Surgical ligation of patent ductus arteriosus in very low birth weight infants: A 9-year single center experience

Background We analyzed the feasibility outcomes weight infants (VLBWIs) with hemodynamically significant patent ductus arteriosus (HSPDA) and investigated predictors for surgical treatment after unsuccessful medical management. Methods Medical records from the neonatal intensive care unit of Hanyang University Seoul Hospital from January 2010 to December 2018 were retrospectively reviewed. 233 VLBWIs with HSPDA were enrolled in our study. Of these infants, 134 underwent surgical ligation and were subdivided into the early ligation group (n = 49; within 10 days of age) and the late ligation group (n = 85; after 10 days of age). Results The mean gestational age and birth weight were significantly lower in the patent ductus arteriosus (PDA) ligation group than in the Non-ligation group (p < 0.001). PDA ductal diameter > 2.0 mm (p < 0.001), low Apgar score at 5 minutes (p = 0.033), and chorioamnionitis (p = 0.037) were the predictors for receiving surgical treatment for PDA. Early ligation was significantly associated with a low incidence of culture-proven sepsis (p = 0.004), mechanical ventilator time > 4 weeks (p = 0.007), necrotizing enterocolitis stage (NEC) ≥ III (p = 0.022), and intraventricular hemorrhage (IVH) grade ≥ III (p = 0.035). day 6 (± 1 day), day 9 (± 1 day), and day 14 (± 2 days) to identify symptomatic PDA in preterm infants. Symptomatic PDA indicated HSPDA, which was defined as a ductal diameter ≥ 1.5 mm, or a ratio of 1.5 or more of the size of the left atrium to the diameter of the aortic root on at least one echocardiography (HD11 Diagnostic Ultrasound Imaging System and We suggest that predicted VLBWIs with HSPDA that is

If pharmacologic treatment is contraindicated or fails, surgical ligation can be considered.Surgical ligation can be performed at the bedside in the neonatal intensive care unit (NICU) without a high risk of surgical morbidity or mortality [5].Although PDA surgical ligation after unsuccessful medical treatment is a definitive treatment, studies on the proper timing of surgery for HSPDA are few [4,6], and the proper timing of surgical ligation remains controversial.
In this study, we analyzed the feasibility of early surgical ligation (within 10 days of age) in VLBWIs with HSPDA and investigated parameters that would be helpful for deciding on early surgery.

Study populations
Hanyang University Seoul Hospital is a tertiary referral center for patients with a multidisciplinary PDA team in Seoul, South Korea.We retrospectively reviewed all the medical records of the NICU at our center from January 2010 to December 2018 to identify VLBWIs (< 1,500 g).Our institutional review board approved this study, and the need for patient consent was waived (IRB number; HYUH 2019-07-004-003).

Medical Treatment
The direction of treatment for PDA was determined by the neonatologist.Most HSPDA patients were initially treated with 2 or 3 cycles of nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin or ibuprofen.The protocol for indomethacin and ibuprofen treatment is described in Table 1.Contraindications to NSAID treatment at our center were gastrointestinal bleeding, IVH grade > I, poor urine output (< 0.6 mL/kg/hr), high serum creatinine (> 1.8 mg/dL), high blood urea (> 30 mg/dL), positive disseminated intravascular coagulation (DIC) profiles, or thrombocytopenia (< 60,000 /mm 3 ), as in our previous publication [4].

Surgical Treatment
The decision to refer an HSPDA infant to the department of Thoracic and Cardiovascular Surgery for surgical ligation after failure or due to contraindications of medical therapy was performed by a neonatologist specialized in echocardiography.All operations were performed at the NICU bedside with the infant under general anesthesia.A left transaxillary mini-thoracotomy via the 3rd or 4th intercostal space was used as the PDA approach.The ductus arteriosus was ligated using a single medium or medium-large sized titanium Horizon clip (Teleflex Medical, Research Triangle Park, NC, USA).Immediately after the operation, the attending neonatologist checked with echocardiography to determine whether the PDA ligation was successful.

Endpoints, Definitions And Follow-up
The PDA ligation group comprised patients who underwent surgical ligation, and the Non-ligation group comprised patients who did not undergo surgical treatment.As mentioned above, the early ligation (EL) group comprised patients who underwent PDA ligation within 10 days of age, and the late ligation (LL) group comprised patients who underwent surgery after 10 days of age.
The primary outcome of this study was a comparison of mortality between the PDA ligation and Nonligation groups and the EL and LL groups.Secondary outcomes were factors associated with PDA surgical ligation and postoperative clinical outcomes such as NEC, BPD, IVH (grade ≥ III), sepsis, retinopathy of prematurity (ROP), and periventricular leukomalacia (PVL).
Echocardiography was performed within 3 days of birth, and subsequent echocardiographic parameters were obtained on day 6 (± 1 day), day 9 (± 1 day), and day 14 (± 2 days) to identify symptomatic PDA in preterm infants.Symptomatic PDA indicated HSPDA, which was defined as a ductal diameter ≥ 1.5 mm, or a ratio of 1.5 or more of the size of the left atrium to the diameter of the aortic root on at least one echocardiography (HD11 Diagnostic Ultrasound Imaging System and Transducers; Philips Ultrasound, Bothell, WA, USA).This definition was based on the description of the previous publication [9].Associated symptoms with HSPDA classified at our center have been described previously [4].
IVH was classified by Volpe's grading system [10].Culture-proven sepsis was defined as the presence of positive findings in one or more blood cultures and clinical symptoms of infection.NEC was defined using Bell's modified staging criteria [11].BPD was defined by Jobe and Bancalari's criteria [12].The stages of ROP were classified using the international classification of retinopathy of prematurity [13].

Statistical Analyses
Data were expressed as either the mean ± standard deviation or frequency and proportion.
Comparisons between groups were performed with chi-square tests and Fisher's exact tests for categorical variables.Two sample Student's t-tests were used for continuous variables when a normal distribution was found.The Mann-Whitney U test was used for variables with skewed distributions.All tests were two-tailed.Logistic regression analysis was used to determine risk factors between the PDA ligation and Non-ligation groups, and clinical morbidities between the EL and LL groups.Receiver operating characteristic (ROC) curves were constructed for the assessment of significant factors associated with PDA surgical ligation.All p values of less than 0.05 were considered statistically significant.Statistical analysis was performed using SPSS, version 22.0 (SPSS, Chicago, IL, USA).

Results
A total of 383 VLBWIs were diagnosed in the NICU from January 2010 to December 2018.Infants with other congenital anomalies (n = 9), incomplete data including echocardiography findings (n = 4), and a diameter less than 1.5 mm (n = 57) were excluded, along with 29 patients who died within 10 days of birth.After the exclusion of 51 infants who were diagnosed with HSPDA but did not undergo any treatment such as surgical or medial therapy, 233 VLBWIs with HSPDA were ultimately enrolled in our study.Of these infants, 134 (57.5%) underwent surgical ligation and were subdivided into the EL group (n = 49, 36.6%) and the LL group (n = 85, 63.4%).The conditions of 99 infants improved with medical treatment alone (Fig. 1).
The baseline characteristics of the patients in the PDA ligation and Non-ligation groups are summarized in Table 2. Regarding maternal characteristics, histologic chorioamnionitis was significantly higher in the PDA ligation group than in the Non-ligation group (p = 0.027), while pregnancy-induced hypertension (PIH) was significantly lower in the PDA ligation group than in the No patients died during their operations.Two infants required reoperation due to residual flow of PDA, as diagnosed by immediate postoperative transthoracic echocardiography.Three patients died during the postoperative hospital day.In the LL group, one infant died 100 days after PDA ligation due to NEC.In the Non-ligation group, two infants died 12 and 17 days after birth, and the cause of death was sepsis.There were no statistically significant differences in mortality rate between the PDA ligation and Non-ligation groups (p = 0.576), or between the EL and LL groups (p > 0.999).
The logistic regression analysis for factors associated with PDA surgical ligation is presented in Fig. 2.
The ROC curve for the ability to predict PDA surgical ligation showed that PDA ductal diameter > 2.0 mm predicted surgical treatment with an area under the curve (95% confidence interval (CI)) of 0.650 (0.579-0.721).Histologic chorioamnionitis showed an area under the curve (95% CI) of 0.570 (0.495-0.645), making it statistically significant in relation to the factors associated with PDA surgical ligation (Fig. 3).
The clinical factors that were shown to affect the postoperative clinical outcomes of the patients (EL versus LL) in the multivariate model are shown in Fig. 4. Clinical outcomes with associations with p < 0.1 in the univariate analyses were analyzed by multivariate logistic regression with adjustments for cesarean delivery, weight on PDA ligation and PDA diameter > 2.0 mm.After adjustments were made for confounders, EL was found to be significantly associated with a low incidence of IVH grade ≥ III (p = 0.035), culture-proven sepsis (p = 0.004), NEC stage ≥ III (p = 0.022) and time on a mechanical ventilator > 4 weeks (p = 0.007).

Discussion
In this retrospective cohort study of VLBWIs with HSPDA that is unresponsive to pharmacological treatment, there was no statistically significant difference in mortality rate between the PDA ligation and Non-ligation groups.PDA ductal diameter > 2.0 mm, low GA, low Apgar score at 5 minutes, and histologic chorioamnionitis were related to the need for surgical ligation of HSPDA.Additionally, early surgical ligation was not significantly associated with increased mortality among VLBWIs with HSPDA.
The LL group was significantly related to an increased risk of NEC (stage ≥ III), IVH (grade ≥ III), culture-proven sepsis and time on a mechanical ventilator > 4 weeks.
The role of HSPDA surgical ligation in VLBWIs is still controversial.Although surgical treatment can close HSPDA immediately, multiple postoperative comorbidities such as left recurrent laryngeal nerve injury, bleeding, chylothorax, development of coarctation and acute hemodynamic compromise, can be associated with in-hospital mortality [5].In addition, previous observational studies have demonstrated that surgical treatment is associated with an increased risk of chronic lung disease (CLD), ROP, and neurodevelopmental impairment (NDI) [5,[14][15][16][17][18][19].In contrast, a recent observational study demonstrated that there was no significant difference in NDI between the PDA ligation and Nonligation groups [9].Furthermore, another previous publication suggested that the preferred option for PDA after unsuccessful medical management should be surgical ligation to avoid prolonged low levels of cerebral saturation [20].
PDA surgical ligation is a viable option that is safe and effective [21], and it can be performed at the bedside in the NICU without transfer to the operating room [5,22].In our cohort, no infants died during their operations, and there was no statistically significant difference in mortality rate between the PDA ligation and Non-ligation groups, and between the EL and LL groups.Although this was a small retrospective study with only three infants who died and although its statistical power may be limited, this result was shown to be noninferior to those of previous publications [6,9].
In this study, histologic chorioamnionitis, which is diagnosed by histologic biopsy of the maternal placenta, showed a significant association with factors related to PDA surgical ligation.The role of infection in maintaining the patency of PDA can be considered [23].Infection may induce the production of cyclooxygenase (COX) -2 and inducible nitric oxide synthetase (iNOS), and together, they increase the production of vasodilatory prostaglandins such as COX-1 and NOS [24].The infant born from a mother with chorioamnionitis can have PDA with a persistent opening due to increased levels of vasodilatory prostaglandins and nitric oxide.In addition, clinical factors such as the PDA ductal size and signs reflected in the Apgar score should be emphasized when considering surgical intervention to improve clinical outcomes.
In VLBWIs with HSPDA, it is important to determine the optimal timing of surgical ligation [21,25].
Our results showed that the EL group was associated with lower odds of severe NEC and IVH than the LL group.This may be explained by the diastolic steal of systematic circulation through HSPDA, which can induce intestinal ischemia resulting in NEC, renal hypoperfusion, and a reduction in the blood flow rate in the middle cerebral artery [26] and increase the risk of IVH [27].In our previous publication, early surgical ligation had the benefit of reducing the incidence of NEC and improving feeding intolerance [4].The difference between this previous study and the current observational study is embodied, and there is a significant difference in severe NEC (stage ≥ III) between the EL and LL groups.
Additionally, sepsis with increased serum levels of inflammatory mediators or prostaglandins can be associated with smooth muscle relaxation of the ductus arteriosus [28].Thus, as previously mentioned, the role of infection in maintaining the patency of PDA can be considered [23].EL may reduce the duration of infection exposure and can be expected to minimize the risk of sepsis.
Prolonged patency of PDA increases pulmonary circulation that can be injurious to the capillary endothelium and stimulate an inflammatory cascade that results in pulmonary edema, CLD development, and increased ventilator support [29].EL may diminish the period of exposure to HSPDA [30], and can decrease pulmonary edema [29] and facilitate earlier endotracheal extubation [9].
This study has several limitations.First, this was a small retrospective study with only 233 patients, and a randomized and prospective trial could not be performed.Thus, the statistical power of population may be limited.Second, all operations were performed by one cardiac surgeon with a high level of experience in pediatric heart surgery.One goal of future research is to perform a large prospective multicenter study with long-term and close follow-up of VLBWIs with HSPDA that is refractory to pharmacological treatment.

Conclusions
Early surgical ligation minimizes adverse effects of HSPDA in predicted infants who subsequently require surgical treatment for PDA.We suggest that predicted VLBWIs with HSPDA that is

Figures Figure 1 Flow
Figures

Figure 2 Logistic
Figure 2 Logistic regression analysis for risk factors associated with PDA surgical ligation.OR, odds ratio; CI, confidence interval; PDA, patent ductus arteriosus.*Odds ratios were adjusted for gestational age, histologic chorioamnionitis, PIH, Apgar score at 5 minutes, and PDA ductal diameter > 2.0 mm.

Figure 3 Receiver
Figure 3 Receiver operating characteristic curve for factors associated with PDA surgical ligation.Figures represent the area under the curve (95% confidence interval).PDA, patent ductus arteriosus.

Figure 4 Postoperative
Figure 4 Postoperative clinical outcomes of the patients (early ligation versus late ligation).OR, odds ratio; CI, confidence interval; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis.Data are the mean ± SD or number (%).*Odds ratios were adjusted for cesarean delivery, weight on PDA ligation, and PDA ductal diameter > 2.0 mm.

Table 1
Protocol for NSAID treatment.

Table 2
Non-ligation group (p = 0.031).Regarding infant characteristics, gestational age (GA), birth weight, length, head circumference, and Apgar scores at 1 minute and 5 minutes were significantly lower in the PDA ligation group than in the Non-ligation group.In contrast, time on a mechanical ventilator or on oxygen therapy, total parenteral nutrition and hospitalization, and age at PDA closure were significantly higher in the PDA ligation group than in the Non-ligation group.Additionally, PDA size Characteristics of preterm infants of the PDA ligation and Non-ligation groups.in the EL group than in the LL group (p = 0.044).In contrast, culture-proven sepsis (p = 0.026), NEC stage ≥ III (p = 0.030), and time on a mechanical ventilator (p = 0.048) was significantly lower in the EL group than in the LL group.
and LL groups.The baseline maternal characteristics and preoperative status did not differ significantly between the EL and LL groups.Regarding infant characteristics, cesarean section was significantly higher

Table 3
Characteristics of preterm infants of the early ligation and late ligation groups.