Surgical Ligation of Patent Ductus Arteriosus in Extremely Low Birth Weight Premature Neonates

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1 Original Article Acta Cardiol Sin 005;1:0 4 Congenital Heart Disease Surgical Ligation of Patent Ductus Arteriosus in Extremely Low Birth Weight Premature Neonates Haw-Kwei Hwang, 1 Ming-Ren Chen, 1,4 Shye-Jao Wu, Hsin-An Kao, Chyong-Hsin Hsu, Han-Yang Hung and Shou-Hsien Hou Background: Closure of a patent ductus arteriosus (PDA) in premature neonates may be achieved through vigorous medical management alone, indomethacin administration, or surgical ligation. Indomethacin has been the initial treatment of choice for PDA in premature neonates despite reports of varying success and the risk of renal insufficiency, necrotizing enterocolitis, and intraventricular hemorrhage. Early surgical therapy has been advocated with variable results. Methods: From January of 1999 to January of 00, the charts of 57 extremely low birth weight (weighing less than 1000 g) neonates who had a PDA were retrospectively reviewed in this series. Of them, 16 were only treated with aggressive medical therapy and 7 received one to two courses of intravenous indomethacin. Surgical ligation was performed in patients in whom indomethacin therapy was contraindicated or failed. Results: The overall response rate to indomethacin alone was 70.4 per cent. No mortality was associated with the surgical procedure itself. The incidence of indomethacin-associated morbidity was comparable with that previously reported. The surgical group had higher rate of renal dysfunction than the indomethacin group because many patients in whom indomethacin was contraindicated due to renal problems received surgery. There was no difference in the post-treatment duration intubation, hospital stay, and rate of discharge on oxygen between the two groups. Conclusion: Surgical ligation of PDA might be considered early in the treatment of extremely low birth weight neonates who have either a lower probability of PDA closure with indomethacin or an increased risk of developing complications from this treatment. Key Words: PDA ligation Extremely low birth weight Indomethacin complications INTRODUCTION Delayed closure of a patent ductus arteriosus (PDA) in premature neonates may cause congestive heart failure and increase the risk of chronic lung disease in these small infants. Closure of a PDA in premature neonates may be achieved through vigorous medical management alone, indomethacin administration, or surgical ligation. Received: July 7, 004 Accepted: November 17, Divisions of Cardiology and Neonatology, Department of Pediatrics; Division of Cardiovascular Surgery, Department of Surgery, Mackay Memorial Hospital, 4 Mackay Medicine, Nursing and Management College, Taipei, Taiwan. Address correspondence and reprint requests to: Dr. Ming-Ren Chen, Department of Pediatrics, Mackay Memorial Hospital, No. 9, Sec., Chung Shan North Road, Taipei 104, Taiwan. Tel: ; Fax: ; mingren@ms.mmh.org.tw Indomethacin has been the initial treatment of choice for PDA in premature neonates despite reports of varying success and the risk of renal insufficiency, necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH). 1, Early surgical therapy has been advocated with variable results. 1,,4 Encouraging outcome of surgical ligation of PDA in very low birth weight (less than 1500 g) newborns has been reported by some authors. 5,6 In this study, we tried to answer the question, Is it still safe to ligate the PDA even in extremely low birth weight (ELBW) premature neonates (less than 1000 g)?. MATERIAL AND METHODS From January of 1999 to January of 00, the charts Acta Cardiol Sin 005;1:0 4 0

2 PDA Ligation in ELBW Premature Neonates of 57 ELBW (weighing less than 1000 g) neonates who had a PDA were retrospectively reviewed in this series. Of the 57 children, 45 were born in our hospital, 11 were referred by local obstetrician, and 1 was transferred for PDA ligation from another center. Echocardiography confirmed the diagnosis of PDA in all the 57 children (Table 1). Of them, 16 were only treated with aggressive medical therapy (supportive care including inotropic agents, fluid restriction, diuretics, blood transfusion) and 7 received one to two courses of intravenous indomethacin. The indomethacin treatment protocol in Mackay Memorial Hospital includes 0. mg/kg/dose iv q1 h for three consecutive doses in the absence of contraindications (the third dose was discontinued in some patients who developed significant oliguria after the second dose). Of the patients in whom indomethacin therapy was contraindicated or failed, surgical ligation through a posterolateral thoracotomy was carried out in OR under general endotracheal anesthesia in 1 children. One had surgical ligation at bedside. Chest drainage for 4 hours was used in the majority of the patients. All patients received a follow-up echocardiography after surgery. Statistical analyses were performed using ANOVA, chi-squared test, and Fisher s exact test. RESULTS Birth weights of the total group ranged between 56 and 996 g, with an average of 811 g. 0 infants were male and 7 were female. Overall comparison between the four groups (Table ): Of the 57 infants, 16 only received vigorous medical treatment (11 had small PDA responsive to medical treatment, 5 had large PDA but indomethacin was contraindicated). This group had the highest mortality due to underlying prematurity (68.8%) (group IV). Fourteen patients received surgery alone (indomethacin was contraindicated or there was emergency due to congestive heart failure or unstable hemodynamics). There were no operative complications such as phrenic nerve palsy or chylothorax in this group (group III). No mortality was associated with the surgical procedure itself. Table 1. Demographic data of the 57 premature neonates having PDA Patients receiving Patients receiving surgery (n = ) Patients receiving Indomethacin alone Indomethacin+Surgery Surgery alone Medical treatment alone Patient No Sex (M;F) 10; 9 ; 5 9; 5 8; 8 Mean (SD) gestational age (week) 6.4 (1.6) 5.0 (1.) 6.5 (.) 6. (.6) Mean (SD) birthweight (g) 87 (70.) 744 (10.6) 784 (145.0) 796 (160.1) Table. Clinical conditions associated with PDA in 57 premature infants weighing < 1000 g overall Indomethacin alone (n = 19) Indomethacin+surgery (n = 8) Surgery alone (n = 14) Medical treatment (n = 16) RDS >= Gr.III 11 (57.9%) (7.5%) 6 (4.9%) 6 (7.5%) Intubated 19 (100%) 8 (100%) 14 (100%) 15 (9.8%) Mean (SD) duration intubation (days) * 47.7 (5.0) 7.5 (54.0) 9 (17.) (19.8%) Mean posttreatment duration intubation (days).8 (.4) 40.8 (56.7).6 (15.) Mean hospital stay (days)# 97.0 (18.4) 16.8 (64.4) (67.8) 85.8 (1.) Discharge on oxygen* 14 (7.7%) 4 (50%) 6 (4.9%) (18.8%) NEC (10.5%) 1 (1.5%) 0 (0%) 0 (0%) Intestinal perforation 1 (5.%) 1 (1.5%) 1 (7.1%) 0 (0%) IVH >= Gr.III* (10.5%) 0 (0%) 5 (5.7%) 8 (50%) Bleeding disorder (excluding DIC) 1 (5.%) 1 (1.5%) (14.%) (18.8%) Renal dysfunction (BUN>0 or Cr>1.7)* 5 (6.%) 4 (50%) 11 (78.6%) 7 (4.8%) Sepsis (including suspect sepsis) 9 (47.4%) 5 (6.5%) 10 (71.4%) 6 (7.5%) Deaths* 0 (0%) 1 (1.5%) 4 (8.6%) 11 (68.8%) * p < 0.05; For patients extubated before discharge; # For surviving patients. 1 Acta Cardiol Sin 005;1:0 4

3 Haw-Kwei Hwang et al. Four deaths in this group were attributed to underlying prematurity (mean gestation age 6.8 weeks) and suspected sepsis. The mean duration between postoperative death and surgery was 4. days. One to two courses of intravenous indomethacin was administered in 7 infants. Treatment was successful in closing the PDA in 19 patients who comprised the indomethacin alone group (response rate 70.4%) (group I). There was no death in this group. Indomethacin treatment failed in 8 patients requiring surgical ligation of the PDA. There were no surgical complications in this group (Indomethacin + surgery group) (group II). One late death in this group occurred 69 days after surgery and was attributed to underlying meconium ileus with perforation and suspected sepsis. Overall, there was no statistically significant difference in the gestational ages and birth weights among the four groups. Comparison between indomethacin alone and surgical groups (Table ): Infants who required surgery had a significantly lower average birth weight (769 vs. 87 g; p < 0.05) when compared with the indomethacin alone group. The average birth gestational ages between the two groups were similar (6.0 vs. 6.4 wk). The mean weight and mean age at which patients received surgery were 741 g (ranged 468 to 1118 g) and 17 days (ranged 1 to 75 days), respectively. The average PDA size measured at surgery was 4.5 mm (ranged to 8 mm). After ligation, there was no significant residual PDA in any patient. The congestive heart failure was ameliorated in all surgical patients. No patients developed significant postoperative peripheral pulmonary stenosis or aortic coarctation, either. The surgical group had higher rate of renal dysfunction than the indomethacin group because many patients in whom indomethacin was contraindicated due to renal problems received surgery. DISCUSSION Continuing experience with the use of indomethacin revealed a significant incidence of complications and identified a subgroup of low birth weight neonates less likely to respond to medical therapy. 1,,7 In this series, response rate to indomethacin therapy alone was 70.4 per cent, which correlates with previously reported results.,8 The incidence of indomethacin-associated morbidity (NEC: 10.5%, IVH Gr.III: 10.5%, renal dysfunction: 6.%) was comparable with that previously reported. 9,10 At first, we divided our patients into four groups according to different treatment strategies and analyzed the overall differences. In order to focus on whether earlier PDA ligation for ELBW infants might result in better outcome than indomethacin, we also excluded patients in the medical treatment group and compared only the indomethacin alone group to the patients who ever received surgery (group II + III). Although there were 8 patients in this summation group who had received prior indomethacin, it was obvious that it Table. Clinical conditions associated with PDA in premature infants weighing < 1000 g (indomethacin alone group vs. surgical group) Patients receiving Patients receiving surgery (n = ) Indomethacin alone (n = 19) (with or without prior indomethacin) RDS>=Gr.III 11(57.9%) 9(40.9%) Intubated 19 (100%) (100%) Mean (SD) duration intubation (days) 47.7 (5.0) 5.9 (40.7) Mean posttreatment duration intubation (days).8 (.4) 6. (8.) Mean hospital stay (days)# 97.0 (18.4) 16. (65.1) Discharge on oxygen 14 (7.7%) 10 (45.5%) NEC (10.5%) 1 (4.5%) Intestinal perforation 1 (5.%) (9.1%) IVH > = Gr.III (10.5%) 5 (.7%) Bleeding disorder (excluding DIC) 1 (5.%) (1.6%) Renal dysfunction (BUN > 0 or Cr > 1.7)* 5 (6.%) 15 (68.%) Sepsis (including suspect sepsis) 9 (47.4%) 15 (68.%) Deaths* 0 (0%) 5 (.7%) * p < 0.05; For patients extubated before discharge; # For surviving patients. Acta Cardiol Sin 005;1:0 4

4 PDA Ligation in ELBW Premature Neonates was surgery that contributed to these patients recovery from cardiac failure. The duration between the last indomethacin dose and surgery was about 1 to days, which was too short to account for any statistically significant differences in duration intubation or hospital stay. Our results showed that surgical ligation of PDA in ELBW neonates was not associated with significant morbidity or mortality. There was no difference in the post-treatment duration intubation, hospital stay, and rate of discharge on oxygen between indomethacin alone and surgical groups (Table ), suggesting that both treatment strategies could lead to similar short-term clinical outcome. There were more deaths in the surgical group than the indomethacin alone group because patients in the surgical group had a more complicated clinical course. No mortality was associated with the surgical procedure itself. Although the surgical group (group II + III) had higher rate of renal dysfunction than the indomethacin alone group, the renal dysfunction happened before surgery and was not considered as a postoperative complication. In fact, many patients in this group received surgery because indomethacin was contraindicated due to renal problems, which could be due to underlying prematurity. As shown in Table, surgical patients seemed to have a higher percentage of sepsis than the indomethacin group patients. However, it did not reach statistical significance. No sepsis was directly attributed to the surgical procedure itself, either. Overall, there was a significant difference in the total intubation times among the four groups. However, the total intubation time was similar when comparing only the indomethacin alone and surgical groups. That was because patients in the medical group were in two extremes; some expired soon due to underlying prematurity, whereas others improved smoothly; in both conditions the intubation time shortened. This also explained the overall difference in the rates of discharge on oxygen. The limitations of this study include that it was conducted retrospectively by reviewing the charts of the patients and that treatment options were not randomly decided but followed a traditional stepwise approach. Therefore, there were patients who received indomethacin treatment as well as subsequent surgical ligation for their PDA. Distinct comparison between these two treatment strategies might be difficult. A double-blind prospective study of adequate sample size in the future is more preferable. Nevertheless, group I and group III patients still had similar short-term outcome in terms of duration intubation, post-treatment duration intubation, hospital stay, and rate of discharge on oxygen, if group II patients were to be excluded from this study. Although our results did not show better short-term outcome in terms of post-treatment duration intubation, hospital stay, and rate of discharge on oxygen in operated patients when compared with those treated solely with indomethacin, PDA ligation was still a safe procedure, even in ELBW neonates. It carried a high success rate and was not associated with significant complications. Without the hazard of indomethacin-associated morbidity, surgical ligation might be considered early in the treatment of ELBW neonates who have either a lower probability of PDA closure with indomethacin or an increased risk of developing complications from this treatment. REFERENCES 1. Palder SB, Schwartz MZ, Tyson KR, et al. Association of closure of patent ductus arteriosus and development of necrotizing enterocolitis. J Pediatr Surg 1988;:4-.. Hammerman C, Strates E, Komar K, et al. Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant. Dev Pharmacol Ther 1987;10: Grosfeld JL, Chaet M, Molinari F, et al. Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Ann Surg 1996;4: Cotton RB, Stahlman MT, Bender HW, et al. Randomized trial of early closure of symptomatic patent ductus arteriosus in small preterm infants. J Pediatr 1978;9: Perez CA, Bustorff-Silva JM, Villasenor E, et al. Surgical ligation of patent ductus arteriosus in very low birth weight infants: Is it safe? Am Surg 1998;64(10): Ghosh PK, Lubliner J, Mogilnar M, et al. Ligation of patent ductus arteriosus in very low birthweight premature neonates. Thorax 1985;40: Neu J, Ariagno RL, Johnson JD, et al. A double blind study of the effects of oral indomethacin in preterm infants with patent ductus arteriosus who failed medical management. Pediatr Pharmacol (New York) 1981;1: Trus T, Winthrop AL, Pipe S, et al. Optimal management of patent ductus arteriosus in the neonate weighing less than 800 g. J Pediatr Surg 199;8: Harris JP, Merritt TA, Alexson CG, et al. Parenteral indomethacin for closure of the patent ductus arteriosus: clinical experience with 67 preterm infants. Am J Dis Child 198;16: Mavroudis C, Backer CL, Gevitz M. Forty-six years of patent ductus arteriosus division at Children s Memorial Hospital of Chicago: standards for comparison. Ann Surg 1994;0:40-9. Acta Cardiol Sin 005;1:0 4

5 Original Article Acta Cardiol Sin 005;1:0 4 極度低體重早產兒的開放性動脈導管關閉手術 1 黃浩魁 1,4 陳銘仁 吳協兆 高信安 許瓊心 洪漢陽 侯守賢 台北市馬偕紀念醫院兒科部小兒心臟科 1 新生兒科 外科部心臟外科 台北市馬偕醫護管理專科學校 4 背景對於早產兒的開放性動脈導管可以經由積極的抗鬱血性療法, 給予 indomethacin, 或是外科手術來關閉 長久以來, 雖然可能造成腎功能不良 壞死性腸炎, 以及腦室內出血等併發症,indomethacin 一直是早產兒開放性動脈導管治療的首選藥物 歷年文獻關於 indomethacin 的使用成效, 報告有所差異, 因此部分學者提出了早期手術關閉的主張 方法針對本院 1999 年 1 月至 00 年 1 月間 57 位存有開放性動脈導管的極度低體重早產兒 ( 出生體重 1000 公克以下 ) 進行回溯性的研究 其中 16 位僅接受積極的抗鬱血性療法, 另外 7 位分別給予 1 到 個 indomethacin 療程, 有 位病人因為對 indomethacin 有使用禁忌或 indomethacin 治療失敗, 接受了外科關閉手術 結果對於 indomethacin 治療的反應率為 70.4%, 沒有與手術本身相關的死亡個案 與 indomethacin 使用相關的不良障害發生率與文獻報告接近 相較於 indomethacin 使用組, 手術接受組之腎功能不良比例較高, 因為這些病人就是由於腎功能不良才無法給予 indomethacin 而接受手術關閉 在治療後的插管天數 住院日數 及出院時仍需要氧氣的比例方面,indomethacin 使用組與手術接受組並沒有統計學上的差異 結論對於處理極度低體重早產兒的開放性動脈導管, 若事先考慮到 indomethacin 治療可能無效或是可能導致嚴重不良障害者, 早期外科關閉手術不失為另一個良好的選擇 關鍵詞 : 動脈導管關閉手術 極度低體重早產兒 indomethacin 併發症 4