Prophylactic Ibuprofen for the Prevention of Intraventricular Hemorrhage Among Preterm Infants: A Multicenter, Randomized Study

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Prophylactic Ibuprofen for the Prevention of Intraventricular Hemorrhage

Among Preterm Infants: A Multicenter, Randomized Study

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.

1

_{This 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.

6–10

_{Indomethacin 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, experimental

20

_{and preliminary}

clini-cal

21–24

_{studies demonstrated that ibuprofen (another}

cyclooxygenase inhibitor of prostaglandin synthesis)

was effective in closing PDA without reducing CBF

25

or affecting cerebral vasoreactivity to arterial carbon

dioxide tension

26

_{or intestinal}

27,28

_{or renal}

29

hemody-namics. Furthermore, ibuprofen enhances CBF

auto-regulation

30

_{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

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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.21_{All 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.35_Diagnosis

of bronchopulmonary dysplasia was based on the requirement for supplemental oxygen to maintain adequate oxygenation at 36 weeks’ postconceptional age.36_{Necrotizing 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).37_The

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.

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mean values and SDs or rates and percentages. Statistical analyses were performed with Student’sttest 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

ⱖ

2 IVH (n

⫽

20), platelet

counts of

⬍

50 000 platelets per mm

3

_{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/

mm

3

_{, 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 E

₂

and F

₂_␣

, 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,

30

_{and Li et al}

39

_{demonstrated that its effect was}

secondary to the up-regulation of prostaglandin E

2

and F

₂_␣

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 al

21

_{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)

Placebo (n⫽78)

Cesarean delivery, rate (%) 42/77 (55) 56/78 (72)

Prenatal steroids, rate (%) 56/77 (73) 58/78 (74)

No. of cycles, mean⫾SD 1.1⫾0.3 1.3⫾0.8

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

Preeclampsia, rate (%) 24/77 (31) 16/78 (21)

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)

Placebo (n⫽78)

Birth weight, g, mean⫾SD 832⫾215 812⫾209

Gestational age, wk, mean⫾SD 25.3⫾1.2 25.9⫾1.1*

Male/female,n 50/27 32/46

Apgar score, mean⫾SD

1 min 4.2⫾2.3 4.8⫾2.2

5 min 6.6⫾2.2 7.0⫾1.6

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

Respiratory diseases

Rate (%) 75/77 (97) 75/78 (96)

iRDS, rate (%) 70/75 (93) 71/75 (95)

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

Oxygen therapy

Rate (%) 74/77 (96) 75/78 (96)

Duration, d, mean⫾SD 40.9⫾33.1 42.6⫾35.2

Mechanical ventilation

SIMV/SIPPV, rate (%) 57/77 (74) 53/78 (68)

HFOV, rate (%) 26/77 (34) 17/78 (22)

Duration, h, mean⫾SD 397.6⫾426.7 339.0⫾347.1

Surfactant

Rate (%) 57/77 (74) 50/78 (64)

Age at treatment, min, mean⫾SD 63.3⫾47.7 79.5⫾75.8

No. of doses, mean⫾SD 1.8⫾0.9 2.1⫾1.3

Oxygenation index

Initial value, mean⫾SD 6.8⫾7.8 7.3⫾8.5

Highest value, mean⫾SD 10.9⫾12.3 12.3⫾14.5

Age at highest value, h, mean⫾SD 28.1⫾97.6 31.0⫾69.2

Ventilatory index

Initial value, mean⫾SD 257.0⫾246.1 232.9⫾167.0

Highest value, mean⫾SD 389.6⫾326.5 365.2⫾300.3

Age at highest value, h, mean⫾SD 29.6⫾99.1 35.1⫾68.6

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

Fluid intake, mL/kg, mean⫾SD

DOL 1 65.9⫾12.2 65.7⫾17.9

DOL 2 78.8⫾13.9 83.1⫾17.6

DOL 3 98.5⫾14.9 107⫾34.9

DOL 4 121.8⫾19.5 122.5⫾36.7

DOL 5 138.9⫾24.1 134.7⫾27.9

DOL 6 147.9⫾23.3 146.6⫾21.5

DOL 7 156.5⫾21.9 154.5⫾24.9

Vasoactive drugs

Rate (%) 38/77 (49) 37/77 (48)

Dopamine, rate (%) 37/38 (97) 37/37 (100)

Dopamine duration, d, mean⫾SD 10.3⫾9.9 8.0⫾7.9

Dobutamine, rate (%) 18/38 (47) 27/37 (73)

Dobutamine duration, d, mean⫾SD 6.4⫾1.8 7.0⫾6.5

PRC transfusions

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

No. of PRC transfusions, mean⫾SD 1.7⫾0.7 1.8⫾0.9

Plasma transfusions

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

No. of plasma transfusions, mean⫾SD 1.7⫾1.1 1.9⫾1.5

Postnatal steroid treatment

Rate (%) 28/77 (36) 27/78 (35)

Duration, d, mean⫾SD 12.8⫾14.7 10.3⫾9.0

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

Rate (%) P OR (95% CI)

Ibuprofen (n⫽77)

Placebo (n⫽78)

Successful outcome (no IVH or grade 1)

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

Grade 1 4 (5) 6 (8) .760 1.476 (0.761–5.390)

Grade 2 8 (10) 5 (6) .562 0.661 (0.206–2.117)

Grade 3 6 (8) 5 (6) .982 0.856 (0.253–2.898)

Grade 4 2 (3) 3 (4) .972 1.500 (0.227–9.225)

Grade 2–4 16 (21) 13 (17) .652 0.866 (0.246–3.050)

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ing the occurrence of IVH whereas indomethacin,

which is also a cyclooxygenase inhibitor, is

effec-tive.

6–10

_{We found that several authors observed}

de-creased CBF after indomethacin administration, both

in newborn animals

12,41

_{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}

endothelium

44

_{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

study

21

_{it was found to be associated with a plasma}

ibuprofen level 2.5-fold higher than that generated

among adults with arthritis receiving similar doses

46

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 al

24

_{found 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

24 h 48 h 7 d

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)

Placebo (n⫽78)

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

Serum creatinine level, mg/kg, mean⫾SD

DOL 1 0.78⫾0.23 0.77⫾0.27

DOL 3 1.11⫾0.39 1.1⫾0.47

DOL 5 1.09⫾0.34 0.99⫾0.33

Oliguria, rate (%) 7/77 (9) 4/78 (5)

Urine output, mL/kg per h, mean⫾SD

DOL 1 1.7⫾0.9 1.8⫾1.2

DOL 2 2.8⫾1.6 2.5⫾1.3

DOL 3 2.9⫾1.3 2.9⫾1.1

DOL 4 3.0⫾1.4 2.9⫾1.2

DOL 5 2.8⫾1.4 3.1⫾1.2

Bleeding tendency, rate (%) 11/77 (14) 18/78 (23)

Platelet counts of⬍50 000/mm3_{, rate (%)} _{8/77 (10)} _{6/78 (8)}

Platelet counts, platelets⫻109_{/L, mean}_⫾_SD

DOL 1 227 627⫾93 712 205 802⫾78 568

DOL 3 218 047⫾101 750 216 303⫾199 950

DOL 5 224 471⫾94 323 195 966⫾148 685

PDA, rate (%)

DOL 1 57/77 (74) 56/78 (72)

DOL 3 7/77 (9) 23/78 (29)*

DOL 5 3/77 (4) 4/78 (5)

DOL 21 1/77 2/78

Reopening 1/77 1/78

Surgical ligature 0/77 1/78

Sepsis, rate (%) 15/77 (19) 5/78 (6)

Bronchopulmonary dysplasia, rate (%) 16/77 (21) 22/28 (28)

Necrotizing enterocolitis, rate (%) 2/78 (3) 2/78 (3)

ROP, rate (%)

All grades 32/77 (42) 27/78 (35)

Gradeⱖ2 6/32 (19) 6/27 (22)

PVL (all grades), rate (%) 3/77 (4) 4/78 (5)

Death, rate (%) 15/77 (19) 20/78 (26)

Stay in hospital, d, mean⫾SD 82.7⫾21.9 86.9⫾23.1

DOL indicates day of life.

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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.

47

_None

of our patients demonstrated PPHN

47

_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).

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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

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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