 67/77 (87) 70/78 (90)

Fluid intake, mL/kg, mean⫾ SD

Vasoactive drugs

PRC transfusions

PRCs transfused during week 1, rate (%) 49/77 (64) 48/78 (62)

Plasma transfusions

Plasma transfused during week 1, rate (%) 25/77 (32) 23/78 (29)

Postnatal steroid treatment

PRC indicates packed red cell; DOL, day of life; SIMV, synchronized intermittent mandatory ventilation; SIPPV, synchronized intermit-tent positive pressure ventilation; HFOV, high-frequency oscillatory ventilation

* P⫽ 001, placebo group versus ibuprofen group

TABLE 3. Comparison of Incidence of IVH at 7 Days of Life

Ibuprofen

(n⫽ 77) (nPlacebo⫽ 78) Successful outcome

(no IVH or grade 1)

61 (79) 65 (83) 652 0.865 (0.387–1.932)

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ing the occurrence of IVH whereas indomethacin,

which is also a cyclooxygenase inhibitor, is

effec-tive.6–10We found that several authors observed

de-creased CBF after indomethacin administration, both

in newborn animals12,41 and among newborn

in-fants,25,42 but not after ibuprofen treatment.12,25,42,43

Therefore, we concluded that indomethacin can

af-fect cerebral circulation through mechanisms differ-ent from cyclooxygenase blockade and prostaglan-din synthesis,43 such as direct action on vascular endothelium44 and the increase in the circulating level of endothelins,45 which likely can explain also the more frequent occurrence of adverse effects after indomethacin treatment, rather than after ibuprofen treatment In other words, it is probable that the ineffectiveness of ibuprofen in preventing grade 2 to

4 IVH and the lower occurrence of adverse effects after its administration are secondary to more-selec-tive inhibition of cyclooxygenase isoforms, com-pared with indomethacin, which permits the closure

of PDA but is not sufficient to compensate for inad-equate CBF autoregulation among preterm infants Another possible explanation is that we used an inadequate ibuprofen dose However, it is difficult to suggest increasing this dose, because in a previous study21it was found to be associated with a plasma ibuprofen level 2.5-fold higher than that generated among adults with arthritis receiving similar doses46

and there are no studies of ibuprofen pharmacoki-netics among newborn infants.

In the present study, we monitored the possible adverse effects of ibuprofen treatment, in particular

on renal function and the clotting system, but we did not find any difference between the ibuprofen and placebo groups This confirms previous studies,40

except that Van Overmeire et al24found serum

cre-TABLE 4. Comparison of Rates of IVH Before Ibuprofen

Ad-ministration, at 24 and 48 Hours, and at 7 Days of Life

IVH Rate (%) Before

Ibuprofen

Grade 1

Ibuprofen 4 (5) 4 (5) 4 (5) 4 (5)

Placebo 5 (6) 6 (8) 6 (8) 6 (8)

Grade 2

Ibuprofen 0 (0) 6 (8) 7 (9) 8 (10)

Placebo 0 (0) 4 (5) 5 (6) 5 (6)

Grade 3

Ibuprofen 0 (0) 4 (5) 6 (8) 6 (8)

Placebo 0 (0) 4 (5) 5 (6) 5 (6)

Grade 4

Ibuprofen 0 (0) 1 (1) 2 (3) 2 (3)

Placebo 0 (0) 2 (3) 2 (3) 3 (4)

Grade 2–4

Ibuprofen 0 (0) 11 (14) 15 (19) 16 (21)

Placebo 0 (0) 10 (13) 12 (15) 13 (17)

Total IVH

Ibuprofen 4 (5) 15 (19) 19 (25) 20 (26)

Placebo 5 (6) 16 (21) 18 (23) 19 (24)

TABLE 5. Markers of Potential Adverse Effects and Complications in the Ibuprofen and Placebo Groups

Ibuprofen

(n⫽ 77) (nPlacebo⫽ 78) Serum creatinine level of⬎1.5 mg/dL, rate (%) 3/77 (4) 2/77 (3)

Serum creatinine level, mg/kg, mean⫾ SD

Urine output, mL/kg per h, mean⫾ SD

Platelet counts, platelets⫻ 109/L, mean⫾ SD

PDA, rate (%)

ROP, rate (%)

DOL indicates day of life

* P⫽ 0019 for placebo group versus ibuprofen group

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atinine levels to be increased on day 3 of life among

ibuprofen-treated infants The recorded

complica-tions of prematurity also showed similar rates in the

2 groups, except for the incidences of PDA on day 3

of life (9% in the treated group and 29% in the

placebo group), which confirmed that prophylactic

treatment with ibuprofen reduced PDA occurrence

among preterm infants with iRDS at 3 days of life.23

However, among patients in the placebo group who

demonstrated PDA at 3 days of life, 83% (19 of 23

patients) experienced closure of the ductus arteriosus

after the first cycle of ibuprofen, as reported

previ-ously.19,23,24

A final issue in our study was the possible

occur-rence of PPHN among our patients after ibuprofen

administration, as reported by Gournay et al.47None

of our patients demonstrated PPHN47 after

ibupro-fen treatment; we think this was because all infants

with PPHN were excluded from the study In fact, it

is our opinion that the reported PPHN was

preexist-ing, not caused by ibuprofen, and that PDA closure

only worsened and manifested it.

CONCLUSIONS

Our study demonstrated that prophylactic

ibupro-fen was ineffective in preventing grade 2 to 4 IVH

and its use for this purpose cannot be recommended.

We confirmed that ibuprofen therapy for PDA

clo-sure is safe and effective Because ibuprofen cannot

represent an alternative to indomethacin and

indo-methacin treatment might be followed by several

adverse effects, the question of pharmacologic IVH

prevention among preterm infants remains crucial

and additional efforts are necessary to identify other

potentially effective drugs.

ACKNOWLEDGMENTS

The IntraVentricular Ibuprofen Study Group includes G.L

Lista, MD (Milan, Italy); Hubert Messner, MD (Bolzano, Italy);

Fabio Mosca, MD (Milan, Italy); and Paolo Tagliabue, MD (Monza,

Italy)

REFERENCES

1 Rubaltelli FF, Dani C, Reali MF, et al Acute neonatal respiratory

dis-tress in Italy: a one year prospective study Acta Paediatr 1998;87:

1261–1268

2 Krishnamooorthy KS, Shannon DC, DeLong GR, Todres ID, Davis KR.

Neurologic sequelae in the survivors of neonatal intraventricular

hem-orrhage Pediatrics 1979;64:233–237

3 Shinnar S, Molteni RA, Gammon K, D’Souza BJ, Altman J, Freeman JM.

Intraventricular hemorrhage in the premature infant N Engl J Med.

1982;306:1464 –1468

4 McMenamin JB, Shackelford GD, Volpe JJ Outcome of neonatal

intra-ventricular hemorrhage with periintra-ventricular echodense lesions Ann

Neurol 1984;15:285–290

5 Szymonowicz W, Yu VYH, Bajuk B, Astbury J Neurodevelopmental

outcome of periventricular hemorrhage and leukomalacia in infants

1250 g or less at birth Early Hum Dev 1986;14:1–7

6 Banstra ES, Montalvo BM, Goldberg RN Prophylactic indomethacin for

prevention of intraventricular hemorrhage in premature infants

Pedi-atrics 1984;74:1107–1112

7 Bada HS, Green RS, Pourcyrous M, et al Indomethacin reduced the

risks of severe intraventricular hemorrhage J Pediatr 1989;115:631– 637

8 Ment LR, Duncan CC, Ehrenkrnaz RA Randomized indomethacin trial

for prevention of intraventricular hemorrhage in very low birth weight

neonates J Pediatr 1985;107:937–943

9 Ment LR, Oh W, Ehrenkrnaz RA, et al Low-dose indomethacin and

prevention of intraventricular hemorrhage: a multicenter randomized

trial Pediatrics 1994;93:543–550

10 Fowlie PW, Davis PG Prophylactic intravenous indomethacin for

pre-venting mortality and morbidity in preterm infants Cochrane Database

Syst Rev 2002;(3):CD000174

11 Leffler CW, Busija DW, Fletcher AM, Beasley DG, Hessler JR, Green RS Effects of indomethacin upon cerebral hemodynamics of newborn pigs.

Pediatr Res 1985;19:1160 –1164

12 Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV Difference in the effects in the newborn piglet of various non-steroidal anti-inflammatory drugs on cerebral blood flow but not on cerebrovascular

prostaglan-dins Pediatr Res 1991;30:106 –111

13 Dahlgren N, Nilsson B, Sakabe T The effect of indomethacin on cerebral blood flow and oxygen consumption in the rat at the normal and

increased carbon dioxide tension Acta Physiol Scand 1982;3:475– 485

14 Ment LR, Stewart WB, Ardito TA, Huang E, Madri JA Indomethacin promotes germinal matrix microvessel maturation in the newborn

bea-gle pup Stroke 1992;23:1132–1137

15 Betkerur MV, Yeh TF, Miller K, Glasser RJ, Pildes RS Indomethacin and its effects on renal function and urinary kallikrein excretion in

prema-ture infants with patent ductus arteriosus Pediatrics 1981;68:99 –102

16 Van Bel F, Guit GL, Schipper J, Van de Bor M, Baan J Indomethacin-induced changes in renal blood flow velocity waveform in premature

infants investigated with color Doppler imaging J Pediatr 1991;118:

621– 626

17 Grosfeld JL, Chaedt M, Molinari F Increased risk of necrotizing entero-colitis in premature infants with patent ductus arteriosus treated with

indomethacin Ann Surg 1996;224:350 –357

18 Ojala R, Ikonen S, Tammela O Perinatal indomethacin treatment and

neonatal complications in preterm infants Eur J Pediatr 2000;159:

153–155

19 Lago P, Bettiol T, Salvadori S, et al Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus

arteriosus: a randomized control trial Eur J Pediatr 2002;161:202–207

20 Coceani F, White E, Bodach E, Olley PM Age-dependent changes in the

response of the lamb ductus arteriosus to oxygen and ibuprofen Can

J Physiol Pharmacol 1979;57:825– 831

21 Varvarigou A, Bardin LC, Beharry K, Chemtob S, Papageorgiu A, Aranda JV Early ibuprofen administration to prevent patent ductus

arteriosus in premature newborn infants JAMA 1996;275:539 –544

22 Van Overmeire B, Follens I, Hartmann S, Creten WL, van Acker KJ.

Treatment of patent ductus arteriosus with ibuprofen Arch Dis Child.

1997;76:F179 –F184

23 Dani C, Bertini G, Reali MF, et al Prophylaxis of patent ductus

arteri-osus with ibuprofen in preterm infants Acta Paediatr 2000;89:1369 –1374

24 Van Overmeire B, Smets K, Lecoutere D, et al A comparison of

ibupro-fen and indomethacin for closure of patent ductus arteriosus N Engl

J Med 2000;343:674 – 681

25 Mosca F, Bray M, Lattanzio M, Fumagalli M, Tosetto C Comparative evaluation of the effect of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus

arte-riosus J Pediatr 1997;131:549 –554

26 Mosca F, Bray M, Colnaghi MR, Fumagalli M, Compagnoni G Cerebral vasoreactivity to arterial carbon dioxide tension in premature infants:

effect of ibuprofen J Pediatr 1999;135:644 – 646

27 Grosfeld JL, Kamman K, Gross K, Cikrit D, Ross D, Wolfe M Compar-ative effects of indomethacin, prostaglandin E 1 and ibuprofen on bowel

ischemia Pediatr Surg 1983;18:738 –742

28 Pezzati M, Vangi V, Biagiotti R, Bertini G, Cianciulli D, Rubaltelli FF Effects of indomethacin and ibuprofen on mesenteric and renal blood flow

in preterm infants with patent ductus arteriosus J Pediatr 1999;135:733–738

29 Malcom DD, Segar JL, Robillard E, Chemtob S Indomethacin compro-mises hemodynamics during positive-pressure ventilation

indepen-dently of prostanoids J Appl Physiol 1993;74:1672–1678

30 Chemtob S, Beharry K, Barna T, Varma DR, Aranda JV Prostanoids determine the range of cerebral blood flow autoregulation of newborn

piglets Stroke 1990;21:777–784

31 Chemtob S, Roy M-S, Abran D, Ferandez H, Varma DR Prevention of post-asphyxial increase in lipid peroxides and retinal function deterio-ration in the newborn pig by inhibition of cyclooxygenase activity and

free radical generation Pediatr Res 1993;33:336 –340

32 Papile LA, Burstein J, Burstein R, Keffler H Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with

birthweight less than 1500 grams J Pediatr 1978;92:529 –534

33 De Vries LS, Eken P, Dubowitz LM The spectrum of leukomalacia

using cranial ultrasounds Behav Brain Res 1992;49:1– 6

34 Rastogi A, Akintorin SM, Bez ML, Morales P, Pildes PS A controlled trial of dexamethasone to prevent bronchopulmonary dysplasia in

sur-factant-treated infants Pediatrics 1996;98:204 –210

Downloaded from

Trang 8

35 American Academy of Pediatric, Committee on Drugs, Committee on

Fetus and Newborn, and Committee on Infectious Diseases

Prophy-laxis and treatment of neonatal gonococcal infections Pediatrics 1980;

65:1047–1048

36 Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM Abnormal

pulmonary outcomes in premature infants: prediction from oxygen

requirement in the neonatal period Pediatrics 1988;82:527–532

37 Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L,

Brotherton T Neonatal necrotizing enterocolitis: therapeutic decisions

based upon clinical staging Ann Surg 1978;187:1–12

38 Committee for the Classification of Retinopathy of Prematurity An

international classification of retinopathy of prematurity Arch

Ophthal-mol 1984;102:1130 –1134

39 Li DY, Hardy P, Abran D, et al Key role for cyclooxygenase-2 in PGE 2

and PGF 2␣ receptor regulation and cerebral blood flow of the newborn.

Am J Physiol 1997;273:R1283–R1290

40 Shah SS, Ohlsson A Ibuprofen for the prevention of patent ductus

arteriosus in preterm and/or low birth weight infants Cochrane Database

Syst Rev 2003;(2):CD004213

41 Pappius HM, Wolfe LS Effects of indomethacin and ibuprofen on

cerebral metabolism and blood flow in traumatized brain J Cereb Blood

Flow Metab 1983;3:448 – 459

42 Patel J, Robert I, Azzopardi D, Hamilton P, Edwards AD Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent

ductus arteriosus Pediatr Res 2000;47:36 – 42

43 Pellicer A, Aparicio M, Cabanas F, Valverde E, Quero J, Stiris TA Effects of the cyclo-oxygenase blocker ibuprofen on cerebral blood flow

during normocarbia and hypercarbia in newborn piglets Acta Paediatr.

1999;88:82– 88

44 Siesjo BK Cerebral circulation and metabolism J Neurosurg 1984;60:

883–908

45 Therkelsen K, Jensen KA, Freundlich M, Thorshange H, Bunemann

L, Bogeskov-Nielsen L Endothelin-1 and cerebral blood flow: influ-ence of hypoxia, hypercapnia, and indomethacin on circulating

en-dothelin levels in healthy volunteers Scand J Clin Lab Invest 1994;

54:441– 451

46 Gallo JM, GalI IP, Gillespie WR, Albert KS, Perrier D Ibuprofen kinetics

in plasma and synovial fluid of arthritic patients J Clin Pharmacol.

1986;26:65–70

47 Gournay V, Savagner C, Thiriez G, Kuster A, Roze´ JC Pulmonary

hypertension after ibuprofen prophylaxis in very preterm infants

Lan-cet 2002;259:1486 –1488

WHILE BRAIN IMAGING OFFERS NEW KNOWLEDGE,

IT CAN BE AN ILLUSION

“There, right there, see that spot of blazing red in a cool blue sea of your cortex?

That’s your brain on drugs Or, more specifically, that’s the brain of a recovering

cocaine addict, clean for months, who sees a mound of white powder His brain

responds with the same craving and anxiety—marked by the red on the brain

scan—as when he was snorting every night, which is why addiction is so tenacious.

And here, see how a chess grandmaster activates the region of the brain that stores

memories, such as those of games he has played or studied? But in the brain

of a neophyte the activity is over here, in a region that analyzes positions from

scratch Neuroimaging such as PET and MRI are seducing laypeople and

scientists alike into believing we know more than we do about how and why we

think, feel and behave, some scientists say The power of brain imaging, says

Frank Keil, a Yale University psychology professor, reflects ‘the illusion of

ex-planatory depth If people see something, they are often deluded into thinking they

understand it better than they really do.’ In a fit of physics envy, researchers

in economics, political science and even philosophy are deciding that

neuroimag-ing is just the thneuroimag-ing to make them more scientific Yet the results are less than

groundbreaking For all its flaws, neuroimaging is here to stay No

self-respect-ing psych department can afford to forgo it.”

Begley S Wall Street Journal 2005

Noted by JFL, MD

Trang 9

DOI: 10.1542/peds.2004-1178

2005;115;1529

Pediatrics

Martano and Firmino F Rubaltelli Carlo Dani, Giovanna Bertini, Marco Pezzati, Chiara Poggi, Pietro Guerrini, Claudio

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