January
2007 VOLUME
4, NUMBER 5
 |
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In this issue...
Patent ductus arteriosus (PDA) is a clinical diagnosis made
within the first few days of life in a premature neonate in which failure
to detect a PDA can result in severe clinical complications. The incidence
of PDA is up to 60% in infants <28 weeks gestational age, compared
to 20% in infants
>32
weeks.[1] The first-line therapy for PDA closure has been
intravenous indomethacin for the past 30 years with surgical ligation
for pharmacological failures. Recently, a new formulation of intravenous
ibuprofen has been approved that may provide a new and potentially
safer treatment approach.
In this issue, we review
the clinical trial information for intravenous ibuprofen (pharmacologically
related to indomethacin) for the treatment and prophylaxis of PDA,
and its effect on intraventricular hemorrhage (IVH) prophylaxis.
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Course Directors
Edward E, Lawson, M.D.
Professor
Department of Pediatrics
Neonatology
The Johns Hopkins University
School of Medicine
Lawrence M. Nogee, M.D.
Associate Professor
Department of Pediatrics
Neonatology
The Johns Hopkins University
School of Medicine
Christoph U. Lehmann, M.D.
Assistant Professor
Department of Pediatrics,
Health Information
Science and Dermatology
The Johns Hopkins University
School of Medicine
Mary Terhaar, RN
Assistant Professor
Undergraduate Instruction,
The Johns Hopkins University
School of Nursing
Robert J. Kopotic, MSN, RRT, FAARC
Director of Clinical Programs
ConMed Corporation
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Learning
Objectives |
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The
Johns Hopkins University School of Medicine and The Institute for
Johns Hopkins Nursing take responsibility for the content, quality,
and scientific integrity of this CME/CE activity.
At
the conclusion of this activity, participants should be able to:
- Discuss the efficacy of IV ibuprofen compared to IV indomethacin
in the treatment of PDA
- Compare the use of IV ibuprofen for prophylaxis of PDA to IV indomethacin
- Identify the role of IV ibuprofen for intraventricular hemorrhage
prophylaxis
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Commentary |
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Ibuprofen
lysine injection (NeoProfen®) was approved by the FDA on April 13,
2006 as a priority review and orphan drug. Approval was based on the review
of a multi-center randomized double-blind placebo controlled trial conducted
by the NICHD-Pediatric Pharmacology Research Unit Network in the United
State.[1,2] This study enrolled 136 premature infants less
than 30 weeks gestation with birth weights of 500-1000 grams. Infants
were randomized to receive either a 3-day treatment course of IV ibuprofen
at 10 mg/kg, followed by doses of 5 mg/kg at 24 and 48 hours after the
initial dose (n=68), or saline placebo (n=68), within 72 hours of life.
The primary outcome of this trial was the proportion of infants that required
rescue treatment for PDA (IV indomethacin or surgery) on or prior to study
day 14.[1,2] Patient demographics (mean +/- SD; range) of the
infants enrolled include: gestational age 26.2 +/- 1.4; 23-30 weeks and
birth weight 798+ 130.3; 530-1015 grams. Age at when the first dose of
study drug was administered was 1.4 +/- 0.7 days. Demographics were similar
in both groups. Ibuprofen significantly decreased the need for rescue
therapy (25% vs 48%; p<0.005). Of the infants requiring rescue intervention,
there was no difference between the 2 groups with respect to mean age
at start of first rescue (8.7 days, range 4-15 days, for ibuprofen vs.
6.9 days, range 2-15 day for placebo).[1] Death, IVH, NEC,
daily fluid intake/output, liver function, BPD, and ROP were not statistically
significant between groups.[1,2]
The development of IV ibuprofen in the United
States is a welcome addition to the Neonatal Pharmacopeia with equal efficacy,
including duct reopening, and a more favorable renal side effect profile
compared to the previous standard pharmacological agent IV indomethacin.
The difference in renal side effect profile between the two drugs may be
attributed to both indomethacin being more potent against cyclooxygenase-1
(COX-1) as well as COX-1 being apparently more involved in basal kidney
physiology than cyclooxygenase-2 (COX-2).[3,4] However, in animal
studies, both COX-1 and COX-2 seem to have a role in the pathophysiology
of PDA.[5,6]
Interestingly, all reported comparative trials
of ibuprofen and indomethacin for PDA treatment have been conducted internationally,
in Europe (7 trials) and Asia (1 trial).[7] Will we experience
similar comparative efficacy and the safer renal side effect profile in
the much more ethnically diverse patient population in the United States?
While long-term and widespread data do not yet exist, perhaps ibuprofen
PDA outcomes may be explained by pharmacogenomics rather than the differences
in ethnicity.
The molecular response to cyclooxygenase
(COX) inhibition has been recently described in analgesic response to ibuprofen
after minor oral surgery.[8] The level of COX-2 gene (PTGS2)
expression was significantly higher at 2-4 hours after surgery for patients
with the G/G allele at the nucleotide position of the -765G>C in the
COX-2 gene (p=0.012) compared to patients with the G/C and C/C alleles.[8] The
authors concluded that the wide variability in gene expression and functional
polymorphisms in PTGS2 may explain the interindividual variations
in acute pain and analgesic efficacy of nonsteroidal anti-inflammatory
drugs.[8] Ibuprofen and indomethacin have been shown, through
in vitro studies, to be primarily metabolized by the hepatic cytochrome
P450 2C9 isoenzyme system.[9,10] Genetic polymorphisms of the
*2 and *3 alleles have reduced 2C9 activity.[11] Individuals
carrying the homozygous *3/*3 genotype have been shown to have between
a 5- and 10- fold reduced activity depending on the particular drug.[11] Allele
frequency for *2 and *3 have been reported at 11% and 7% in Caucasians
and 4% and 2% in Africans, respectively.[11] A patient carrying
this genotype may have reduced ibuprofen clearance leading to a potentially
higher risk for side effects such as oliguria. Thus, the potential collective
differences in COX-2 and cytochrome P450 2C9 genotype expressions may be
responsible for the interpatient differences in the efficacy and safety
with ibuprofen use in PDA. Follow-up phase IV US pharmacoepidemiology studies
and pharmacogenetic evaluations should be performed such that potential
differences in efficacy and safety can be identified.
There are two different formulations of intravenous
ibuprofen, ibuprofen tris-hydroxyamino-methane
(THAM) and ibuprofen L-lysine. Neonatal pulmonary
hypertension had been a reported side effect
in three infants treated with ibuprofen THAM
and in one infant with the lysine formulation.[15] The
cause of pulmonary hypertension with the
THAM formulation has been thought to be related
to the early administration of the drug (within
6 hours of life) or to the acid formulation
of the product that could precipitate and
result in microembolism in the lungs. It is unclear now at the present
moment as to the true risk for pulmonary hypertension with the L-lysine
product. Ibuprofen L-lysine is the formulation currently available in the
United States.[7]
The lack of beneficial effects on IVH prophylaxis
with ibuprofen would require Neonatal Intensive Care units to carry both
ibuprofen and indomethacin. Heightened educational efforts are necessary
for all healthcare providers involved in the prescribing, dispensing and
administration of these sound alike medications so that that potential
medication errors will be avoided. IV ibuprofen dosages are 5 or 10 mg/kg/dose
and IV indomethacin dosages for IVH have ranged from 0.1 to 0.2 mg/kg/dose.[12,13] Recommended
medication prevention strategies may include the use of tall man lettering
(e.g. ibuPROfen, indoMETHacin), posting dosing charts to contrast the potential
100-fold difference (e.g. ibuprofen 10 mg/kg/dose vs. indomethacin 0.1
mg/kg/dose), dose warning limits checks in electronic physician order entry
and pharmacy computer systems, and traditional in-service education.
IV ibuprofen (NeoProfen®) is available as single-use vials containing
2 mL of 10 mg/mL sterile solution and is manufactured by Ovation Pharmaceuticals.
The recommended dosage for the treatment of PDA is 10 mg/kg/dose initially
followed by single doses of 5 mg/kg/dose at 24 and 48 hours later. All
doses should be based on the patient’s birth weight. A second three-dose
course may be administered if the PDA persists or reopens. Although not
labeled as an approved use by the FDA, the aforementioned dosage recommendation
for PDA treatment has been used for PDA prophylaxis.[14] IV
ibuprofen is administered intravenously over 15 minutes and may be diluted
with dextrose or saline. Diluted dosages should be administered within
30 minutes of preparation.[1] Contraindications to this medication
include anuria or oliguria (urinary output <0.6 mL/kg/hr), active or
suspected NEC, thrombocytopenia, coagulation defects, active IVH and GI
bleeds, ductus arteriosus dependent congenital heart disease, and untreated
infections.[1] Based on average wholesale pricing, IV ibuprofen
lysine can be as high as 44% more expensive in drug costs alone when comparing
an equipotent dose of IV indomethacin for the treatment of PDA. However,
when factoring the cost savings with the lower risk of oliguria with ibuprofen,
a more favorable overall cost benefit with ibuprofen is likely.
References:
| 1. |
Product information. NeoProfen® (ibuprofen
lysine) injection. Ovation Pharmaceuticals. Deerfield, IL. April 2006. |
| 2. |
Aranda JV for the IV Ibuprofen – PDA
Study Team and for the Pediatric Pharmacology Research Unit Network
(NICHD-PPRU). Multicenter Randomized Double-Blind Placebo Controlled
Trial of Ibuprofen L-Lysine Intravenous Solution (IV Ibuprofen) in Premature
Infants for the Early Treatment of Patent Ductus Arteriosus (PDA). SPR-PAS
Annual Meeting, Washington DC, 2005. |
| 3. |
Vane JR, Botting RM. Mechanism of
action of anti-inflammatory drugs. In: Sinzinger H, Samuelsson B, Vane
JR, Paoletti R, Ramwell P, Wong PY-K, eds. Recent advances in prostaglandin,
thromboxane, and leukotriene research. Vol. 433 of Advances in experimental
medicine and biology. New York: Plenum Press, 1997;137-8.
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| 4. |
Smith WL, DeWitt DL. Biochemistry
of prostaglandin endoperoxide H synthase-1 and synthase-2 and their
differential susceptibility to nonsteroidal anti-inflammatory drugs.
Semin Nephrol. 1995:15:179-94. |
| 5. |
Loftin GD, Trivedi DB, Tiano HF, and
et al. Failure
of ductus arteriosus closure and remodeling in neonatal mice deficient
in cyclooxygenase-1 and cyclooxygenase-2. Proc. Natl. Acad. Sci.
2001;98(3):1059-64. |
| 6. |
Toyoshima K, Takeda A, Imarmura S, and
et al. Constriction
of the ductus arteriosus by selective inhibition of cyclooxygenase-1
and -2 in near-term and preterm fetal rats. Prostaglandins and other
Lipid Mediators. 2006;79:34-42. |
| 7. |
Thomas RL, Parker GC, Van Overmeire
B, Aranda JV. A
meta-analysis of ibuprofen versus indomethacin for closure of patent
ductus arteriosus. Eur J Pediatr. 2005;164:135-40 |
| 8. |
Lee YS, Kim H, W TX, and et al. Genetically
mediated interindividual variation in analgesic responses to cyclooxygenase
inhibitory drugs. Clinical Pharmacology and Therapeutics. 2006;79(5):407-18. |
| 9. |
McGinnity DF, Parker AJ, Soars M, and
Riley RJ. Automated
Definition of the Enzymology of Drug Oxidation by the Major Human Drug
Metabolizing Cytochrome P450s. Drug Metabolism and Disposition.
2000;28(11):1327-34 |
| 10. |
Nakajima M, Inoue T, Shimada N, et al. Cytochrome
P450 2C9 Catalyzes Indomethacin O-Demethylation in Human Liver Microsomes.
Drug Metabolism and Disposition. 1998;26(3):261-66 |
| 11. |
Kirchheiner J, Roots I, Goldammer M,
et al. Effect
of Genetic Polymorphisms in Cytochrome P450 (CYP) 2C9 and CYP2C8 on
the Pharmacokinetics of Oral Antidiabetic Drugs. Clin. Pharmacokinet.
2005:44(12):1209-25 |
| 12. |
Yanowitz TD, Baker RW, Sobchak BB. Prophylactic
indomethacin reduces grades III and IV intraventricular hemorrhages
when compared to early indomethacin treatment of a patent ductus arteriosus.
J Perinatol. 2003;23(4):317-22 |
| 13. |
Kumar N-PA, Pai MG, Gazil HA, and et
al. Indomethacin
prophylaxis for intraventricular hemorrhage in very low birth weight
babies. Indian Pediatr. 2004;41(6):551-8 |
| 14. |
Ohlosson A, Walia R, Shah S. Ibuprofen
for the treatment of patent ductus arteriosus in preterm and/or low
birth weight infants (Review). Cochrane Database Syst Rev. 2006
Jan 25;(1):CD004213 |
| 15. |
Bellini C, Campone F, Serra G. Pulmonary
hypertension following L-lysine ibuprofen therapy in a preterm infant
with patent ductus arteriosus. CMAJ. 2006 Jun 20;174(13):1843-4 |
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INTRAVENOUS
(IV) IBUPROFEN TREATMENT COMPARED TO IV INDOMETHACIN FOR PDA |
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Patel
J, Marks KA, Roberts I et al. Ibuprofen treatment of patent
ductus arteriosus. Lancet. 1995;346:255.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Van
Overmeire B, Follens I, Hartmann, S et al. Treatment of patent
ductus arteriosus with ibuprofen. Arch Dis Child. 1997;76:F179-F184.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Mosca
F, Bray M, Lattanzio M et al. Comparative evaluation of the
effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation
in preterm infants with patent ductus arteriosus. J Pediatr.
1997;131:549-54.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Pezzati
M, Vangi V, Biagiotti R et al. Effects of indomethacin and ibuprofen
on mesenteric and renal blood flow in preterm infants with patent ductus
arteriosus. J Pediatr. 1999;135:733-8.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Van
Overmeire B, Smets K, Lecoutere D et al. A comparison of ibuprofen
and indomethacin for closure of patent ductus arteriosus. N
Engl J Med. 2000;343:674-681.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Lago
P, Bettiol T, Salvadori S et al. Safety and efficacy of ibuprofen
versus indomethacin in preterm infants treated for patent ductus arteriosus:
a randomised controlled trial. Eur J Pediatr. 2002;161:202-207.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Su
PH, Chen JY, Su CM et al. Comparison of ibuprofen and indomethacin
therapy for patent ductus arteriosus in preterm infants. Pediatrics
International. 2003;45:665-670.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Several randomized clinical trials have been
conducted to compare the efficacy of IV ibuprofen with that of IV indomethacin
in inducing closure of a PDA in premature infants. The alternative use
of IV ibuprofen for PDA closure was first studied in 1995 by Patel J et
al. Concerns related to the decline in cerebral perfusion and reduced
oxygenation with the use of IV indomethacin resulted in a study of an
alternative prostaglandin inhibitor with a focus on potentially less concerning
cerebral effects. Infants included were between 23 and 28 weeks gestation.
The study compared the effects of two IV ibuprofen doses (5mg/kg (n=12)
and 10mg/kg (n=6)) and indomethacin 0.1mg/kg (n=15). The results indicated
that IV ibuprofen did not impair cerebral hemodynamics or oxygenation.
The authors concluded that the cerebral effects of IV indomethacin must
be unique to this specific prostaglandin inhibitor. Although the authors
did find a difference in cerebral effects, there was no apparent difference
in rate of PDA closure (57% closure in both indomethacin and ibuprofen
treated infants).
In 1997, Van Overmeire et al conducted a
study in 40 premature infants to evaluate if IV ibuprofen is as effective
as IV indomethacin in closing a PDA. Secondary outcomes were adverse drug
effects. Premature infants included in this study had a gestational age <33
weeks with respiratory distress syndrome and echocardiographically confirmed
PDA. Infants were randomized at days 2 and 3 of life to receive 3 doses
of IV indomethacin (0.2mg/kg every 12 hours) or IV ibuprofen (10mg/kg,
followed by 5mg/kg after 24 and 48 hours). After receiving this treatment
course, 15/20 (75%) infants in the IV indomethacin group and 16/20 (80%)
infants in the IV ibuprofen group had PDA closure. Mosca et al evaluated
16 infants (<31 weeks gestation) receiving 0.2mg/kg IV indomethacin
or 10mg/kg IV ibuprofen. Following the first dose, ductal closure occurred
in 6/8 receiving IV indomethacin and 5/8 receiving IV ibuprofen. These
results are consistent with other early studies evaluating PDA closure
rates. In a small study by Pezzati M et al, PDA closure rates of 88% with
indomethacin and 78% with ibuprofen were noted following the first dose.
Prior to 2000, the clinical trials evaluating
IV ibuprofen were of small sample size (n of <100). In that year, the
study by Van Overmeire et al comparing ibuprofen and indomethacin included
148 premature infants of gestational age 24 to 32 weeks with evidence of
a PDA by echocardiogram, requiring respiratory support due to respiratory
distress syndrome. Premature infants were randomly assigned to receive
either IV indomethacin (0.2mg/kg every 12 hours for 3 doses) or IV ibuprofen
(10mg/kg, followed by 5mg/kg after 24 and 48 hours). Rescue doses of indomethacin
were indicated if there was no PDA closure and the infant continued to
require respiratory support following the initial 3 study drug doses. Rescue
doses were indomethacin (0.2mg/kg every 12 hours for 3 doses) and were
given if indicated to both groups (indomethacin and ibuprofen) independent
of the initial randomization.
In 2002, a second large, randomized clinical
trial by Lago et al was conducted that included 175 premature infants (gestational
age 23 to 34 weeks) with significant PDA and respiratory distress syndrome.
The methods of this study were similar to the 2000 Van Overmeire study;
however, in the event that rescue doses were indicated for a persistent
PDA, three doses of the same initial randomization drug were given versus
standard indomethacin. From previous trial results, the sample size for
these 2000 and 2002 studies were calculated based on the ability to detect
a difference of at least 20 percentage points in the closure rate between
the ibuprofen and indomethacin groups. A more recent study, in 2003, was
conducted by Su P et al in 63 premature infants with respiratory distress
syndrome and a gestational age * 32 weeks. This study had the same methods
of intervention as the 2000 and 2002 studies mentioned previously – however
no rescue doses of drug were given for lack of PDA closure or reopening.
In all of these aforementioned studies, premature infants with major congenital
anomalies, bleeding risks, and renal impairment were excluded.
With the primary outcome of PDA closure in
these comparative trials, IV ibuprofen has been found to be as efficacious
as IV indomethacin. In 2000, Van Overmeire et al found the rate of ductal
closure to be 66% (49/74) in the IV indomethacin group compared to 70%
(52/74) in the IV ibuprofen group (p=0.41). In this same study, infants
requiring rescue doses did not differ significantly between the two groups
(12% IV indomethacin group vs. 16% IV ibuprofen group, p=0.48). Lago et
al found similar closure rates of PDA following the initial three drug
doses (69% IV indomethacin group vs. 73% IV ibuprofen group). Following
three rescue doses, PDA closure rates were similar (82% IV indomethacin
vs. 86% with IV ibuprofen). In 2003, Su et al found PDA closure rates following
three drug doses to be similar as well (80.6% IV indomethacin vs. 84.4%
IV ibuprofen).
With respect to adverse effects, renal impairment
was most commonly found to be significantly different between the IV ibuprofen
and IV indomethacin groups. In the earlier Van Overmeire trial, premature
infants receiving IV ibuprofen had increased urine output and no rise in
serum creatinine compared to the IV indomethacin group. In the 2000 Van
Overmeire trial, oliguria developed in 14 infants receiving indomethacin
and 5 infants receiving ibuprofen during the three days following the start
of treatment (p=0.03). A greater increase in serum creatinine from day
4 to day 8 also occurred in the indomethacin group (p=0.04). Lago et al
found a similar difference in oliguria between groups, with oliguria noted
to be higher in those infants receiving IV indomethacin (15% vs. 1% with
IV ibuprofen, p=0.017). Consistent with previous adverse effects, Su et
al found serum creatinine values to be lower in the ibuprofen group at
24, 48, and 72 hours after treatment compared to the indomethacin group
(p < 0.01). Also, a significantly lower urine volume was found in the IV
indomethacin group at 24 hours after treatment compared to the IV ibuprofen
group (p < 0.02). In all of these studies, there were generally no differences
between groups for developing necrotizing enterocolitis, intraventricular
hemorrhage, etc.
In conclusion, IV ibuprofen has consistently
been shown to be as effective as IV indomethacin for the closure of PDA
in premature infants. Secondary outcomes of these comparative trials have
primarily looked at adverse effects, finding that IV ibuprofen has less
adverse effects on renal function compared to IV indomethacin. In summary,
IV ibuprofen has been shown to be as efficacious as the gold standard for
treatment of PDA, IV indomethacin, with improved adverse effects on renal
function.
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INTRAVENOUS
(IV) IBUPROFEN PROPHYLAXIS FOR PDA IN PREMATURE NEONATES |
|
Varvarigou
A, Bardin CL, Beharry K et al. Early ibuprofen administration
to prevent patent ductus arteriosus in premature newborn infants. JAMA.
1996;275(7):539-44.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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De
Carolis MP, Romagnoli C, Polimeni V et al. Prophylactic ibuprofen
therapy of patent ductus arteriosus in preterm infants. Eur
J Pediatr. 2000;159:364-368.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Gournay
V, Roze JC, Kuster A et al. Prophylactic ibuprofen versus placebo
in very premature infants: a randomised, double-blind, placebo-controlled
trial. Lancet. 2004;364:1939-44
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Although IV ibuprofen has shown to be
efficacious for treatment of PDA in premature infants, the role for
IV ibuprofen prophylaxis has less evidence to date in the literature.
Several studies comparing IV ibuprofen prophylaxis to placebo have demonstrated
efficacy in reducing the incidence of PDA. However, not all studies
have shown a benefit without the risk of adverse effects.
A prospective, controlled trial with
three treatment arms was conducted by Varvarigou et al in 1996. Thirty-four
premature infants (mean gestational age 26.9 weeks, range 22.4 to 31.0
weeks) were assigned within 3 hours of birth to a treatment, receiving
either three doses of IV ibuprofen (10mg/kg, followed by 5mg/kg after
24 and 48 hours), one dose of IV ibuprofen (10mg/kg), or saline. The incidence
of PDA did not differ between the infants receiving one dose of IV ibuprofen
or the saline group. However, those infants that received three doses
of IV ibuprofen had no PDA, which was a statistically significant finding
compared to the saline group (0/12 vs. 7/11, p <0.02). No adverse effects
were noted to be associated with IV ibuprofen in this study. A similar
study was conducted in 2000 by De Carolis et al, in which IV ibuprofen
prophylaxis was given as 3 standard doses (10mg/kg, followed by 5mg/kg
after 24 and 48 hours). Forty-six premature infants (<31 weeks gestation)
were randomly assigned to treatment at 2 hours of life. The control group
received no placebo. At 72 hours of life, a greater number of infants
in the IV ibuprofen group versus the control group were found to have
no presence of PDA [20/23 (87%) vs. 7/23 (30.4%)]. No significant adverse
effects were noted to occur with IV ibuprofen.
Until recently, IV ibuprofen for PDA
prophylaxis had shown consistent efficacy with little reports of adverse
effects. In 2004, the larger, randomized, double-blind, placebo-controlled
trial performed by Gournay et al was stopped early following the enrollment
of 135 premature infants, in which three cases of severe pulmonary hypertension
were noted to occur in the IV ibuprofen group. This trial included premature
infants <28 weeks gestation receiving either three doses of ibuprofen
(10mg/kg, followed by 5mg/kg after 24 and 48 hours) or placebo within
6 hours of birth. IV ibuprofen prophylaxis appeared to reduce the rate
of surgical ligation (9% placebo vs. 0% IV ibuprofen, p=0.03), but survival
with IV ibuprofen was not improved compared to the placebo group due to
the frequency of adverse effects.
In summary, IV ibuprofen has been shown
to have beneficial effects in decreasing the occurrence of PDA when compared
to placebo. No significant adverse effects were generally noted, but there
have been cases of severe pulmonary hypertension related to prophylaxis
with IV ibuprofen. Additional data are needed to determine the safety
of ibuprofen before it can be recommended in the prophylaxis of PDA. |
|
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INTRAVENOUS
(IV) IBUPROFEN LACKS EFFICACY FOR INTRAVENTRICULAR HEMORRHAGE (IVH) PROPHYLAXIS |
| |
Van
Overmeire B, Allegaert K, Casaer A et al. Prophylactic ibuprofen
in premature infants: a multicentre, randomised, double-blind, placebo-controlled
trial. Lancet. 2004;364:1945-49.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
|
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Dani
C, Bertini G, Pezzati M et al. Prophylactic ibuprofen for the
prevention of intraventricular hemorrhage among preterm infants: a multicenter,
randomized study. Pediatrics. 2005;115:1529-1535.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
|
|
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Mosca
F, Bray M, Lattanzio M et al. Comparative evaluation of the
effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation
in preterm infants with patent ductus arteriosus. J Pediatr.
1997;131:549-54.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
|
|
| |
Patel
J, Roberts I, Azzopardi D et al. 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.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
|
|
| |
Gournay
V, Roze JC, Kuster A et al. Prophylactic ibuprofen versus placebo
in very premature infants: a randomized, double-blind, placebo-controlled
trial. Lancet. 2004;364:1939-44.
(For non-journal subscribers,
an additional fee may apply for full text articles) |
|
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|
Indomethacin has also been used for IVH
prophylaxis in premature infants. However, the beneficial use of indomethacin
is often limited due to the adverse effects on renal and gastrointestinal
function, apparently related to interference with perfusion and oxygen
delivery. Prospective, randomized trials have been conducted to assess
the efficacy of IV ibuprofen for IVH prophylaxis, while other studies
have looked at the effects of IV ibuprofen on cerebral hemodynamics.
Like indomethacin, IV ibuprofen has been shown to be efficacious in
the treatment and prevention of PDA, although with an improved adverse
effect profile.
In 2004, Van Overmeire et al studied
the efficacy of early IV ibuprofen in reducing the frequency of severe
IVH in 415 infants (gestational age <31 weeks). Infants were randomized
to receive IV ibuprofen (10mg/kg, followed by 5mg/kg after 24 and 48 hours)
or placebo within 6 hours after birth. Severe IVH was noted in 17/205
(8%) infants in the IV ibuprofen group and 18/210 (9%) infants in the
placebo group.
In 2005, a multicenter, prospective,
double-blind randomized controlled trial conducted by Dani et al hypothesized
that prophylactic IV ibuprofen would reduce the occurrence of IVH and
make the worsening of IVH toward grades 2 to 4 less likely among premature
infants. Premature infants of gestational age <28 weeks received IV
ibuprofen or placebo within the first 6 hours of life. Infants received
the same doses prescribed in previous studies (10mg/kg, followed by 5mg/kg
after 24 and 48 hours). Of the 155 infants included in this study, grade
2 to 4 IVH developed in 21% in the IV ibuprofen group compared to 17%
in the placebo group. Comparing the IVH rates at baseline, 24 hours, 48
hours, and at 7 days of life, the investigators found no difference in
rates between the IV ibuprofen and placebo groups.
With respect to cerebral hemodynamics,
Mosca et al’s 1997 study compared the effects of IV indomethacin and IV
ibuprofen on cerebral perfusion and oxygenation in premature infants.
In this study of 16 infants (<31 weeks gestation), treatment with IV
ibuprofen did not significantly reduce cerebral perfusion and oxygen availability.
These results were further confirmed in a prospective, randomized controlled
trial by Patel J et al in 2000. The investigators measured cerebral hemodynamics
in 33 preterm infants during treatment of PDA with IV ibuprofen or IV
indomethacin. Following the first dose of IV ibuprofen, no change was
noted in cerebral oxygen delivery. However, cerebral oxygen delivery changed
significantly after the first dose of IV indomethacin: while cerebral
blood volume was reduced with IV indomethacin by a mean decrease of-0.5mL/100Gm,
no significant reduction was observed with IV ibuprofen (p=0.022). Following
the 24 hour dose of IV indomethacin, significant reductions in cerebral
blood flow, cerebral blood volume, and cerebral oxygen delivery were noted.
In contrast, no significant changes were seen with IV ibuprofen.
In 2004, Gournay et al evaluated the
effects of prophylactic IV ibuprofen on IVH in 135 premature infants (<28
weeks gestation). The need for surgical ligation of PDA was chosen as
the primary endpoint, as the sample size needed for prevention of IVH
as a primary endpoint was determined to be too large. Although underpowered,
as a secondary endpoint a decrease in the rate of grade 3 or 4 IVH was
seen with prophylactic IV ibuprofen compared to placebo (11% vs. 23%,
p=0.10). The overall rate of IVH was similar between both groups.
In conclusion, IVH prophylaxis with IV
ibuprofen has been shown to be ineffective and is not recommended. In
animal studies, indomethacin has vasoconstrictive effects in the brain – however
ibuprofen is not known to cause these same effects. Although ibuprofen
has an improved safety profile, especially in regards to renal and gastrointestinal
function, the lack of efficacy in IVH prophylaxis does not warrant its
use. With no alternative for IVH prophylaxis, the risks and benefits of
IV indomethacin must be considered. |
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LAST
MONTH’S Q & A January 2007 - Volume 4 - Issue
5
In our January 2007 issue, we reviewed the
clinical trial information for intravenous ibuprofen (pharmacologically
related to indomethacin) for the treatment and prophylaxis of PDA, and
its effect on intraventricular hemorrhage (IVH) prophylaxis.
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Commentary:
Carlton K.K. Lee, Pharm.D., MPH
Assistant Professor, Department of Pediatrics
School of
Medicine
Johns Hopkins
University
Clinical
Specialist, Pediatrics
Department
of Pharmacy
The Johns
Hopkins Hospital |
 |
Reviews:
Melissa D. Meekins, Pharm.D.
Pediatric Specialty Resident
Department
of Pharmacy
The Johns
Hopkins Hospital |
| |
Our
readers asked the January faculty the following questions: |
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Is
there any evidence that oral ibuprofen is as effective as IV ibuprofen
in the treatment of PDA for preemies? |
 |
The
experience with oral ibuprofen in treating PDA for preemies is
currently limited to four small clinical trials: two open-labeled
studies and two comparison trials to indomethacin. When combining
the subjects of the two open label trials, ductal closure was
achieved in 91.4% (32 of 35) of patients[1,2]. Ductal
reopening did not occur in one of these studies (N=22)[1] and
was not reported in the other (N=13)[2]. There were
no drug related side effects of oliguria or bleeding[1,2].
The comparison
pilot studies of oral ibuprofen to indomethacin have reported statistically
similar rates of ductal closure at 77.8% (7/9) vs. 88.9% (8/9)[3] and
46.7% (7/15) vs. 66.7% (10/15)[3,4], respectively (p=NS
for both). Slightly favorable response rates with indomethacin
in both of these trials may be attributed to better drug absorption
with the intravenous (IV) route of administration compared to oral
ibuprofen. Indomethacin subjects in the Supapannachart et al[3] trial
received their doses by either IV or PO, and indomethacin was administered
exclusively intravenously in the study by Chotigeat et al[4].
Ductal reopening was statistically similar at 40% vs 33% (p=NS),
ibuprofen vs indomethacin respectively, in one of these studies[4].
In regards to adverse drug events, favorable renal effects were
observed with ibuprofen. Ibuprofen use was associated with higher
urine output (with no significant increase in serum creatinine
or blood urea nitrogen)[3]; and significantly less diuretic
(furosemide) use (p<0.01)[4] Despite the lack of
statistical significance, a higher rate of NEC was also observed
with indomethacin (66.7% vs 40%) in the study by Chotigeat and
associates[4].
Despite promising
closure rates as high as 90% with open-labeled studies, unanswered
issues in regards to dosing and other potential side effects still
remain. Three different oral ibuprofen dosing regimens were used
in the four aforementioned trials; 10 mg/kg/dose x 1 followed by
5 mg/kg/dose x 2 given every 24 hours (same as the IV treatment
dose), or every 12 hours, or 10 mg/kg/dose x 3 given every 24 hours.
A PO/IV bioavailability study is needed to determine the proper
oral dose. Spontaneous intestinal perforation, without signs of
NEC, has been reported in two very-low birth-weight infants receiving
oral ibuprofen for PDA treatment[5].
References:
| 1. |
Heyman E, Morag
I, Batash D et al. Closure
of patent ductus arteriosus with oral ibuprofen suspension
in premature newborns: a pilot study. Pediatrics. 2003;112:354-358. |
| 2. |
Hariprasad P, Sundarrajan V,
Srimathy G, et al. Oral
ibuprofen for closure of hemodynamically significant PDA in
premature neonates. Indian Pediatrics. 2002;39(1):99-100. |
| 3. |
Supapannachart S, Limrungsiul
A, Khowsathit P. Oral
ibuprofen and indomethacin for treatment of patent ductus arteriosus
in premature infants: a randomized trial at Ramathibodi Hospital.
J Med Assoc Thai. 2002;85(Suppl 4):S1252-8. |
| 4. |
Chotigeat U, Jirapapa K, Layangkool,
T. A
comparison of oral ibuprofen and intravenous indomethacin for
closure of patent ductus arteriosus in preterm infants. J.
Med Assoc Thai. 2003;86 (Suppl 3):S563-9. |
| 5. |
Tatli MM, Kumral A, Duman N, et al. Spontaneous
intestinal perforation after oral ibuprofen treatment of patent
ductus arteriosus in two very-low-birthweight infants.
Acta Paediatr. 2004;93(7):999-1001. |
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As
a prophylactic protocol, is there any evidence that oral ibuprofen
may be beneficial when the IV preparation is not available? |
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The
available clinical data on oral ibuprofen use with PDA prophylaxis
is currently limited to a small, randomized, controlled study
conducted in Thailand[6]. Twenty-two neonates between
28-32 weeks gestational age with a birth weight of approximately
1500 grams received PO ibuprofen, while 20 neonates of similar
age, birth weight, and other clinical characteristics received
placebo. An oral ibuprofen dosage of 10 mg/kg/dose every 24 hours
for 3 doses, with the first dose initiated within 24 hours of
life, was given. The investigators found the prevalence of symptomatic
PDA to be lower in the ibuprofen prophylaxis group compared to
placebo (0/22 vs. 5/22, p<0.05)[6]. Although there
were no significant side effects, gastrointestinal bleeding did
occur more frequently with ibuprofen (12/22 vs. 6/20, p=0.196)[6].
It is also
important to consider the unpredictability of the oral administration
of drugs in infants. Infants, especially premature infants, may
have irregular gastric emptying and decreased intestinal and/or
biliary function. Additionally, in the presence of a PDA, decreased
mesenteric blood flow may also play a role in altering absorption.
The pharmacokinetics of oral ibuprofen have been studied in premature
infants and results have shown large inter-individual variability
with respect to drug exposure, area under the curve (AUC), and
peak plasma concentration (Cmax). In a pharmacokinetic
study by Sharma et al, the coefficient of variation was 88.5% for
AUC and 74.1% for Cmax[7]. This is quite
variable considering a relatively homogeneous patient population
[mean gestational age 30.45 +/- 1.48 weeks (range 26 to 32 weeks)
and mean birth weight 1262.5 +/- 247.76 grams (range 750 to 1900
grams)]. Additional oral pharmacokinetic studies are needed to
fine-tune the dosing strategy with oral ibuprofen by reducing the
inter-individual variability of drug exposure (AUC and Cmax).
References:
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The Johns Hopkins University School of Medicine designates
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Target Audience • back
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This activity has been developed for Neonatologists, NICU Nurses
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Learning Objectives • back
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At the conclusion of this activity, participants should be able
to:
- Discuss the efficacy of IV ibuprofen compared to IV indomethacin in the
treatment of PDA
- Compare the use of IV ibuprofen for prophylaxis of PDA to IV indomethacin
- Identify the role of IV ibuprofen for intraventricular hemorrhage prophylaxis
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for Johns Hopkins Nursing takes responsibility for the content, quality,
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As providers accredited by the Accreditation Council for Continuing
Medical Education and American Nursing Credentialing Center’s Commission
of Accreditation, it is the policy of The Johns Hopkins University School
of Medicine and The Institute of Johns Hopkins Nursing to require the disclosure
of the existence of any significant financial interest or any other relationship
a faculty member or a provider has with the manufacturer(s) of any commercial
product(s) discussed in an education presentation. The presenting faculty
reported the following:
- Dr. Nogee has indicated a financial relationship of grant/research support
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from the NIH. He also receives financial/material support from Nature Publishing
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This presentation will include off-label and unapproved uses of intravenous
Indomethacin and Ibuprofen for prophylaxis of PDA and intraventricular hemorrhage
in premature neonates as well as NeoProfen as prophylaxis for intraventricular
hemorrhage and PDA in premature neonates.
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