Table 1.
Experimental studies investigating paracetamol administration in PDA treatment (2015-2016).
| Authors | Year | Patients | GA (weeks) | BW (gr) | Treatment | Study | Dose | Results | Side effects |
|---|---|---|---|---|---|---|---|---|---|
| Härkin et al. [108] | 2016 | 48 | <32 | Mean: 1.220 Para group, 1.120 placebo group |
iv Para (n = 23) versus placebo | Controlled trial, fase I.II, double blind, randomized | 20 mg/kg at 24 h followed by 7,5 mg/kg every 6 h for 4 days | Faster closure in Para group (95% CI 0.25–0.97, P = 0.016). Mean (95% CI) postnatal closure age 177 h (31.1–324) for Para versus 338 h (118–557) for controls (P = 0.045) GA > 27 w: mean postnatal closure age 80 h in Para group versus h placebo 322 h (P = 0.004). GA < 27 w: n = 8, not Para effect on ductus (P = 0.63), 4 (50%) required PDA ligation (Para n = 3, placebo n = 1). Para closure in males (HR 0.31, 95% CI 0.12–0.85, P = 0.023), higher than females (95% CI 0.27–1.96, P = 0.52) |
No adverse effects or hepatotoxicity |
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| Valerio et al. [87] | 2016 | 48 | 23–32 | Mean: “first-line” group 853,3 ± 286,9; “rescue” group 887,7 ± 297 |
iv Para (n = 48) (n = 30 for ibu contraindications. N = 18 after ibu failure) |
Observational longitudinal prospective study | ibu 10-5-5 mg/Kg versus Para 15 mg/kg every 6 h | No significant differences in closure rate “first-line” versus “rescue” groups after 2 (56.7% versus 61.1%, P = 0.7624) or 3 cycles (63.3 versus 77.8% P = 0.2959).(1) Surgical ligation rate higher in “first-line” (26.7%) versus “rescue” group (16.7%). Reopening rate In “first-line” higher versus “rescue” group (10 versus 0%), and 91% of needing surgical closure had GA ≤27 w | No hepatotoxicity |
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| Bagheri et al. [18] | 2016 | 129 | <37 | Mean: 1.646,26 Para group, 1.642,62 ibu group | Oral Para (n = 67) versus oral ibu (n = 62) | Randomized trial | ibu 20-10-10 mg/Kg versus Para 15 mg/kg every 6 h | After 1° course of treatment: closure in 82.1% n = 55 patients oral Para vs. 75.8% n = 47 oral Ibu (P = 0.38). 2° course: closure oral Para group versus oral ibu group 50% versus 73.3% (P = 0.21) | No significant complications for both drugs |
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| Dani et al. [84] | 2016 | 110 | 25–31+6 | — | Para iv (n = 55) versus ibu iv (n = 55) | Randomized multicenter controlled study | Para 15 mg/kg/dose every 6 h for 3 days. Ibu 10-5-5 mg/kg/day | On course | — |
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| Tofé Valera et al. [117] | 2016 | 3 | <32 | <1.900 | 3 iv Para for ibu contraindications | Case series | Para 15 mg/kg every 6 h for 3–6 days | 100% closure (3/3 Patients) | Hypertransaminasemia n = 1 patient |
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| Yang et al. [88] | 2016 | 87 | <37 | Mean: Para group 2.219 ± 606, ibu group 2.091 ± 657 | Oral ibu (n = 43) versus oral Para (n = 44) | Randomized controlled trial | 10-5-5 mg/kg ibuprofen versus Para 15 mg/kg every 6 h for 3 days | Plasma and urinary PGE2 levels in Para group (45.0 ± 36.9 ng/l) significantly lower than ibu group (73.5 ± 44.8 ng/l, P = 0.002). Closure rate similar between Para (n = 31, 70.5%) and ibu groups (=33, 76.7%, P = 0.50). Lower oliguria in Para group (n = 1, 2.3%) than ibu group (n = 6, 14.0%) | Low adverse events in Para group |
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| Memisoglu et al. [118] | 2016 | 11 | 23–30+3 | 415–1.580 | iv Para for contraindications to Ibu or Indo | Case series | 15 mg/kg every 6 h for 3 days | Closure rate 90.9% (n = 10/11) | No adverse or side effects |
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| Sancak et al. [119] | 2016 | 18 | n.k. | <1.500 | iv Para (n = 10) versus oral Para (n = 8) | Retrospective study | 15 mg/kg every 6 h for 3 days | After 2 courses of treatment, higher closure rate in oral Para group versus iv Para group (88% versus 70%), not statistically significant (P = 0.588) | Liver function tests normal |
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| Weisz et al. [120] | 2016 | 26 | <28 | n.k. | Oral Para for Indo failure | Retrospective cohort study |
15 mg/kg every 6 h for 3–7 days | Echo indices improved in 46% (n = 12) infants (3 closed and 9 reduced to mild shunt), all avoiding ligation. No echo improvement in 54% (n = 14) infants (n = 8/14 underwent ligation) | No differences in 2ry outcomes |
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| Mohanty et al. [121] | 2016 | 40 | <32 | n.k. | Para for ibu contraindication | Prospective study | n.k. | 72.5% (n = 29/40) successful closure versus 29.5% (n = 11/40) not response | No major complications |
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| El-Mashad et al. [55] | 2016 | 300 | <28 | <1.500 | iv Para (n = 100) versus iv ibu (n = 100) or iv Indo (n = 100) | Prospective randomized Study |
Para 15 mg/kg/6 h iv. Ibu iv 10 mg/kg on 1° day, 5 mg/kg on the 2° and 3° days. 0.2 mg/kg/12 h ind iv for 3 doses | No significant difference in closure rate (P = 0.868). Cumulative closure rate higher after 2° course (88% in Para group, 83% in ibu group, 87% in Indo group). After closure, improvement in ventilatory settings (P < 0.001) |
Serum creatinine levels and BUN higher in Indo versus ibu group (P value < 0.001). PLT and UOP lower in Indo than ibu group (P < 0.001). Increase in bilirubin levels in ibu group (P < 0,05 ). No difference of HB level or liver enzymes (P > 0.05). GIT bleeding rate higher in Indo and Ibu groups (P < 0.05) |
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| Roofthooft et al. [22] |
2015 | 33 | <28 | <1.500 | Para for contraindication to ibu or failure of treatment | Prospective observational single center Study |
ibu 1 or 2 courses (10 mg/kg on 1° day, 5 mg/kg on the 2° and 3° days). Para iv (15 mg/kg/6 h) 3–7 days | Group A: 46% Para efficacy Groups B-C: Para treatment ineffective in all patients (2 died, in the others surgical ligation)(2). After previous exposure to ibu, Para ineffective in 100% |
No adverse effects |
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| Dash et al. [85] | 2015 | 77 | Mean: 28,5 Para group, 28,9 ibu group |
≤1.500 | Enteral Para (n = 38) versus iv Indo (n = 39) | Randomized controlled trial | Para per os (15 mg/kg/dose, 6 hourly for 7 days) or iv Indo (0.2 mg/kg/dose, once daily for 3 days) | Closure rate 100% (n = 36/36) in enteral Para group versus 94.6% (n = 35/37) in iv Indo group (P = 0.13). 2° outcomes similar in the two groups. 26,3% of GI bleeding in Para group | No hepatotoxicity in Para group |
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| Tekgündüz et al. [122] | 2015 | 13 | 24–31 | 470–1.390 | iv Para for contraindication to oral ibu | Case series |
N = 1 patient 15 mg/kg/dose every 6 h N = 12 patients, 10 mg/kg/dose every 6 h for 3 or 4 days |
PDA closure in 76.9% (n = 10/13) | Hepatotoxicity N = 1 patient |
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| Peňa-Juárez et al. [123] | 2015 | 10 | 30–36 | 840–1.600 | Oral Para | Case series | 15 mg/kg/dose every 6 h for 1-2 days | Closure in n = 7/10 patients (70%); n = 3/10 (30%) patients underwent surgical ligation N = 2 patients died (causes not related to drug administration) |
No significant changes in liver function and platelet count |
Para = paracetamol. Ibu = ibuprofen. Indo= indomethacin. iv = intravenous. GA = gestational age. BW= birth weight. w = weeks. gr = grams. BUN = serum blood urea nitrogen. UOP = urine output. HB = hemoglobin. PGE2 = Prostaglandin E2. GI = gastrointestinal. n.k. = not known data. (1) “First-line” group: paracetamol as first-choice therapy for ibuprofen contraindications. “Rescue” group: paracetamol after ibuprofen failure or for development of contraindications during its administration. (2) Group A: paracetamol first choice for ibuprofen primary contraindications. Group B: paracetamol after ibuprofen incomplete courses for development of contraindications during its administration. Group C: paracetamol after failure of two complete ibuprofen courses.