1. Notkun ibuprofens í meðferð PDA
Tryggvi Þorgeirsson
29. september 2006

2. Ductus arteriosus í fósturlífi
60% blóðs um hægri slegil
Meirihluti þess um DA
Opinn ductus
lágt súrefnisinnihald
PG (COX-2)
DA in the fetus is kept widely patent by low arterial oxygen content and circulating prostaglandins, which are produced in part by the placenta. This effect appears to be mediated by the COX-2 isoform, since constriction of the fetal DA in mice is induced by selective COX-2 inhibitors (sbr. coxib) but not selective COX-1 inhibitors [4]. This role of prostaglandins constitutes the rationale for the administration of nonsteroidal antiinflammatory drugs in the treatment of PDA.
The rise in systemic oxygen saturation with the onset of ventilation has a second effect, causing active constriction in the DA. Gene transfer studies suggest that an oxygen-sensitive potassium channel mediates DA constriction
Constriction of the DA usually results in functional hemodynamic closure within 10 to 15 hours after delivery
Structural closure is usually completed by 2 to 3 weeks of age. Following initial constriction, a series of histologic changes occur involving infolding of endothelial cells and migration of undifferentiated smooth muscle cells which result in obliteration of the ductus and conversion into the ligamentum arteriosum. There is histologic evidence that this process fails to occur in a PDA suggesting distinct anatomic differences in the DA tissue [9].

3. DA eftir fæðingu Samdráttur súrefnisstýrð kalíumgöng PG
starfræn lokun: klst
vefræn lokun: 2-3v

4. Opin fósturæð Nýgengi Klíník
Ísland: 11,5% meðfæddra hjartagalla; 0,19% lifandi fæddra barna ( ) (Sigurður Stephensen, Gunnlaugur Sigfússon et al, Læknablaðið 2002)
erlendar tölur: 12% hjartagalla; 2-4/ fullbura; allt að 60% fyrirbura <28v
Klíník
engin einkenni  vanþrif, andnauð, hjartabilun lungnaháþrýstingur
fyrirburar
apnea, andnauð, NEC
hár púlsþrýstingur
hjartaóhljóð (vi sternal brún)
fyrst í systolu, svo bæði systolu og diastolu
This murmur is best heard over the upper left sternal edge, associated with a thrill, and is characteristically continuous and machinery-like. It should be differentiated from a venous hum, a common innocent murmur often heard in children. Uptodate: Venous hum is more often on the right side and changes with position and local compression
Fékk hjartahljóðið hér (þar er líka hægt að fá venous hum):
Greining: — The diagnosis of PDA is typically confirmed by echocardiography, with chest x-ray and the electrocardiogram being useful but less specific.
COMPLICATIONS — Individuals with PDA have increased morbidity and mortality, primarily due to HF and infective endocarditis (IE) [23]. Pulmonary vascular resistance is a less common problem.

5. Meðferð Lyfjagjöf Skurðaðgerð Hjartaþræðing hindrun á PG-framleiðslu
coil occlusion
Amplatzer Duct Occluder

6. Indomethacin Notað síðan 1970 Fyrsta meðferð fyrir flesta fyrirbura
lakari verkun fyrir fullbura
Aukaverkanir
skert nýrnastarfsemi (tímabundið/langvarandi)
oliguria, hækkað s-krea
NEC, GI-blæðingar
minnkað blóðflæði til heila
minnkað flæði um kransæðar

7. Ibuprofenum Dýratilraunir lokar ductus í lömbum (1979)
bætir autoregulation blóðflæðis í heila grísa
dregur ekki úr blóðflæði til heila grísa, ólíkt indomethacin (staðfest í klínískum tilraunum)
Chemtob (nr. 2 og 3 á listanum, þeas blóðflæði til heila – notaði piglets): CBF increased after the administration of aspirin, decreased to almost the same extent after both low and high doses of indomethacin, and did not change after the administration of ibuprofen and naproxen.

8. Thomas RL et al. (Eur J Pediatr, 2005)
Metaanalysa á 9 klínískum rannsóknum
n = 566
ekki marktækur munur á virkni (p = 0.70)
ibuprofen
minni hækkun á s-krea (p < 0,001; n = 443)
minni lækkun á þvagútskilnaði (p < 0,001; n = 443)
aukin þörf á súrefnisgjöf við 28. d (55% vs. 40%; p < 0,05; n = 188)
Aranda JV tók líka þátt í þessari

9. Thomas RL et al. Ekki marktækur munur á:
dánartíðni, IVH, periventricular leukomalaciu, NEC, GI-blæðingum, aðgerðatíðni, sepsis, recurrence
Ályktun: jöfn virkni, minni aukaverkanir => hallast frekar að ibuprofen
In view of equal efficacy but with less toxicity, this suggests a slight therapeutic superiority in favor of ibuprofen.

10. Cochrane neonatal group (Cochrane Database of Systematic Reviews, 2006)
Allar slembistýrðar rannsóknir til og með júlí 2005
<37v eða <2500 g; PDA; IBU og/eða IMC
Enginn marktækur munur á
verkun (n = 620, CI 0,74-1,25)
dánartíðni, tíðni skurðaðgerða, IVH, PVL, NEC, sepsis, GI-blæðingum
Eleven studies including 620 patients compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. There was no statistically significant heterogeneity of treatment effect for any of the outcomes. For the primary outcome (failure of ductal closure), there was no statistically significant difference between ibuprofen and indomethacin groups [typical RR 0.96 (95% CI 0.74, 1.25)]. There were no statistically significant differences in mortality, surgical duct ligation, duration of ventilator support, IVH, PVL, NEC, time to full enteral feeds, ROP, sepsis, duration of hospital stay or gastrointestinal bleed. For many of these outcomes the sample size was small and the estimates imprecise.

11. Cochrane neonatal group frh.
Ibuprofen
sjaldnar minnkaður þvagútskilnaður (NNT 9, CI 5-14)
oftar þörf á súrefnisgjöf eftir 28. dag (RR 1,37, CI 1,01-1,86)
3 fyrirburar fengið lungnaháþrýsting eftir ibuprofen profylaxa – ath síðar
Samantekt
enginn munur á virkni
ibuprofen hefur ekki ótvíræða kosti
indomethacin verði áfram fyrsta lyf
The incidence of decreased urine output (< 1cc/kg/hr) was lower in the ibuprofen group as compared to the indomethacin group [NNT 9 (95% CI 5-14)]. This was the only statistically significant clinical finding favouring ibuprofen. CLD defined as oxygen requirement at 28 days post-natally was statistically significantly more likely to occur in the ibuprofen group [typical RR 1.37 (95% CI 1.01, 1.86); NNH 7 (95% CI )]. There was a similar trend for CLD at 36 weeks corrected gestational age. Authors' conclusions We found no statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing the PDA. Ibuprofen reduces the risk of oliguria. However, ibuprofen may increase the risk for CLD, and pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen. Based on currently available information ibuprofen does not appear to confer a net benefit over indomethacin for the treatment of a PDA. We conclude that indomethacin should remain the drug of choice for the treatment of a PDA. The most urgent research question to be answered is weather ibuprofen compared to indomethacin confers an improved rate of intact survival (survival without impairment) at 18 months corrected age.

12. Aranda JV, Thomas RL et al. (Semin Perinatol 2006)
Tvö form af iv ibuprofen
ibuprofen-lysin og –THAM
mæla með sitthvorum öryggisprófílnum
Blóðflæði/súrefnisflutningur til heila
indomethacin: 
ibuprofen: óbreytt
PVH-IVH: ibuprofen ekki verndandi; e.t.v. indomethacin
Indomethacin significantly decreased cerebral blood flow after the first dose. In contrast, no significant changes in CBF were observed with the first dose of ibuprofen. Cerebral oxygen delivery changed significantly after the first dose in the indomethacin group but not in the ibuprofen group.

13. Aranda JV, Thomas RL et al. frh.
Meltingarvegur
ibuprofen-THAM og indomethacin auka hættu á NEC
ekki ibuprofen-lysin
Bilirubin
ibuprofen er 99% próteinbundið
in vitro: hækkun á fríu Bi, en aðeins í háum skömmtum
in vivo (n=15): enginn munur
Indomethacin significantly decreased cerebral blood flow after the first dose. In contrast, no significant changes in CBF were observed with the first dose of ibuprofen. Cerebral oxygen delivery changed significantly after the first dose in the indomethacin group but not in the ibuprofen group.

14. Aranda JV, Thomas RL et al. frh.
Lungnaháþrýstingur
3 tilfelli eftir ibuprofen–THAM, ekki –lysine
Nýru
ibuprofen: lægra s-krea og meiri þvagútskilnaður
Indomethacin significantly decreased cerebral blood flow after the first dose. In contrast, no significant changes in CBF were observed with the first dose of ibuprofen. Cerebral oxygen delivery changed significantly after the first dose in the indomethacin group but not in the ibuprofen group.

16. Aranda JV, Thomas RL et al. Samantekt
Ibuprofen-lysin
jafnvirkt og indomethacin
minni áhrif á nýrnastarfsemi, dregur ekki úr blóðflæði til heila og meltingarvegar
ekki verndandi fyrir IVH
nota því frekar indomethacin ef forvörn er óskað
annars ætti ibuprofen-lysine að vera fyrsta val
1x10 mg/kg/d + 2x5 mg/kg/d
Therapeutic Strategy for Ibuprofen and Indomethacin Use in Newborns
Data described above indicate that ibuprofen has no effect on IVH prevention. Thus, when NSAID is indicated at age 1 day where IVH prevention is timely, indomethacin but not ibuprofen should be used. After days 2 and 3, when early therapy of pharmacologic closure of a hemodynamically significant PDA is desired, ibuprofen should be the first choice due to its better safety profile.
In summary, clinical trials have compared IV Ibuprofen to placebo, or to indomethacin, and have shown efficacy of this drug for ductal closure of patent ductus arteriosus. IV ibuprofen decreased PDA without little effect on renal function.4, 7 and 8 One study using another formulation of IV Ibuprofen (ibuprofen-THAM) showed decreased renal function and increased risk of NEC, and PPHN.5 and 6 Compared with indomethacin, IV ibuprofen exerted similar efficacy (75% to 93% closure). However, indomethacin increased abnormal renal function and decreased mesenteric and cerebral blood flow and bio-energetics (see below). Thus, it appears that enough data are now available to support the use of ibuprofen lysine in the management of PDA in the newborn. Further safety evaluation of ibuprofen-THAM appears warranted. A head-on comparison of the two intravenous ibuprofen preparations is also needed.
10 mg/kg loading dose followed by 5 mg/kg/d every 24 hours twice (total of 3 doses in 3 days)
A higher dose regimen ( mg/kg) might achieve a greater closure rate but must be balanced with the tolerability and safety.35

17. Takk fyrir