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Patent ductus arteriosus - managementxManagement of Persistent Ductus Arteriosus (PDA)
PDA is a common complication of prematurity, affecting 60% of babies under 28
weeks’ gestation. It is associated (not necessarily causally) with neonatal morbidities
including IVH, NEC and CLD. Antenatal steroids and restricted fluid intake in the
early neonatal period are associated with a reduced risk of PDA. It is generally
accepted that symptomatic PDA warrants medical and/or surgical intervention,
although the criteria for diagnosis of a ‘significant’ PDA remain controversial.
There are three main ways of managing PDA in preterm infants: prophylactic
therapy, early asymptomatic treatment and treatment of the symptomatic PDA. The
two drugs most widely used for pharmacological closure of the ductus are
indometacin and ibuprofen, both of which work by interfering with prostaglandin
synthesis through cyclo-oxygenase inhibition.
Prophylactic therapy offers the benefit of closing the ductus at the earliest
opportunity, but carries the risk of exposing babies who were never destined to
develop a symptomatic PDA to a potentially harmful drug.
Prophylactic indomethacin is effective in reducing the incidence of symptomatic PDA (NNT = 4) and the need for surgical ligation of PDA (NNT=20). It is also effective in reducing the risk of severe IVH (NNT = 20) and PVL/white matter injury (NNT = 20). However, there is no evidence of benefit in terms of medium to long-term outcomes such as CLD and neurodevelopmental status. Although there are some theoretical concerns about the effects of indometacin on cerebral, gut and renal blood flow, there is no convincing evidence that prophylactic indomethacin is associated with an increase in adverse clinical outcomes such as NEC, persistent renal dysfunction or ischaemic brain injury. Prophylactic ibuprofen is also effective in reducing the risk of symptomatic PDA and surgical ligation, but does not confer any benefit in terms of IVH or white matter injury. There is no information about long term outcome following ibuprofen prophylaxis. b) Early asymptomatic treatment Treating the ductus at an early pre-symptomatic stage on the basis of pre-defined echocardiographic criteria may be theoretically preferable to prophylactic therapy because it allows targeted treatment of babies before they develop a symptomatic PDA. However, a meta-analysis of three small randomised controlled trials of indometacin for early asymptomatic treatment of PDA failed to demonstrate any important clinical benefits with this strategy. This approach cannot be recommended at present although there are ongoing trials evaluating the effectiveness of this strategy. c) Treatment of a symptomatic PDA The commonest approach to management of the ductus is to defer treatment until a baby becomes symptomatic and has echocardiographic criteria confirming a significant ductal shunt. Although this strategy allows treatment to be restricted to those babies who actually have a ‘significant’ PDA, it will inevitably result in babies receiving treatment only after they have developed signs of cardiorespiratory compromise. One trial comparing early (d3) versus later (d7) indomethacin therapy for moderately large PDA did not demonstrate any important clinical benefits of early symptomatic treatment. Diagnosis of PDA
Diagnosis of symptomatic PDA based solely on clinical criteria is unreliable.
2D/Doppler echocardiography is the gold standard for (1) diagnosing PDA and
quantifying the likely magnitude of any ductal shunt and (2) exclusion of other
cardiac defects including duct-dependent lesions prior to attempted ductal closure.
Treatment of symptomatic PDA
1. Fluid restriction/diuretics
Although fluid restriction and diuretic therapy is widely advised and practised, there
is little evidence supporting the routine use of either treatment in the management of
symptomatic PDA. Fluid restriction is associated with compromised nutritional intake
and poor growth. Diuretics such as furosemide often result in electrolyte
derangements and are themselves associated with prolonged ductal patency.
Nevertheless, there may be a role for using diuretics to control symptoms in some babies with PDA and evidence of left heart failure whilst awaiting spontaneous closure, or in those in whom other pharmacological or surgical treatment is contraindicated or delayed (eg. those with pulmonary haemorrhage). 2. Pharmacological closure Note: Indometacin is currently not available because of unspecified manufacturing problems. • Indometacin and ibuprofen are both licensed preparations for treatment of symptomatic PDA in preterm babies. Randomised controlled trials have demonstrated similar efficacy for ductal closure with ibuprofen compared to indometacin (approximately 70%).  Although ibuprofen is associated with less disruption of cerebral blood flow, less renal impairment and tendency to less NEC, it may equally be associated with a prolonged oxygen requirement. There is no information on long-term neurodevelopmental outcome after ibuprofen or indometacin therapy for symptomatic PDA. • Anecdotally, repeat treatment with indometacin or ibuprofen is sometimes • There is no evidence to support the practice of withholding enteral feeds in babies receiving drug treatment for ductal closure. Although ductal ligation is more effective than indomethacin for achieving permanent ductal closure when used as first line therapy in symptomatic PDA, there is no evidence of a benefit in terms of important neonatal outcomes. Ligation is also associated with significant morbidity (1-16%, including pneumothorax, chylothorax, haemorrhage and wound infection) and mortality (0-10%). There is also some evidence that ductal ligation is itself independently associated with important short and long term adverse clinical outcomes, including CLD, ROP and neurodisability at 18 months. 1. Preterm babies, especially those < 28 weeks and/or < 1000g, should be examined regularly for signs of a symptomatic PDA. 2. Babies with a suspected symptomatic PDA on clinical grounds should have an echocardiogram performed to confirm or refute the diagnosis prior to treatment. 3. Only babies with a symptomatic (‘haemodynamically significant’) PDA, confirmed echocardiographically, should be considered for pharmacological ductal closure. The decision to treat a symptomatic PDA should be made following discussion with a Consultant. 4. Restriction of fluid intake and/or diuretics should not be used routinely in the management of symptomatic PDA, but may be useful as symptomatic therapy in some babies with evidence of left heart failure. 5. Ibuprofen should be used as the first line agent for the treatment of symptomatic PDA. Refer to the Drug Information Folder for the dosage regimen. 6. A second treatment course of ibuprofen for symptomatic PDA should not be used routinely but may be appropriate in selected cases. 7. Surgical closure is indicated in babies with a symptomatic PDA who have contraindications to pharmacological treatment or in whom medical treatment has failed. References
1. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants.Cochrane Database Syst Rev. 2010 Jul 7;(7):CD000174. 2. Shah SS, Ohlsson A. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants.Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004213. 3. Cooke L, Steer P, Woodgate P. Indomethacin for asymptomatic patent ductus arteriosus in preterm infants.Cochrane Database Syst Rev. 2003;(2):CD003745. 4. Van Overmeire B, Van de Broek H, Van Laer P, Weyler J, Vanhaesebrouck P. Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome.J Pediatr. 2001 Feb;138(2):205-11. 5. Skelton R, Evans N, Smythe J.A blinded comparison of clinical and echocardiographic evaluation of the preterm infant for patent ductus arteriosus. J Paediatr Child Health. 1994 Oct;30(5):406-11. 6. Wyllie J. Treatment of patent ductus arteriosus. Semin Neonatol. 2003 Dec;8(6):425-32. 7. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2010 Apr 14;(4):CD003481. 8. Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J,Degroote K, Langhendries JP. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med. 2000 Sep 7;343(10):674-81. 9. Malviya M, Ohlsson A, Shah S. Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants.Cochrane Database Syst Rev. 2003;(3):CD003951. 10. Van Overmeire B, Chemtob S. The pharmacologic closure of the patent ductus arteriosus. Semin Fetal Neonatal Med. 2005 Apr;10(2):177-84. Epub 2004 Dec 15. 11. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A; Trial of Indomethacin Prophylaxis in Preterms Investigators. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr. 2007 Mar;150(3):229-34, 234.e1. 7th December 2010 (version3-NICU74)
North Shore Cancer Research Association Study List Edward Kaplan, MD 9631 Gross Point Rd. Suite 10 847.675.3900 (phone) Marlon Kleinman, MD Skokie, IL 60076 847.675.3930 (fax) Sponsor Protocol # Study Title A Phase II Study of Systemic High-Dose Methotrexate for the Treatment of Glioblastoma Multiforme in Newly Diagnosed A Phase III (Phase I Closed) Randomiz