Discussion

Haemodynamically significant patent ductus arteriosus is a prevalent issue in extremely low birth weight infants and is associated with increased hospital morbidity and mortality. ^{Reference Benitz2,Reference Hamrick, Sallmon and Rose5–Reference Koch, Hensley, Roy, Brown, Ramaciotti and Rosenfeld10,Reference Liu, Manganiello, Waleh and Clyman12} Previous studies have shown that a patent ductus arteriosus in extremely low birth weight infants are less likely to close on their own or they close at much later times than larger birth weight or older gestational age infants. ^{Reference Noori, McCoy and Friedlich7,Reference Koch, Hensley, Roy, Brown, Ramaciotti and Rosenfeld10–Reference Liu, Manganiello, Waleh and Clyman12}

The results of this study indicate that when compared with surgical ligation performed after the first month of life, earlier ligation of haemodynamically significant patent ductus arteriosus in extremely low birth weight infants may improve hospital morbidity, including significantly fewer days of mechanical ventilation, as well as shorter hospital stays. However, we found no statistically significant evidence that early patent ductus arteriosus closure was associated with decreased duration of postoperative mechanical ventilation, use of supplemental oxygen or pulmonary vasodilators at discharge, tracheostomy, or mortality.

As indicated above, we found that infants in the early ligation group had fewer total days of mechanical ventilation (43.9 ± 17.1 days vs. 97.2 ± 84.9 days, p < 0.05), but postoperative days of mechanical ventilation did not differ significantly. Due to the large systemic to pulmonary shunt resulting from a patent ductus, surgical ligation of the patent ductus arteriosus likely improved the subsequent pulmonary oedema produced by the pulmonary over-circulation. ^{Reference Eilers, Kyle, Allen and Qureshi1,Reference Tashiro, Perez and Sola13–Reference Hsiao, Wung, Tsao and Chang22} Therefore, infants who underwent earlier surgical ligation could be weaned off support earlier, which may explain the difference in total days of mechanical ventilation between the early ligation and late ligation groups. Prior studies by Jaillard, Ibrahim, and Hsiao also documented improved ventilatory outcomes among premature infants receiving earlier surgical closure of patent ductus arteriosus, including lower fraction of inspired oxygen needed post-operatively, as well as reduced total time on assisted ventilation. ^{Reference Ibrahim, Azab and Kamal18,Reference Jaillard, Larrue, Rakza, Magnenant, Warembourg and Storme21,Reference Hsiao, Wung, Tsao and Chang22} Our study provides further evidence to the benefits of early closure on the ventilation period, but the effects on other indicators of respiratory status remain undetermined. ^{Reference Willis and Weems23}

Similarly, our results also indicate that early ligation, as compared to late ligation, is associated with decreased hospital length of stay (114.2 ± 17.7 days vs. 169.0 ± 53.9 days, p < 0.05). In addition to the improvements in respiratory outcomes, as stated above, surgical closure of patent ductus arteriosus in this cohort has also been shown to improve nutritional status, and it is possible that earlier surgical ligation can subsequently contribute to earlier hospital discharge in extremely low birth weight infants as well. ^{Reference Ibrahim, Azab and Kamal18,Reference Jaillard, Larrue, Rakza, Magnenant, Warembourg and Storme21,Reference Hsiao, Wung, Tsao and Chang22,Reference Vida, Lago and Salvatori24}

There are few reports currently regarding the optimal timing of surgical ligation in the extremely low birth weight cohort, specifically. One randomised controlled trial by Cassady et al. examined early ligation of the patent ductus arteriosus in 84 extremely low birth weight infants with one group undergoing prophylactic ligation on the day of birth and the other group receiving standard treatment. ^{Reference Cassady, Crouse and Kirklin14} They found that early surgical closure was associated with a lower incidence of necrotising enterocolitis. However, despite the reduced exposure to patent ductus arteriosus in the surgical group, performing prophylactic surgery on day 1 of life is an aggressive procedure that is unlikely to be adopted broadly. Furthermore, this study was unblinded, underpowered and conducted over 30 years ago, and so standard therapies have changed, requiring the results of this study to be interpreted critically. ^{Reference Mosalli and Alfaleh25}

Lee et al. assessed whether early closure of haemodynamically significant patent ductus arteriosus (within 7 days) by either medical or surgical means was associated with morbidity in extremely low birth weight, and they found that early closure was related to significantly decreased incidence of bronchopulmonary dysplasia and intraventricular haemorrhage, shorter hospital stays and ventilatory support, as well as improved nutritional outcomes. ^{Reference Lee, Sim and Jung26} A study by Kabra et al. found that surgical ligation of patent ductus arteriosus in extremely low birth weight infants may result in long-term neurosensory impairment, but a more recent study by Fonseca et al. reported that early closure of patent ductus arteriosus (within the first 21 days of life) in preterm infants may actually improve neurological outcomes, as well as lower rates of bronchopulmonary dysplasia, intraventricular haemorrhage, and acute renal failure. ^{Reference Fonseca, Georgiev, Gorenflo and Loukanov17,Reference Kabra, Schmidt and Roberts27} Additionally, Clyman et al. demonstrated that patients less than 28 weeks gestational age that are exposed to a moderate to large patent ductus arteriosus shunt for at least 7–13 days had an increased risk of developing bronchopulmonary dysplasia and death. ^{Reference Clyman, Hills, Liebowitz and Johng28} Exposure beyond this window (14 days or greater) did not significantly increase the incidence. ^{Reference Clyman, Hills, Liebowitz and Johng28}

Lastly, interventional and medical management of haemodynamically significant patent ductus arteriosus has changed over the last three decades with surgical ligation rates resultantly decreasing. ^{Reference Bixler, Powers, Clark, Walker and Tolia29–Reference Reese, Scott and Patrick31} Medical treatment alone offers moderate success rates as a non-invasive method of closure, but treatment fails in 20–40% of cases. ^{Reference Fraisse, Bautista-Rodriguez, Burmester, Lane and Singh32} Furthermore, the agents used can have adverse effects in neonates or may be contraindicated in cases of infants with renal impairment, necrotising enterocolitis, or intestinal perforations. ^{Reference Fraisse, Bautista-Rodriguez, Burmester, Lane and Singh32} While surgical ligation patients in the current era are a complex cohort secondary to advances in medical care, serious short-term adverse events are seen in a minority of patients with decreased mortality compared to medical treatment alone. ^{Reference Foster, Mallett and Govande33,Reference Weisz, More, McNamara and Shah34} Intraoperative hurdles included avoiding injury to the vascular structures and the recurrent laryngeal nerve. Surgical ligation for this cohort has been further reduced by the advancement of percutaneous patent ductus arteriosus closure in recent years, which has demonstrated relative safety and effectiveness in patients under 2 kilograms when performed by a trained interventionalist. ^{Reference Sathanandam, Gutfinger and O’Brien35–Reference Zahn, Peck and Phillips37} In a retrospective review performed by Sathanandam et al. comparing outcomes of extremely low birth weight infants undergoing transcatheter patent ductus arteriosus closure or surgical ligation, those who received transcatheter closure demonstrated more improved pulmonary outcomes post-procedure compared to surgical closure. ^{Reference Sathanandam, Balduf and Chilakala36} Similarly, a retrospective review by Regan et al. comparing surgical and transcather closure in preterm infants found that neonates undergoing transcatheter closure experienced shorter duration of mechanical ventilation during their post-procedure stay in the neonatal ICU. ^{Reference Regan, Benbrik and Sharma38} Further, compared to surgical ligation, transcatheter closure has been found to result in lower incidence of complications, including post-ligation syndrome. ^{Reference Parkerson, Philip, Talati and Sathanandam39} While transcather closure was not performed at our institution at the time of this study, these observational studies suggest that transcatheter closure may offer improved outcomes compared to surgical closure techniques. However, these findings may be centre-dependent, and large randomised clinical trials comparing transcather and surgical closure are necessary to determine the true differences in short- and long-term outcomes in the extremely low birth weight cohort.

In our study, the surgical closure of patent ductus arteriosus in extremely low birth weight infants within the first 30 days of life was correlated with improved ventilatory outcomes and shorter hospital lengths of stay, similar to previous studies examining more broadly defined cohorts of infants. Nevertheless, the evidence regarding optimal timing of surgical patent ductus arteriosus closure in extremely low birth weight infants remains limited and heterogeneous and is likely to be defined only with prospective randomised studies.