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Three Part Question

In a [ventilated preterm neonate with a patent ductus arteriosus that has reopened or remained open after an initial course of Indometacin] [when is a second course of Indometacin effective] at [closing the patent ductus arteriosus]?

Clinical Scenario

A 25 week gestation neonate is ventilated for RDS, he develops a haemodynamically significant persistent ductus arteriosus (hsPDA) on day ten of life. The PDA is treated with an initial course of Indometacin and despite initial improvement he remains ventilator dependent. On day seventeen a hsPDA is diagnosed again. How effective is a second course of Indometacin (Indo) at closing the PDA?

Search Strategy

PubMed , Cochrane Library , Google scholar.
A search string of [patent ductus arteriosus] AND [Indometacin] was used.

Search Outcome

7 relevant papers identified.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Keller R 2003 USA	374 ventilated newborns <28wks & PDA treated with 1st course of Indo (0.2, 0.1, 0.1 mg/Kg) 32 received 2nd course (0.2, 0.1, 0.1mg/kg) of Indo for recurrent hsPDA at 13 ± 8 days after 1st course PDA echo at 12 - 24 hr after 2nd course to assess closure	Case series (level 4)	Persistence of hsPDA needing ligation after 2nd course of Indo	18/32 (56%) met criteria for ligation after 2nd course. Persistent Doppler flow through PDA after 1st course in 9/32 (28%) predicted PDA ligation (= failed 2nd course). All 9 ligated. Only 9/23 (39%) with absent Doppler flow after 1st course developed a hsPDA & were ligated after 2nd course (p<0.001). Infants with Doppler detectable flow after 1st course had hsPDA sooner than those with no flow after 1st course (8±2 v 15±2 days: p=0.03)	Retrospective case series Rationale of treatment decisions unclear. Some ducts ligated after 1st course, but referral criteria not stated Ventilation status at time of 2nd course unclear Some received prophylactic 1st course, others only if hsPDA
Su B H et al, 1999 Taiwan	93 ventilated infants <1500g with hsPDA on Doppler & clinical signs. Randomisation to 2 groups: 1) Protocol group: 1st course (0.2, then 0.1 or 0.2, then 0.1 or 0.2 mg/Kg). If PDA open on Doppler, 2nd course (0.2mg/kg x 3 mg/kg) & Doppler 24 hrly 'til closure. 2) Echo group Doppler prior to 1st course, then 24 hrly after 1st dose. Further doses only if pulsatile or growing flow pattern on 24 hr Doppler.	Prospective RCT (Level 1b)	Total number of doses of Indo. Need for ligation after 2nd course or if Indo contraindicated. (Protocol group - ligation if PDA symptomatic after 2nd course. Echo group -ligation if no 'closing' or 'closed' pattern after 6 doses)	Doses of Indo: Protocol = 3.2, Echo = 1.6 (p<0.01), Using PDA flow pattern analysis as a guide to Indo treatment allows the use of significantly fewer doses. Ligation rates: Protocol =5 (10.9%) Echo =5 (10.6%).	Wording changes from "courses of" to "doses of Indometacin" Need for daily Doppler by skilled operator No comment on the relationship of Doppler flow to later re-opening
Clyman R et al 1985 USA	123 premature infants weighing <2500g at birth who required Indo (0.2, 0.1, 0.1mg/kg) for treatment of PDA	Case series (level 4)	Clinical & Doppler evidence of PDA after 1st and 2nd courses	87% of infants had no clinical or echo evidence of PDA after 1st course. Duct reopened in 23% of those initially closed by Indo. Incidence of reopening inversely related to birth weight, <1000g 33% reopened, >1500g 8%.76% who had 2nd course closed their duct again.	Brief details of human babies, possibly not all ventilated, in a paper about lambs No calculations of significance No follow up to see if closures permanent. No ligation rates.
Tammela O et al 1999 Finland	Infants <33 weeks with hsPDA & L to R shunt on Doppler. Treatment with Indo decided by attending neonatologist 2 groups: Short course (n=31) - 3 doses (0.2, 0.1, 0.1 mg/kg) at 12 hr intervals. Long course (n= 30) - 7 doses (0.1 mg/kg) at 24 hr intervals. Echo in all if signs of PDA (operator blinded to drug regimen) then repeated on 3rd, 9th, 14th days after 1st dose, also if non-closure or reopening suspected clinically	Individual RCT (level 1b)	Echo presence or absence of clinically & hsPDA on 9th day. Complete closure rate, reopening rates.	Primary responders:Short 94%, Long 67% p=0.011. PDA reopened needing treatment: Short 19%, Long 7%, NS. Sustained closure after 1st course: Short 74%, Long 60% NS. Indo repeated: 29% both groups. Final closure with Indo: Short 90%, Long 63%, p=0.016. Ligation: Short 7%, Long 30% p=0.022. After closure confirmed by Doppler, 50% re-openers responded to 2nd course Indo.	No information on method of randomisation Possibly not all ventilated. Dosing schedule & timing of 2nd course not given. Claims that prophylaxis was better but 29% received a 2nd course of Indo in both groups.
Rajadurai 1991	103 ventilated preterm neonates (24 – 36 wk), who survived to day 3 1st course (3-6 doses) given between 3-7 days of age, if large L - R shunt on Doppler but before cardiovascular compromise Serial echo performed & further courses considered if large L - R shunt persisted/recurred Ligation if duct remained after > 1 course of Indo or course incomplete due to complications	"Outcomes" research (level 2C)	Response of duct to Indo (success, constriction, failure, recurrence) using Doppler. Complications from Indo therapy.	1st course closure in 61%, constriction in 19%, failure in 19%. 7 (5 non-responders & 2 re-openers) had 2nd course: 2 (28%) successful closure. Treatment failure, ligation & major complications exclusively at <28 wk. Success with Indo: 61% at 24-28 wks, 100% at 29-36 wks (p=<0.025). Recurrence: 11% at 24-28 wks, 6% at 29 -36 wks. >1 course of Indo: 33% at 24-28 wks, 6% at 29-36 wks. Ligation: 22% at 24-28 wks, 0% at 29-36 wks.	Number of doses & dosing schedule in 1st & 2nd courses unclear (3-6 doses at 12-24 hr intervals) Serial echo performed but no times given Time between courses not given
Quinn D et al 2002 USA	341 babies < 27 weeks treated with Indo. 28 died. 30 had no response. 69 had partial duct closure with 1st course of Indo (0.2, 0.1, 0.1 mg/Kg) i.e. clinical closure but luminal flow evident on Doppler - they formed the core of the study. Ducts in 214 babies closed permanently.	Retrospective case series (level 4)	Echo closure by further doses of Indo or ligation	1 death. 51/68 (75%) reopened duct symptomatically. 48/68 (71%) eventually ligated. Only 2 factors related independently with ductal closure: the longer course of Indo (6 days v 3 days ), and higher gestation.	Unclear why 30 non-responsive PDAs were ligated after a 1st course of Indo rather than give 2nd course or 6 doses. Possibly not all ventilated

Comment(s)

There are no RCTs that specifically address this question. In these studies ligation was performed only after unsuccessful medical treatment – however defined. Reported ligation rates after two courses of indometacin ranged from 0 – 71% (Keller, Su, Tammela, Rajadurai, Quinn) with rates of 56% at < 28 weeks (Keller) and 71% at < 27 weeks (Quinn). Better prediction to the response to a second course of indometacin can be achieved by considering gestation (Rajadurai), birth weight (Clyman), post natal age (Firth) length of first course (Tammela), and Doppler evidence of persistent ductal flow (Keller). Of these the Doppler flow appears to offer 100% sensitivity for persistence of a hsPDA when Doppler flow is present after the first course, but with a 39% false negative rate amongst those with no Doppler flow (Keller).

Clinical Bottom Line

Echo with/without Doppler aids the prediction of those babies who will respond to a second course of Indometacin. Persistent Doppler evidence of blood flow through a PDA following 1st course is a significant predictor of failure of a 2nd course (Keller). If there is persistent Doppler flow through the duct after the first course then opting for surgical ligation is better than a second course in neonates <28 weeks gestation, but a second course in older infants appears to have a greater than 50% chance of closure. In view of the low success rate of second courses of indometacin, greater attention needs to given to optimising first courses of the drug.

References

1. Keller RL, Clyman RI. Persistent Doppler flow predicts lack of response to multiple courses of indomethacin in premature infants with recurrent patent ductus arteriosus. Paediatrics 2003; 112: 583-7
2. Su BH, Peng CT, Tsai CH. Echocardiographic flow pattern of patent ductus arteriosus: a guide to indomethacin treatment in premature infants. Arch Dis Child Fetal Neonatal Ed 1999; 81:F197-F200
3. Clyman R, Campbell D, Hymann M, Mauray F. Persistent responsiveness of the neonatal ductus arteriosus in immature lambs: a possible cause for reopening of patent ductus arteriosus after indomethacin – induced closure. Circulation 1985; 71: 141-5.
4. Tammela O, Ojala R, Iivainen T, Lautmatti V, Pokela ML, Janas M, Koivisto M, Ikonen S. Short versus prolonged therapy for patent ductus arteriosus in preterm infants. J Pediatr 1999; 134: 552-7
5. Rajadurai V, Yu V. Intravenous indomethacin therapy in preterm neonates with patent ductus arteriosus. J Paediatr Child Health 1991; 27: 370-5.
6. Quinn D, Cooper B, Clyman RI. Factors associated with permanent closure of the ductus arteriosus: A role for prolonged indomethacin therapy. Pediatrics 2002; 110: e10
7. Firth J, Pickering D. Timing of Indomethacin therapy in persistent ductus [letter]. Lancet 1980;July:144