Download April 2014 – Neobriefs

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April 2014
http://www.jpeds.com/article/S0022-3476(13)01394-2/abstract
The Journal of Pediatrics Volume 164, Issue 3 , Pages 510-514.e1, March 2014
Oral Paracetamol versus Oral Ibuprofen in the Management of Patent Ductus Arteriosus in Preterm Infants: A
Randomized Controlled Trial Mehmet Yekta Oncel, MD, Sadik Yurttutan, MD, Omer Erdeve, MD, Nurdan Uras,
MD, Nahide Altug, MD, Serife Suna Oguz, MD, Fuat Emre Canpolat, MD, Ugur Dilmen, MD
Abstract:
OBJECTIVE:
To compare the efficacy and safety of oral paracetamol and oral ibuprofen for the pharmacological closure of patent
ductus arteriosus (PDA) in preterm infants.
STUDY DESIGN:
This prospective, randomized, controlled study enrolled 90 preterm infants with gestational age ≤30 weeks,
birthweight ≤1250 g, and postnatal age 48 to 96 hours who had echocardiographically confirmed significant PDA.
Each enrolled patient received either oral paracetamol (15 mg/kg every 6 hours for 3 days) or oral ibuprofen (initial
dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours).
RESULTS:
Spontaneous closure rate for the entire study group was 54%. After the first course of treatment, the PDA closed in
31 (77.5%) of the patients assigned to the oral ibuprofen group vs. 29 (72.5%) of those enrolled in the oral
paracetamol group (P = .6). The reopening rate was higher in the paracetamol group than in the ibuprofen group, but
the reopening rates were not statistically different (24.1% [7 of 29] vs. 16.1% [5 of 31]; P = .43). The cumulative
closure rates after the second course of drugs were high in both groups. Only 2 patient (2.5%) in the paracetamol
group and 3 patients (5%) in the ibuprofen group required surgical ligation.
CONCLUSION:
This randomized, controlled clinical study compared oral paracetamol with ibuprofen in preterm infants and
demonstrated that paracetamol may be a medical alternative in the management of PDA.
COMMENTS:
This is a prospective, randomized controlled trial comparing the efficacy and safety of oral paracetamol
(acetaminophen) and oral ibuprofen for the closure of patent ductus arteriosus (PDA) in preterm infants. 80 patients
that were <30 weeks gestation and < 1250 g were enrolled. The closure rate after treatment was similar, between 72
– 77%, in both groups. There was no statistically significant difference between the 2 groups for any complications
including renal tolerance, hypertransaminasemia, and hyperbilirubinemia, GI bleeding, NEC, IVH, CLD and ROP.
There have been few randomized controlled studies to determine the efficacy and safety of oral ibuprofen in preterm
infants with a PDA and IV therapy remains that standard of care in much of the world. However the availability,
lower cost of oral medications, and ease of administration has led some physicians, especially in developing
countries to use this treatment for the closure of PDA.
This study looked at infants < 30 weeks although many of their PDAs will close spontaneously. Just over half of the
patients in this study were < 28 weeks. 54% of the infants in this study had spontaneous closure of their ductus
when in fact the reported rate of closure in ELBW infants is closer to 34%. Therefore results may have been different
if including only patients < 28 weeks. Also, this study did not consider the possible side-effects of the osmolarity of
the oral medications and was not large enough to evaluate safety.
It may be beneficial to conduct larger trials to evaluate the efficacy of oral versus intravenous paracetamol or
oral/intravenous paracetamol versus oral/intravenous ibuprofen in infants < 28 weeks and < 1000 g who are the
infants most likely to benefit from these treatments.
Stacey Stone, M.D.
http://www.jpeds.com/article/S0022-3476(14)00023-7/abstract
DOI: 10.1016/j.jpeds.2014.01.017
Randomized Controlled Trial of Oxygen Saturation Targets in Very Preterm Infants: Two Year Outcomes
Brian A. Darlow, Simone L. Marschner, Mark Donoghoe, Malcolm R. Battin, Roland S. Broadbent, Mark J. Elder,
Michael P. Hewson, Michael P. Meyer, Alpana Ghadge, Patricia Graham, Nicolette J. McNeill, Carl A. Kuschel,
William O. Tarnow-Mordi
Abstract:
OBJECTIVE:
To assess whether an oxygen saturation (Spo2) target of 85%-89% compared with 91%-95% reduced the incidence
of the composite outcome of death or major disability at 2 years of age in infants born at <28 weeks' gestation.
STUDY DESIGN:
A total 340 infants were randomized to a lower or higher target from <24 hours of age until 36 weeks’ gestational
age. Blinding was achieved by targeting a displayed Spo2 of 88%-92% using a saturation monitor offset by ±3%
within the range 85%-95%. True saturations were displayed outside this range. Follow-up at 2 years' corrected age
was by pediatric examination and formal neurodevelopmental assessment. Major disability was gross motor
disability, cognitive or language delay, severe hearing loss, or blindness.
RESULTS:
The primary outcome was known for 335 infants with 33 using surrogate language information. Targeting a lower
compared with a higher Spo2 target range had no significant effect on the rate of death or major disability at 2 years’
corrected age (65/167 [38.9%] vs 76/168 [45.2%]; relative risk 1.15, 95% CI 0.90-1.47) or any secondary outcomes.
Death occurred in 25 (14.7%) and 27 (15.9%) of those randomized to the lower and higher target, respectively, and
blindness in 0% and 0.7%.
CONCLUSIONS:
Although there was no benefit or harm from targeting a lower compared with a higher saturation in this trial, further
information will become available from the prospectively planned meta-analysis of this and 4 other trials comprising a
total of nearly 5000 infants.
COMMENTS:
The Benefits of Oxygen Saturation Targeting- New Zeland trial (BOOST-NZ) was one of the 5 large trials included in
the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration to address the question: does
targeting a lower oxygen saturation range in extremely premature infants from birth increase or decrease the
composite outcome of death or major disability in survivors by 4% or more? All studies included were planned with
similar design, comparing long term outcomes of a lower (85-89%) versus a higher (91-95%) oxygen saturation
target range in premature infants born less than 28 weeks gestation. This multicenter RCT with 340 infants, a high
follow up rate (> 98%) and no changes in the saturation monitor software throughout, showed no difference between
the groups in the primary outcome of death or major disability at 2 years corrected age. Their results are similar to
the 18-22 months outcomes in the SUPPORT trial from North America (n= 1,310) and COT trial from Canada,
Europe, Israel and Argentina (n=1,200). The authors also reported no differences in any of the secondary outcomes
(mortality prior to discharge, CLD, severe ROP), contrasting with the results from the SUPPORT and BOOST II in
Australia and UK, which reported higher mortality rates at 36 weeks corrected age among infants randomized to the
lower range of saturation (85-89%). The results of the BOOST-NZ did not clarify what is the most appropriate
oxygen target range. Until results of the NeoProM Collaboration compiling data from approximately 5,000 patients
from nearly all continents are published, it may be prudent not to target saturation of 85 to 89% for extreme
premature infants.
Joana Machry, M.D.
http://pediatrics.aappublications.org/content/133/2/e379.full
Pediatrics Vol. 133 No. 2 February 1, 2014 pp. e379 -e385 (doi: 10.1542/peds.2013-1834)
Closed-Loop Automatic Oxygen Control (CLAC) in Preterm Infants: A Randomized Controlled Trial Antonietta
Hallenberger, Christian Friedrich Poets, Werner Horn, Andreas Seyfang, Michael Siegfried Urschitz, on behalf of the
CLAC Study Group
ABSTRACT
BACKGROUND AND OBJECTIVE:
In preterm infants receiving supplemental oxygen, routine manual control (RMC) of the fraction of inspired oxygen
(FIO2) is often difficult and time consuming. We developed a system for closed-loop automatic control (CLAC) of the
FIO2 and demonstrated its short-term safety and efficacy in a single-center study. The objective of this study was to
test the hypothesis that this system is more effective than RMC alone in maintaining arterial oxygen saturation within
target levels when evaluated over 24 hours under routine conditions and with different target levels.
METHODS:
We performed a multicenter, randomized controlled, crossover clinical trial in 34 preterm infants receiving mechanical
ventilation or nasal continuous positive airway pressure and supplemental oxygen. Twenty-four–hour periods with
RMC were compared with 24-hour periods of RMC supported by CLAC.
RESULTS:
The median (range) percentage of time with arterial oxygen saturation levels within target range was 61.4 (31.5–
99.5) for RMC and 71.2 (44.0–95.4) for CLAC (P < .001). The median (range) number of manual FIO2 adjustments
was reduced from 77.0 (0.0–224.0) for RMC to 52.0 (10.0–317.0) for CLAC (P = .007).
CONCLUSIONS:
CLAC may improve oxygen administration to preterm infants receiving mechanical ventilation or nasal continuous
positive airway pressure while reducing workload related to RMC.
Comments:
Several studies have shown the advantages of maintaining oxygen saturations in premature infants within a predefined target range and avoiding episodes of hypoxemia or extreme saturation values whenever possible. However,
maintaining saturations within a narrow target range is difficult.
The authors in this multi-center study used an automatic oxygen control system using a closed loop FIO2 Controller
that was programmed to acquire SPo2 values from the pulse oximeter, analyze the data and derive FIO2
adjustments in the ventilator O2 blender. They compared the closed loop automatic control system with the traditional
routine manual control. They found that the median percentage of time with arterial oxygen saturation levels within
target range was significantly better when comparing the automatic closed loop with the routine manual control, 71%
versus 61%. If this technology becomes commercially available and user friendly, we will see a significant
improvement in management of extreme premature infants where a narrow target range of oxygen saturations is
desired.
Roberto Sosa, MD
This is a review of 4 articles from various journals. The title and links have been provided.
Article 1
http://www.nature.com/jp/journal/v34/n2/abs/jp2013155a.html
Journal of Perinatology (2014) 34, 125–129; doi:10.1038/jp.2013.155; published online 19 December 2013
Coagulase-negative staphylococcus sepsis in preterm infants and long-term neurodevelopmental outcome
B Alshaikh, W Yee, A Lodha, E Henderson, K Yusuf and R Sauve
Article 2
http://pediatrics.aappublications.org/content/133/1/55.abstract
Intraventricular Hemorrhage and Neurodevelopmental Outcomes in Extreme Preterm Infants Srinivas
Bolisetty, MD, FRACP, Anjali Dhawan, MD, FRACP, Mohamed Abdel-Latif, FRACP, MRCPCH, MPH, MScEpid,
Barbara Bajuk, MPH, Jacqueline Stack, FRACP, Kei Lui, MD, FRACP , on behalf of the New South Wales and
Australian Capital Territory Neonatal Intensive Care Units’ Data Collection
Article 3
http://www.nature.com/jp/journal/v34/n1/abs/jp2013128a.html
Journal of Perinatology (2014) 34, 64–70; doi:10.1038/jp.2013.128; published online 17 October 2013
Neurodevelopmental outcomes of extremely low birth weight infants with spontaneous intestinal perforation
or surgical necrotizing enterocolitis R Wadhawan, W Oh, S R Hintz, M L Blakely, A Das, F Bell, S Saha, A
R Laptook, S Shankaran, B J Stoll, M C Walsh, and R D Higgins for NICHD Neonatal Research Network
Article 4
http://www.nature.com/jp/journal/v34/n3/abs/jp2013162a.html
Journal of Perinatology (2014) 34, 203–208; doi:10.1038/jp.2013.162 published online 26 December 2013
Outcomes of extremely preterm infants following severe intracranial hemorrhage A S Davis, S R Hintz, R
F Goldstein, N Ambalavanan, C M Bann, B J Stoll, E F Bell, S Shankaran, A R Laptook, M C Walsh, E C Hale, N
S Newman, A Das and R D Higgin for the Eunice Kennedy Shriver National Institute of Child Health and Human
Development Neonatal Research Network
COMMENT:
Food for thoughts (FFT)
The review of the 4 articles shows a heterogeneous group in terms of GA, risk factors for developmental delay, and
age at follow-up. But the message remains the same. See for yourselves.
-1 An association was found between Coagulase-negative Staphylococcus sepsis in infants < 29 weeks GA and
cognitive delay at 30-42 months.
FFT: Study weaknesses include: 1) retrospective; 2) small sample size of 121; 3) span over 13 year period; 4)
Definition of “true CoNS sepsis” as one blood, urine or CSF culture positive plus suggestive clinical signs. Of note,
Infants with CoNS sepsis were of lower GA, lower BW and had a higher incidence of postnatal steroid exposure.
-2 Study confirmed current knowledge of increased risk of developmental delay, CP, deafness and blindness in
infants < 29 weeks GA with Grades III and IV IVH. However, it found that isolated Gr I-II IVH, even without
documented white matter injury or other late U/S abnormalities, is associated with adverse neurodevelopmental
outcome at 2-3 years of age.
FFT: Cranial U/S remains of poor prognostic value for long-term developmental outcome, and we need to inform all
families, irrespective of IVH, of the increased risk their infants face growing up.
-3 The 18-22 months developmental outcome was compared among the Neonatal Research Network VLBW infants
with a) spontaneous intestinal perforation without NEC (SIP), b) surgical NEC (SurgNEC) and c) no NEC/no SIP.
Important findings: 1) SurgNEC was associated with a higher rate of death prior to NICU discharge as compared to
the other 2 groups. 2) Both SurgNEC and SIP were associated with higher rates of death/NDI at follow-up as
compared to the noNEC/noSIP group. Interestingly, 3) SIP had similar higher rates of death/NDI at follow-up as the
SurgNEC group.
FFT: Both SIP and surgNEC groups had a higher incidence of significant morbidities, and a greater proportion of
PDA requiring medical treatment as well surgical ligation. The paper does not address the management of SIP (drain
vs. laparostomy).
-5 Compared to “no chorioamnionitis” (Group A), infants less than 27 weeks GA exposed to either “histologic
chorioamnionitis” (Group B) or” histologic plus clinical chorioamnionitis” (Group C) had a lower GA, higher rate of
early-onset sepsis and severe IVH. Important findings: 1) Chorioamnionitis of any kind (Groups B or C) was
associated with increased risk of cognitive impairment at 18-22 months as compared to no chorioamnionitis (Group
A). 2) Group C had increased risk of Death/Neurodevelopmental impairment as compared to Group B. 3) However,
the association diminished after controlling for GA.
FFT: Impressive, yet not conclusive results based on 2390 infants from NICHD. Gestational Age at birth is still a
major determinant of outcome.
Sandra brooks, MD