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Patent ductus arteriosus ligation in premature infants: who really benefits, and at what cost?
Journal of Pediatric Surgery (2007) 42, 69 – 75
www.elsevier.com/locate/jpedsurg
Patent ductus arteriosus ligation in premature infants: who really benefits, and at what cost?B Mehul V. Ravala, Matthew M. Laughonb, Carl L. Boseb, J. Duncan Phillipsa,* a
Division of Pediatric Surgery, Department of Surgery, University of North Carolina at Chapel Hill, NC 27599-7223, USA Division of Neonatal/Perinatal Medicine, Department of Pediatrics, University of North Carolina at Chapel Hill, NC 27599-7223, USA b
Index words: Patent ductus arteriosus; Patent ductus arteriosus ligation; Prematurity; Chronic lung disease
Abstract Purpose: Patent ductus arteriosus (PDA) ligation in premature infants has been shown to have low surgical morbidity and mortality. Ligation goals include prompt improvement in cardiorespiratory failure, with rapid wean from mechanical ventilation; less risk of prolonged mechanical ventilation and subsequent chronic lung disease (CLD); and survival to discharge. This study was designed to examine true morbidity after ligation and elucidate which preoperative factors might predict favorable outcomes. Methods: Institutional review board–approved retrospective review of 197 infants less than 38 weeks of gestational age (GA), undergoing PDA ligation via thoracotomy between January 1, 1992, and January 1, 2004. Chronic lung disease defined as need for supplemental oxygen at 36 weeks corrected GA. Student t and v 2 tests were used. Results: Mean GA was 27 weeks (range, 23-35 weeks), birth weight was 957 g (range, 440-3170 g); infants underwent ligation at 16 days of life (range, 1-132 days). Duration of surgery was 50.5 minutes (range,13-150 minutes). Mean postoperative times were 27 days to extubation, 60 days to wean from supplemental oxygen, and 84 days to discharge. Early extubation (within 10 days of ligation) occurred in only 54 patients (30%). Only 44 (22%) survived to discharge without CLD. Forty patients (20%) died, with respiratory failure the most common cause (70%). In general, early extubation, survival without CLD and survival to discharge were associated with greater GA and birth weight, higher Apgar scores, greater age and weight at surgery, no preoperative intraventricular hemorrhage, lack of ventilator dependence, and lower ventilator settings ( P b .05). Preoperative amount and duration of indomethacin use, chest x-ray findings, and echocardiographic assessment of ductus size did not predict favorable outcomes (all P N .05). Conclusions: Most premature infants currently undergoing PDA ligation at our institution do not experience the anticipated rapid improvements in cardiorespiratory status and go on to develop CLD. Few preoperative variables (including radiographic and echocardiographic assessments) definitively predict outcomes. D 2007 Elsevier Inc. All rights reserved.
Presented at the 37th Annual Meeting of the American Pediatric Surgical Association, May 20 –24, 2006, Hilton Head, SC. B This study was supported, in part, by a grant (RR00046) from the General Clinical Research Centers program of the Division of Research Resources, National Institutes of Health (University of North Carolina GCRC # 2114) and the Doris Duke Charitable Foundation Medical Research Program. * Corresponding author. Tel.: +1 919 966 4643; fax: +1 919 843 2497. E-mail address: [email protected] (J.D. Phillips). 0022-3468/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2006.09.040
70 Delayed closure of the ductus arteriosus in premature infants has been associated with a variety of morbidities, including pulmonary vascular overload, congestive heart failure, prolonged ventilator dependence, chronic lung disease (CLD), necrotizing enterocolitis, and ultimately, mortality [1,2]. Surgical ligation of PDA is considered standard treatment for symptomatic infants who do not respond to treatment with indomethacin. Since the first reported PDA ligation by Gross in 1938, numerous studies have shown PDA ligation to be both technically feasible and safe, even in premature, low-birth-weight infants [3-8]. It has been felt that PDA ligation benefits critically ill preterm neonates by decreasing pulmonary vascular overload, with a subsequent decreased need for pharmacologic pressor support, mechanical ventilation, and supplemental oxygen. It has been well-documented, however, that some infants who undergo PDA ligation do not demonstrate the expected dramatic improvement in cardiorespiratory status and require prolonged mechanical ventilation, develop CLD, or die before hospital discharge [9]. Chronic lung disease is associated with especially poor long-term outcomes [10]. When considering PDA ligation, the clinician would hope to predict which infants would indeed benefit from the procedure in order to best manage patients, inform parents, and assess risk. The aim of this study was to assess true morbidity and mortality risks in these patients and elucidate which preoperative factors might predict favorable outcomes.
M.V. Raval et al. improvement in cardiorespiratory status would occur if PDA ligation were performed), most consistent with newborn respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (implying, radiographically, no significant improvement in cardiorespiratory status would occur if PDA ligation were performed), or others. Preoperative echocardiograms were reviewed by pediatric cardiologists. Data collected included ductus size, direction of flow, and presence of associated intracardiac shunts. Size was graded as small, medium, or large [12]. Surfactant use, as well as number of indomethacin doses, actual indomethacin dosage per weight, and number of courses of indomethacin (with 3 doses = 1 course) were collected [13]. Outcomes collected included survival of surgery (defined as 30 days postoperatively), days to extubation, wean from all supplemental oxygen, postoperative complications, survival to discharge, and cause of death (if applicable). Chronic lung disease was defined as being mechanically ventilated or requiring supplemental oxygen at corrected GA of 36 weeks [14-16]. Student t test and v 2 tests were used to provide descriptive univariate analysis.
2. Results 2.1. General demographics Demographic data are presented in Table 1.
1. Methods
2.2. Preoperative variables
Medical records of all newborns in the neonatal intensive care unit (NICU) at the North Carolina Children’s Hospital, a tertiary pediatric referral center, who underwent PDA ligation between January 1, 1992, and January 1, 2004 (144 months) were reviewed. Record review was approved by the University of North Carolina (UNC) Institutional Review Board and the UNC General Clinical Research Center. Using hospital records and a patient database managed by the NICU, 273 infants were identified. Of these, 34 (12%) were excluded for gestational age (GA) greater than or equal to 38 weeks. Forty-two patients (15%) were excluded because they were born with complex cyanotic congenital cardiac disease, and the PDA ligations were performed in conjunction with more complex repairs by the cardiothoracic surgery service. The remaining 197 (73%) underwent ligation by fellowship-trained pediatric general surgeons via standard muscle-sparing left posterolateral thoracotomies [11] with double-clip technique [4]. No thoracoscopic procedures were included in this review. Surgical procedures were typically performed in the operating room. If patients were deemed unstable for transport by the operating surgeon, PDA ligations were done in the NICU. Preoperative chest x-rays were reviewed by pediatric radiologists and interpreted as most consistent with pulmonary vascular overload (implying, radiographically, an
2.2.1. Patent ductus arteriosus diagnosis/assessment One hundred eighty-five patients had preoperative echocardiograph data available for review. Fifty-nine (32%) were described as having a small ductus, 48 (26%) Table 1
Demographic data % (n = 197)
Sex Male Female
58% (114) 42% (83)
Race Black White Other Maternal age (y) Gestational age (wk) Birth weight (g) Very low birth weight Surfactant at birth
52% 37% 11% 25 27 955 71% 86%
Location of birth UNC Not at UNC
64% (126) 36% (71)
Range
(102) (74) (21) 14-39 23-35 440-3170 (140) (170)
Very low birth weight is defined as weight less than 1000 g.
Patent ductus arteriosus ligation in premature infants Table 2
Postoperative complications Incidence (n)
Survived surgery NEC/intestinal perforation IVH Wound infection Wound dehiscence Chylothorax Pleural effusion Clinical vocal cord paralysis/paresis Postoperative pneumonia a b
83% 17% 32% 1% 0% b1% 2% 3% 6%
(164) (33)a (63)b (2) (0) (1) (4) (6) (11)
Thirty cases of NEC/perforation were present preoperatively. Fifty-nine cases of IVH were present preoperatively.
moderate, and 67 (36%) large. Eleven (6%) of the patients did not have a patent ductus arteriosus visualized on the echocardiogram performed immediately before surgery. Of the 185 infants with preoperative echocardiograph findings available for review, 134 (72%) had an associated atrial septal defect/patent foramen ovale, and 12 (7%) had a small ventricular septal defect. 2.2.2. Cardiorespiratory failure diagnosis/assessment Immediately preoperative mean heart rate was 167 beats per minute (range, 110-215 beats per minute) and mean systolic blood pressure was 55 mm Hg (range, 30-110 mm Hg). Preoperative pressor support with dopamine or dobutamine was noted in 121 patients (61%) and 59 patients (30%), respectively. Mean maximal preoperative infusion rates were 7.2 lg/kg per minute (dopamine) and 3.9 lg/kg per minute (dobutamine). Mean preoperative arterial blood gas measures included pH of 7.34 (range, 7.08-7.66), Pco2 of 48.43 (range, 18-86), and Po2 of 72.64 (range, 26-467). Twenty-one of the 197 patients (11%) were not receiving mechanical ventilation just before surgery. The mean preoperative Fio2 for the entire cohort was 0.52 (range, 0.21-1) with a mean of 8.2 days (range, 0-91 days) spent with a Fio2 greater then 0.50. Mean ventilator rate was 21 breaths per minute (range, 0-80). Mean inspiratory time (IT) was 0.29 seconds (range, 0-0.65). Mean airway pressure (MAP) was 6.9 mm Hg (range, 0-17). Peak inspiratory pressure was 19 mm Hg (range, 0-44). Mean tidal volume was 1.1 L (range, 0-2.9). One hundred ninety-two patients had preoperative chest x-rays performed and interpreted at our institution. Five patients had preoperative chest x-rays performed and interpreted only at outside institutions. Eighty seven (45%) were felt to be most consistent with pulmonary Table 3
71 vascular overload, 74 (38%) were felt to be most consistent with newborn RDS or bronchopulmonary dysplasia, and 31 (16%) were felt to have other findings. Other findings included bilateral diffuse parenchymal disease (8% [15]), clear bilateral lung fields/no pathology (4% [7]), pulmonary interstitial emphysema (2% [3]), atelectasis (2% [3]), pneumonia (b1% [1]), pulmonary hemorrhage (b1% [1]), and pneumothorax (b1% [1]). 2.2.3. Preoperative PDA medical management Mean number of preoperative indomethacin doses was 4 (range, 0-15), mean indomethacin courses was 1.4 (range 0 to 11), and mean actual dosage was 0.7 mg/kg (range, 0-4.98 mg/kg). Eighty (41%) patients received at least 6 doses (2 courses of 3 doses each). Preoperative necrotizing enterocolitis (NEC)/intestinal perforation was noted in 30 (15%) of patients, oliguria in 30 (15%), and/or intraventricular hemorrhage (IVH) in 59 (30%).
2.3. Operative management Infants underwent ligation at mean 16 days of life (range, 1-132 days). Mean weight at the time of surgery was 1018 g (range, 430-3235g) with mean increase in weight from birth of 98 g (range, 265 to 1755g) or 6.8% of body weight (range, 25% to 70%). Ligations were performed in either the NICU (9% [18]) or operating room (91% [179]). Mean duration of surgery was 50.5 minutes (13-150 minutes), and mean estimated blood loss was 4.4 mL (0-150 mL). Post/ perioperative chest tubes were placed in 28 (14%) of patients.
2.4. Postoperative outcomes Postoperative outcomes, including survival of surgery (defined as survival to postoperative day 30), are shown in Table 2. No deaths were directly attributable to the surgical procedure itself. Causes of death for patients who did not survive to discharge are listed in Table 3. Outcomes, including days to extubation, days to begin enteral feedings, days to wean from all supplemental oxygen, and length of stay are shown in Table 4.
2.5. Outcomes of interest Patients appeared to either experience the anticipated rapid improvement in cardiorespiratory status and quickly wean from supplemental oxygen (and extubate early postsurgical ligation) or require long-term intubation with gradual improvement in pulmonary function (see Figs. 1 and 2). We Table 4
Cause of death
Cause of death
% (n = 40)
Pulmonary failure Sepsis Renal failure Liver failure
70% 20% 7.5% 2.5%
(28) (8) (3) (1)
Clinically significant postoperative outcomes Mean days (range)
Days to extubation Days to wean from O2 Days to feeds Length of stay
27 60 12 84
(0-181) (0-376) (0-68) (5-247)
72
M.V. Raval et al.
Fig. 1
Days to extubation.
defined 3 distinct favorable outcome groups: (1) early extubation within 10 days of ligation (54 patients [30%]); (2) survival to discharge and no CLD (44 patients [22%]); and (3) survival to discharge (157 patients [80%]). Defining bearly extubatorsQ as being those who were extubated by postoperative day 10 was a decision made by the authors after analyzing the data (Fig. 1) and attempting to avoid including the morbidity typically attributable to the thoracotomy itself (pain, bthird spacingQ of fluids, and alterations in respiratory mechanics for 7-10 postoperative days). In addition, it was hoped to avoid including the typical period of bcardiac decompensationQ seen in over 25% of patients following this procedure [17]. For each outcome, the preoperative factors outlined above were analyzed to determine associations. 2.5.1. Early extubation Sixteen patients were transferred postoperatively to outside institutions while still intubated. One hundred
Fig. 2
eighty-one had adequate in-house follow up to determine date of extubation. Of the 181 patients, 54 (30%) met the criteria for early extubation (see Table 5 for selected results). Early extubation was associated with greater GA, higher body weight (BW), higher 1-minute Apgar scores, higher systolic blood pressure at surgery, no preoperative IVH, not receiving surfactant, being extubated before surgery, or having lower Fio2 dependence at the time of surgery. Furthermore, higher weight at surgery and being older at the time of surgery were associated with early extubation. Factors that did not influence early extubation include sex; race; maternal age; birth at UNC; 5-minute Apgar scores; signs of PDA, including audible murmur, bounding/palmar pulses, active precordium, and/or wide pulse pressures; preoperative chest x-ray findings; echocardiogram findings; amount/duration of indomethacin and/or dopamine/dobutamine use; ventilator settings at time of surgery, including rate, IT, and MAP; heart rate at time of surgery; preoperative
Days to wean from supplemental oxygen.
Patent ductus arteriosus ligation in premature infants Table 5
73
Early extubation Early extubation (181)a
GA (wk) BW (g) % With surfactant Dopamine rate (lg /kg per minute) Apgar scores 1 min 5 min Weight at surgery (g) Systolic BP at surgery (mm Hg) Fio2 at surgery Number days with Fio2 N 0.5 Age at surgery (d) Ligation in OR % With IVH % Intubated at surgery
Yes (30%) (54)
No (70%) (127)
P
28.6 1233 78% 5.7
(23-35) (500-3170) (42) (0-20)
26.4 839 89% 7.8
(23-37) (440-2080) (113) (0-30)
b.01 b.01 .05 .07
5.2 6.8 1370 60.4 0.38 9.5 21 96% 20% 65%
(0-9) (0-9) (520-3235) (40-110) (0.21-1) (0-91) (2-132) (52) (11) (35)
4.4 6.8 873 53.6 0.58 8.0 15 89% 36% 95%
(0-9) (1-9) (430-2610) (30-90) (0.21-1) (0-45) (1-59) (113) (46) (121)
.05 .81 b.01 b.01 b.01 .47 .02 .11 .03 b.01
Values expressed as means, with (range), as appropriate. Statistically significant figures are rendered in boldface. a Date of extubation unknown on 16 patients.
NEC; preoperative oliguria; intraoperative blood loss; chest tube placement; duration of surgery; and location of ligation (all P N .05). 2.5.2. Survival to discharge and no CLD Chronic lung disease has been associated with significant long-term morbidity. Forty four patients (22%) survived to discharge without CLD. Having higher BW, higher 1minute Apgar scores, lower maximal dopamine rates, and having lower Fio2 (for those intubated at the time of surgery) were associated with survival to discharge without CLD. Furthermore, having few days with Fio2 greater than 0.5 and being older at the time of surgery were associated with survival to discharge without CLD. Factors that did not influence survival to discharge without CLD included GA; sex; race; maternal age; birth at UNC; 5-minute Apgar scores; signs of PDA including audible murmur, bounding/ palmar pulses, active precordium, and/or wide pulse pressures; preoperative chest x-ray findings; echocardiogram findings; surfactant use; amount/duration of indomethacin and/or dobutamine use; ventilator dependence at time of surgery; ventilatory settings including rate, IT, and MAP; heart rate and systolic blood pressure at time of surgery; preoperative NEC; IVH and/or oliguria; intraTable 6
b
2.5.3. Survival to discharge One hundred fifty-seven patients (80%) survived to discharge. Having greater GA, being extubated before surgery, or having lower Fio2 dependence at the time of surgery were associated with survival to discharge. Furthermore, higher weight at surgery and having ligation in the operating room as opposed to the NICU were associated with survival to discharge. Factors that did not influence survival to discharge include BW; sex; race; maternal age; birth at UNC; Apgar scores at 1 or 5 minutes; signs of PDA including audible murmur, bounding/palmar pulses, active precordium, and/or wide pulse pressures; reoperative chest x-ray findings; echocardiogram findings; surfactant use; amount/duration of indomethacin and/or dopamine/dobutamine use; heart rate or systolic blood pressure at time of surgery; preoperative NEC; preoperative oliguria; intraoperative blood loss; chest tube placement; or duration of surgery (all P N .05).
2.6. Echocardiographic data Echocardiograph data for each of the 3 major outcome groups are outlined in Table 6. All ductal flows were
Echocardiograph data
PDA size Small (n = 59) Medium ( n = 48) Large (n = 67) None (n = 11) Total (n = 185)a a
operative blood loss; chest tube placement; duration of surgery; and location of ligation (all P N .05).
Early extubation ( P = .24)
Survived without CLD ( P = .01)
Survived to discharge ( P = .07)
Yes 19 8 19 2 48b
Yes 19 4 18 1 42
Yes 51 37 56 6 150
No 38 39 40 6 123b
No 40 44 49 10 143
No 8 11 11 5 35
Twelve Patients missing preoperative echocardiography data. Early extubation patient include an additional 14 patients missing extubation data secondary to transfer to outside hospitals while intubated (total = 171).
74 documented as being left to right. The sole statistically significant group was a poor outcome associated with infants who survived with no CLD who were determined to have a medium-sized PDA. The significance of this is unclear because both small and large PDAs (on echocardiography) showed similar rates of favorable outcome in this same cohort (19/59 and 18/67, respectively).
2.7. Gestational age and birth weight Although only 1 (33%) of 3 of infants weighing less than 500 grams survived and 4 (57%) of 7 of infants born at less than 24 weeks of GA survived, we were unable to demonstrate any babsolute cutoffQ for either variable below which outcomes were uniformly poor. Infants with birth weights of at least 500 grams and GAs of at least 24 weeks had survival rates essentially identical to their larger (and older) counterparts.
3. Discussion It is generally accepted that, in order to minimize the deleterious effects of PDA in premature infants, prompt ductal closure is desirable [18]. Since the late 1970s, fluid restriction and indomethacin have been first-line therapy, with limited exceptions [19]. Surgical ligation has typically been reserved for those infants failing indomethacin or with contraindications to its use. Ligation procedures have been associated with low morbidity and almost certain success from a technical standpoint. Delaying surgical ligation may increase the likelihood of developing morbidity and/or mortality [8,16]. In this study, the incidence of morbidities putatively associated with PDA (CLD, NEC, etc) were high. These patients had an incidence of CLD of 61%, a long duration of hospitalization, prolonged mechanical ventilation, and an inhospital mortality rate of 20%. It is apparent that when consulting with families preoperatively, it should be made clear that a surgical intervention in these patients does not guarantee favorable outcome. Significant morbidity in this series may be secondary to a combination of factors. First, neonatal cardiorespiratory failure may be secondary to RDS and pulmonary immaturity, rather than pulmonary vascular overload. In this case, PDA ligation would be expected to provide little postoperative benefit. Second, the surgical intervention itself, with thoracotomy and spreading of the ribs, may contribute to postoperative ventilator dependence. Left lung compression during ligation may cause intrapulmonary hemorrhage and/or prolonged atelectasis. It is well known that adult thoracotomy patients may experience prolonged postoperative pain, with its associated risk of poor respiratory effort. Third, only postsurgical patients were included in this review, and almost all had either failed multiple attempts at indomethacin closure or had contraindications to further preoperative indomethacin use. One could argue that the bsurgical patientsQ were thus
M.V. Raval et al. preselected to have poor outcomes. Indeed, the baverageQ preoperative patient was small (955 grams), premature (27 weeks GA), receiving dopamine (at 7.2 lg/kg per minute), intubated on mechanical ventilation, and on Fio2 greater than 0.50 for over eight days. Candidates for PDA ligation are usually evaluated with a variety of tests, including chest x-ray and echocardiography. These tests are thought to provide an objective measure of the impact a PDA is having on the infant. Specifically, those infants who are typically felt to have the greatest potential benefit from the operation (those with large PDAs on echocardiography, with chest x-ray evidence of pulmonary vascular overload, on pressor support with dopamine and/or dobutamine) were no more likely to extubate quickly than infants without those presumed bobjectiveQ measures of PDA significance. This study suggests that both chest radiographs and PDA size, as measured by echocardiogram, have limited predictive value in determining which infants will benefit from ligation. In this group of preterm infants who underwent PDA ligation, there were few, if any, reliable clinical predictors of a favorable outcome. Infants who were early extubators and/ or who survived without CLD were larger, had a greater GA, and were typically older at the time of surgery. In addition, these patients were receiving less ventilatory support as evidenced by lower Fio2 and fewer days with Fio2 greater than 0.5. These patients were, essentially, not as clinically bunstableQ as those who did not have favorable outcomes. However, there were no absolute bcutoffsQ in terms of variables below or above which all patients had unfavorable outcomes. This data suggests that there are no absolute contraindications to attempting PDA ligation to benefit the patient regardless of how small, how premature, and how unstable the premature infant is preoperatively. Because only postsurgical patients were included in this study, one cannot determine what would have happened to the patients if they had not undergone surgery. That is, continued nonoperative treatment might have resulted in much higher morbidity, with slower wean from mechanical ventilation, even more CLD, and even greater inhospital mortality. Indeed, in a recently reported series from a neonatal center without ready access to a pediatric surgeon (the closest surgical group was located over 2000 miles away), 98 premature infants with PDAs were studied [20]. Of the 33 patients with PDAs that did not close after 2 courses of indomethacin, 11 patients (33%) died, compared to 7 of 65 patients (11%) whose PDAs closed with indomethacin treatment. After adjustment for slightly different GAs, the relative risk of death (without surgical ligation) was 4.02. Another report examined the outcomes of 1134 extremely low-birth-weight infants in Canada, Australia, and the United States in the Trial of Indomethacin Prophylaxis in Preterms [21]. Of the 426 infants with PDAs, the death rate in the group with persistent PDAs that did not undergo surgery was 22% (71/316) vs only 14% (15/110) in those who underwent surgical closure ( P b .05). A prospective, randomized trial
Patent ductus arteriosus ligation in premature infants comparing PDA ligation to continued nonoperative treatment may be of benefit. In conclusion, this study demonstrates that morbidities associated with PDA in preterm infants are high, even after PDA ligation, and that there are few factors clearly associated with favorable outcomes.
References [1] 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;93(4):647 - 51. [2] Kitterman JA, Edmunds Jr LH, Gregory GA, et al. Patent ductus arteriosus in premature infants. Incidence, relation to pulmonary disease and management. N Engl J Med 1972;287(10):473 - 7. [3] Mikhail M, Lee W, Toews W, et al. Surgical and medical experience with 734 premature infants with patent ductus arteriosus. J Thorac Cardiovasc Surg 1982;83(3):349 - 57. [4] 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 1993;28:1137 - 9. [5] 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):1007 - 9. [6] Niinikoski J, Alanen M, Parvinen T, et al. Surgical closure of patent ductus arteriosus in very-low-birth-weight infants. Pediatr Surg Int 2001;17:338 - 41 [7] Malviya M, Ohlsson A, Shah S. Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants. Cochrane Database Syst 2003;Rev(3):CD003951. [8] Little DC, Pratt TC, Blalock SE, et al. Patent ductus arteriosus in micropreemies and full-term infants: the relative merits of surgical ligation versus indomethacin treatment. J Pediatr Surg 2003;38(3):492 - 6. [9] Palder SB, Schwartz MZ, Tyson KR, et al. Management of patent ductus arteriosus: a comparison of operative vs pharmacologic treatment. J Pediatr Surg 1983;18:835 - 41. [10] Yeo CL, Choo S, Ho LY. Chronic lung disease in very low birthweight infants: a 5-year review. J Paediatr Child Health 1997;33(2):102 - 6. [11] Soucy P, Bass J, Evans M. The muscle-sparing thoracotomy in infants and children. J Pediatr Surg 1991;26(11):1323 - 5. [12] Hines MH, Raines KH, Payne RM, et al. Video-assisted ductal ligation in premature infants. Ann Thorac Surg 2003;76:1417 - 20. [13] Quinn D, Cooper B, Clyman RI. Factors associated with permanent closure of the ductus arteriosus: a role for prolonged indomethacin therapy. Pediatrics 2002;110(1 Pt 1):e10 - 1. [14] Marshall DD, Kotelchuck M, Young TE. Risk factors for chronic lung disease in the surfactant era: a North Carolina population-based study of very low birth weight infants. Pediatrics 1999;104(6):1345 - 50. [15] Shennan AT, Dunn MS, Ohlsson A, et al. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527 - 32. [16] Truog WE, Jackson C, Badura RJ, et al. Bronchopulmonary dysplasia and pulmonary insufficiency of prematurity: lack of correlation of outcome with gas exchange abnormalities at 1 month of age. Am J Dis Child 1985;139:351 - 4 [17] Harting MT, Lally KP, Cox Jr CS, et al. Cardiac decompensation after patent ductus arteriosus ligation in premature infants. Presented at the annual meeting of the Section on Surgery of the American Academy of Pediatrics, San Francisco, CA, 2004. [18] Cassady G, Crouse DT, Kirklin JW, et al. A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N Engl J Med 1989;320:1511 - 6
75 [19] Gersony WM, Peckham GJ, Ellison RC, et al. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr 1983;102:895 - 906 [20] Brooks JM, Travadi JN, Patole SK, et al. Is surgical ligation of patent ductus arteriosus necessary? The Western Australia experience of conservative management. Arch Dis Child Fetal Neonatal Ed 2005;90(3):F235 - 9 [21] Kabra N, Schmidt B, Roberts R, et al. Surgical closure of a patent ductus arteriosus (PDA) is associated with increased neurosensory impairment in extremely low birth weight (ELBW) infants. Presented at the annual meeting of the Pediatric Academic Societies, Washington, DC;2005.
Discussion Dr Caniano, MD (Columbus, OH): A very nice study. I have one question about the timing of the ductal ligation. It was my understanding from the Vermont Oxford data that the neonatologist should consult early and that the procedure should be done within the first few days after recognition of the ductal problem. Did you find that the earlier the procedure was done, you had a better outcome versus your average at 16 days of age? Dr Raval, MD (Chapel Hill, NC) (response): The standard in our NICU is that pediatric surgery is consulted early. The data showed that the older the child was and the more days that had passed since birth, the better they did. It is an issue where you have to weigh the costs and benefits and see how the individual patient is doing. We typically followed the standard 2 courses of indomethacin, which took approximately 2 or 3 days to complete before undergoing the ligation. Dr Kosloske, MD (Sanibel, FL): You just answered the first part of my question. I think what you said just now is that all 197 patients were indomethacin failures? Dr Raval, MD (Chapel Hill, NC) (response): Either they were indomethacin failures or they had a contraindication to indomethacin such as preoperative intraventricular hemorrhage. Dr Kosloske, MD (Sanibel, FL): Well then perhaps ligation of the ductus—perhaps the surgical procedure has nothing to do with the outcome because you have selected for surgery a group of patients that would have a bad outcome anyway. Dr Raval, MD (Chapel Hill, NC) (response): That is true. Dr Kosloske, MD (Sanibel, FL): And the only way you could have comparable groups would be to do early ligation rather than indomethacin and compare groups from the start. Thank you.
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Patent ductus arteriosus ligation in premature infants: who really benefits, and at what cost?B Mehul V. Ravala, Matthew M. Laughonb, Carl L. Boseb, J. Duncan Phillipsa,* a
Division of Pediatric Surgery, Department of Surgery, University of North Carolina at Chapel Hill, NC 27599-7223, USA Division of Neonatal/Perinatal Medicine, Department of Pediatrics, University of North Carolina at Chapel Hill, NC 27599-7223, USA b
Index words: Patent ductus arteriosus; Patent ductus arteriosus ligation; Prematurity; Chronic lung disease
Abstract Purpose: Patent ductus arteriosus (PDA) ligation in premature infants has been shown to have low surgical morbidity and mortality. Ligation goals include prompt improvement in cardiorespiratory failure, with rapid wean from mechanical ventilation; less risk of prolonged mechanical ventilation and subsequent chronic lung disease (CLD); and survival to discharge. This study was designed to examine true morbidity after ligation and elucidate which preoperative factors might predict favorable outcomes. Methods: Institutional review board–approved retrospective review of 197 infants less than 38 weeks of gestational age (GA), undergoing PDA ligation via thoracotomy between January 1, 1992, and January 1, 2004. Chronic lung disease defined as need for supplemental oxygen at 36 weeks corrected GA. Student t and v 2 tests were used. Results: Mean GA was 27 weeks (range, 23-35 weeks), birth weight was 957 g (range, 440-3170 g); infants underwent ligation at 16 days of life (range, 1-132 days). Duration of surgery was 50.5 minutes (range,13-150 minutes). Mean postoperative times were 27 days to extubation, 60 days to wean from supplemental oxygen, and 84 days to discharge. Early extubation (within 10 days of ligation) occurred in only 54 patients (30%). Only 44 (22%) survived to discharge without CLD. Forty patients (20%) died, with respiratory failure the most common cause (70%). In general, early extubation, survival without CLD and survival to discharge were associated with greater GA and birth weight, higher Apgar scores, greater age and weight at surgery, no preoperative intraventricular hemorrhage, lack of ventilator dependence, and lower ventilator settings ( P b .05). Preoperative amount and duration of indomethacin use, chest x-ray findings, and echocardiographic assessment of ductus size did not predict favorable outcomes (all P N .05). Conclusions: Most premature infants currently undergoing PDA ligation at our institution do not experience the anticipated rapid improvements in cardiorespiratory status and go on to develop CLD. Few preoperative variables (including radiographic and echocardiographic assessments) definitively predict outcomes. D 2007 Elsevier Inc. All rights reserved.
Presented at the 37th Annual Meeting of the American Pediatric Surgical Association, May 20 –24, 2006, Hilton Head, SC. B This study was supported, in part, by a grant (RR00046) from the General Clinical Research Centers program of the Division of Research Resources, National Institutes of Health (University of North Carolina GCRC # 2114) and the Doris Duke Charitable Foundation Medical Research Program. * Corresponding author. Tel.: +1 919 966 4643; fax: +1 919 843 2497. E-mail address: [email protected] (J.D. Phillips). 0022-3468/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2006.09.040
70 Delayed closure of the ductus arteriosus in premature infants has been associated with a variety of morbidities, including pulmonary vascular overload, congestive heart failure, prolonged ventilator dependence, chronic lung disease (CLD), necrotizing enterocolitis, and ultimately, mortality [1,2]. Surgical ligation of PDA is considered standard treatment for symptomatic infants who do not respond to treatment with indomethacin. Since the first reported PDA ligation by Gross in 1938, numerous studies have shown PDA ligation to be both technically feasible and safe, even in premature, low-birth-weight infants [3-8]. It has been felt that PDA ligation benefits critically ill preterm neonates by decreasing pulmonary vascular overload, with a subsequent decreased need for pharmacologic pressor support, mechanical ventilation, and supplemental oxygen. It has been well-documented, however, that some infants who undergo PDA ligation do not demonstrate the expected dramatic improvement in cardiorespiratory status and require prolonged mechanical ventilation, develop CLD, or die before hospital discharge [9]. Chronic lung disease is associated with especially poor long-term outcomes [10]. When considering PDA ligation, the clinician would hope to predict which infants would indeed benefit from the procedure in order to best manage patients, inform parents, and assess risk. The aim of this study was to assess true morbidity and mortality risks in these patients and elucidate which preoperative factors might predict favorable outcomes.
M.V. Raval et al. improvement in cardiorespiratory status would occur if PDA ligation were performed), most consistent with newborn respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (implying, radiographically, no significant improvement in cardiorespiratory status would occur if PDA ligation were performed), or others. Preoperative echocardiograms were reviewed by pediatric cardiologists. Data collected included ductus size, direction of flow, and presence of associated intracardiac shunts. Size was graded as small, medium, or large [12]. Surfactant use, as well as number of indomethacin doses, actual indomethacin dosage per weight, and number of courses of indomethacin (with 3 doses = 1 course) were collected [13]. Outcomes collected included survival of surgery (defined as 30 days postoperatively), days to extubation, wean from all supplemental oxygen, postoperative complications, survival to discharge, and cause of death (if applicable). Chronic lung disease was defined as being mechanically ventilated or requiring supplemental oxygen at corrected GA of 36 weeks [14-16]. Student t test and v 2 tests were used to provide descriptive univariate analysis.
2. Results 2.1. General demographics Demographic data are presented in Table 1.
1. Methods
2.2. Preoperative variables
Medical records of all newborns in the neonatal intensive care unit (NICU) at the North Carolina Children’s Hospital, a tertiary pediatric referral center, who underwent PDA ligation between January 1, 1992, and January 1, 2004 (144 months) were reviewed. Record review was approved by the University of North Carolina (UNC) Institutional Review Board and the UNC General Clinical Research Center. Using hospital records and a patient database managed by the NICU, 273 infants were identified. Of these, 34 (12%) were excluded for gestational age (GA) greater than or equal to 38 weeks. Forty-two patients (15%) were excluded because they were born with complex cyanotic congenital cardiac disease, and the PDA ligations were performed in conjunction with more complex repairs by the cardiothoracic surgery service. The remaining 197 (73%) underwent ligation by fellowship-trained pediatric general surgeons via standard muscle-sparing left posterolateral thoracotomies [11] with double-clip technique [4]. No thoracoscopic procedures were included in this review. Surgical procedures were typically performed in the operating room. If patients were deemed unstable for transport by the operating surgeon, PDA ligations were done in the NICU. Preoperative chest x-rays were reviewed by pediatric radiologists and interpreted as most consistent with pulmonary vascular overload (implying, radiographically, an
2.2.1. Patent ductus arteriosus diagnosis/assessment One hundred eighty-five patients had preoperative echocardiograph data available for review. Fifty-nine (32%) were described as having a small ductus, 48 (26%) Table 1
Demographic data % (n = 197)
Sex Male Female
58% (114) 42% (83)
Race Black White Other Maternal age (y) Gestational age (wk) Birth weight (g) Very low birth weight Surfactant at birth
52% 37% 11% 25 27 955 71% 86%
Location of birth UNC Not at UNC
64% (126) 36% (71)
Range
(102) (74) (21) 14-39 23-35 440-3170 (140) (170)
Very low birth weight is defined as weight less than 1000 g.
Patent ductus arteriosus ligation in premature infants Table 2
Postoperative complications Incidence (n)
Survived surgery NEC/intestinal perforation IVH Wound infection Wound dehiscence Chylothorax Pleural effusion Clinical vocal cord paralysis/paresis Postoperative pneumonia a b
83% 17% 32% 1% 0% b1% 2% 3% 6%
(164) (33)a (63)b (2) (0) (1) (4) (6) (11)
Thirty cases of NEC/perforation were present preoperatively. Fifty-nine cases of IVH were present preoperatively.
moderate, and 67 (36%) large. Eleven (6%) of the patients did not have a patent ductus arteriosus visualized on the echocardiogram performed immediately before surgery. Of the 185 infants with preoperative echocardiograph findings available for review, 134 (72%) had an associated atrial septal defect/patent foramen ovale, and 12 (7%) had a small ventricular septal defect. 2.2.2. Cardiorespiratory failure diagnosis/assessment Immediately preoperative mean heart rate was 167 beats per minute (range, 110-215 beats per minute) and mean systolic blood pressure was 55 mm Hg (range, 30-110 mm Hg). Preoperative pressor support with dopamine or dobutamine was noted in 121 patients (61%) and 59 patients (30%), respectively. Mean maximal preoperative infusion rates were 7.2 lg/kg per minute (dopamine) and 3.9 lg/kg per minute (dobutamine). Mean preoperative arterial blood gas measures included pH of 7.34 (range, 7.08-7.66), Pco2 of 48.43 (range, 18-86), and Po2 of 72.64 (range, 26-467). Twenty-one of the 197 patients (11%) were not receiving mechanical ventilation just before surgery. The mean preoperative Fio2 for the entire cohort was 0.52 (range, 0.21-1) with a mean of 8.2 days (range, 0-91 days) spent with a Fio2 greater then 0.50. Mean ventilator rate was 21 breaths per minute (range, 0-80). Mean inspiratory time (IT) was 0.29 seconds (range, 0-0.65). Mean airway pressure (MAP) was 6.9 mm Hg (range, 0-17). Peak inspiratory pressure was 19 mm Hg (range, 0-44). Mean tidal volume was 1.1 L (range, 0-2.9). One hundred ninety-two patients had preoperative chest x-rays performed and interpreted at our institution. Five patients had preoperative chest x-rays performed and interpreted only at outside institutions. Eighty seven (45%) were felt to be most consistent with pulmonary Table 3
71 vascular overload, 74 (38%) were felt to be most consistent with newborn RDS or bronchopulmonary dysplasia, and 31 (16%) were felt to have other findings. Other findings included bilateral diffuse parenchymal disease (8% [15]), clear bilateral lung fields/no pathology (4% [7]), pulmonary interstitial emphysema (2% [3]), atelectasis (2% [3]), pneumonia (b1% [1]), pulmonary hemorrhage (b1% [1]), and pneumothorax (b1% [1]). 2.2.3. Preoperative PDA medical management Mean number of preoperative indomethacin doses was 4 (range, 0-15), mean indomethacin courses was 1.4 (range 0 to 11), and mean actual dosage was 0.7 mg/kg (range, 0-4.98 mg/kg). Eighty (41%) patients received at least 6 doses (2 courses of 3 doses each). Preoperative necrotizing enterocolitis (NEC)/intestinal perforation was noted in 30 (15%) of patients, oliguria in 30 (15%), and/or intraventricular hemorrhage (IVH) in 59 (30%).
2.3. Operative management Infants underwent ligation at mean 16 days of life (range, 1-132 days). Mean weight at the time of surgery was 1018 g (range, 430-3235g) with mean increase in weight from birth of 98 g (range, 265 to 1755g) or 6.8% of body weight (range, 25% to 70%). Ligations were performed in either the NICU (9% [18]) or operating room (91% [179]). Mean duration of surgery was 50.5 minutes (13-150 minutes), and mean estimated blood loss was 4.4 mL (0-150 mL). Post/ perioperative chest tubes were placed in 28 (14%) of patients.
2.4. Postoperative outcomes Postoperative outcomes, including survival of surgery (defined as survival to postoperative day 30), are shown in Table 2. No deaths were directly attributable to the surgical procedure itself. Causes of death for patients who did not survive to discharge are listed in Table 3. Outcomes, including days to extubation, days to begin enteral feedings, days to wean from all supplemental oxygen, and length of stay are shown in Table 4.
2.5. Outcomes of interest Patients appeared to either experience the anticipated rapid improvement in cardiorespiratory status and quickly wean from supplemental oxygen (and extubate early postsurgical ligation) or require long-term intubation with gradual improvement in pulmonary function (see Figs. 1 and 2). We Table 4
Cause of death
Cause of death
% (n = 40)
Pulmonary failure Sepsis Renal failure Liver failure
70% 20% 7.5% 2.5%
(28) (8) (3) (1)
Clinically significant postoperative outcomes Mean days (range)
Days to extubation Days to wean from O2 Days to feeds Length of stay
27 60 12 84
(0-181) (0-376) (0-68) (5-247)
72
M.V. Raval et al.
Fig. 1
Days to extubation.
defined 3 distinct favorable outcome groups: (1) early extubation within 10 days of ligation (54 patients [30%]); (2) survival to discharge and no CLD (44 patients [22%]); and (3) survival to discharge (157 patients [80%]). Defining bearly extubatorsQ as being those who were extubated by postoperative day 10 was a decision made by the authors after analyzing the data (Fig. 1) and attempting to avoid including the morbidity typically attributable to the thoracotomy itself (pain, bthird spacingQ of fluids, and alterations in respiratory mechanics for 7-10 postoperative days). In addition, it was hoped to avoid including the typical period of bcardiac decompensationQ seen in over 25% of patients following this procedure [17]. For each outcome, the preoperative factors outlined above were analyzed to determine associations. 2.5.1. Early extubation Sixteen patients were transferred postoperatively to outside institutions while still intubated. One hundred
Fig. 2
eighty-one had adequate in-house follow up to determine date of extubation. Of the 181 patients, 54 (30%) met the criteria for early extubation (see Table 5 for selected results). Early extubation was associated with greater GA, higher body weight (BW), higher 1-minute Apgar scores, higher systolic blood pressure at surgery, no preoperative IVH, not receiving surfactant, being extubated before surgery, or having lower Fio2 dependence at the time of surgery. Furthermore, higher weight at surgery and being older at the time of surgery were associated with early extubation. Factors that did not influence early extubation include sex; race; maternal age; birth at UNC; 5-minute Apgar scores; signs of PDA, including audible murmur, bounding/palmar pulses, active precordium, and/or wide pulse pressures; preoperative chest x-ray findings; echocardiogram findings; amount/duration of indomethacin and/or dopamine/dobutamine use; ventilator settings at time of surgery, including rate, IT, and MAP; heart rate at time of surgery; preoperative
Days to wean from supplemental oxygen.
Patent ductus arteriosus ligation in premature infants Table 5
73
Early extubation Early extubation (181)a
GA (wk) BW (g) % With surfactant Dopamine rate (lg /kg per minute) Apgar scores 1 min 5 min Weight at surgery (g) Systolic BP at surgery (mm Hg) Fio2 at surgery Number days with Fio2 N 0.5 Age at surgery (d) Ligation in OR % With IVH % Intubated at surgery
Yes (30%) (54)
No (70%) (127)
P
28.6 1233 78% 5.7
(23-35) (500-3170) (42) (0-20)
26.4 839 89% 7.8
(23-37) (440-2080) (113) (0-30)
b.01 b.01 .05 .07
5.2 6.8 1370 60.4 0.38 9.5 21 96% 20% 65%
(0-9) (0-9) (520-3235) (40-110) (0.21-1) (0-91) (2-132) (52) (11) (35)
4.4 6.8 873 53.6 0.58 8.0 15 89% 36% 95%
(0-9) (1-9) (430-2610) (30-90) (0.21-1) (0-45) (1-59) (113) (46) (121)
.05 .81 b.01 b.01 b.01 .47 .02 .11 .03 b.01
Values expressed as means, with (range), as appropriate. Statistically significant figures are rendered in boldface. a Date of extubation unknown on 16 patients.
NEC; preoperative oliguria; intraoperative blood loss; chest tube placement; duration of surgery; and location of ligation (all P N .05). 2.5.2. Survival to discharge and no CLD Chronic lung disease has been associated with significant long-term morbidity. Forty four patients (22%) survived to discharge without CLD. Having higher BW, higher 1minute Apgar scores, lower maximal dopamine rates, and having lower Fio2 (for those intubated at the time of surgery) were associated with survival to discharge without CLD. Furthermore, having few days with Fio2 greater than 0.5 and being older at the time of surgery were associated with survival to discharge without CLD. Factors that did not influence survival to discharge without CLD included GA; sex; race; maternal age; birth at UNC; 5-minute Apgar scores; signs of PDA including audible murmur, bounding/ palmar pulses, active precordium, and/or wide pulse pressures; preoperative chest x-ray findings; echocardiogram findings; surfactant use; amount/duration of indomethacin and/or dobutamine use; ventilator dependence at time of surgery; ventilatory settings including rate, IT, and MAP; heart rate and systolic blood pressure at time of surgery; preoperative NEC; IVH and/or oliguria; intraTable 6
b
2.5.3. Survival to discharge One hundred fifty-seven patients (80%) survived to discharge. Having greater GA, being extubated before surgery, or having lower Fio2 dependence at the time of surgery were associated with survival to discharge. Furthermore, higher weight at surgery and having ligation in the operating room as opposed to the NICU were associated with survival to discharge. Factors that did not influence survival to discharge include BW; sex; race; maternal age; birth at UNC; Apgar scores at 1 or 5 minutes; signs of PDA including audible murmur, bounding/palmar pulses, active precordium, and/or wide pulse pressures; reoperative chest x-ray findings; echocardiogram findings; surfactant use; amount/duration of indomethacin and/or dopamine/dobutamine use; heart rate or systolic blood pressure at time of surgery; preoperative NEC; preoperative oliguria; intraoperative blood loss; chest tube placement; or duration of surgery (all P N .05).
2.6. Echocardiographic data Echocardiograph data for each of the 3 major outcome groups are outlined in Table 6. All ductal flows were
Echocardiograph data
PDA size Small (n = 59) Medium ( n = 48) Large (n = 67) None (n = 11) Total (n = 185)a a
operative blood loss; chest tube placement; duration of surgery; and location of ligation (all P N .05).
Early extubation ( P = .24)
Survived without CLD ( P = .01)
Survived to discharge ( P = .07)
Yes 19 8 19 2 48b
Yes 19 4 18 1 42
Yes 51 37 56 6 150
No 38 39 40 6 123b
No 40 44 49 10 143
No 8 11 11 5 35
Twelve Patients missing preoperative echocardiography data. Early extubation patient include an additional 14 patients missing extubation data secondary to transfer to outside hospitals while intubated (total = 171).
74 documented as being left to right. The sole statistically significant group was a poor outcome associated with infants who survived with no CLD who were determined to have a medium-sized PDA. The significance of this is unclear because both small and large PDAs (on echocardiography) showed similar rates of favorable outcome in this same cohort (19/59 and 18/67, respectively).
2.7. Gestational age and birth weight Although only 1 (33%) of 3 of infants weighing less than 500 grams survived and 4 (57%) of 7 of infants born at less than 24 weeks of GA survived, we were unable to demonstrate any babsolute cutoffQ for either variable below which outcomes were uniformly poor. Infants with birth weights of at least 500 grams and GAs of at least 24 weeks had survival rates essentially identical to their larger (and older) counterparts.
3. Discussion It is generally accepted that, in order to minimize the deleterious effects of PDA in premature infants, prompt ductal closure is desirable [18]. Since the late 1970s, fluid restriction and indomethacin have been first-line therapy, with limited exceptions [19]. Surgical ligation has typically been reserved for those infants failing indomethacin or with contraindications to its use. Ligation procedures have been associated with low morbidity and almost certain success from a technical standpoint. Delaying surgical ligation may increase the likelihood of developing morbidity and/or mortality [8,16]. In this study, the incidence of morbidities putatively associated with PDA (CLD, NEC, etc) were high. These patients had an incidence of CLD of 61%, a long duration of hospitalization, prolonged mechanical ventilation, and an inhospital mortality rate of 20%. It is apparent that when consulting with families preoperatively, it should be made clear that a surgical intervention in these patients does not guarantee favorable outcome. Significant morbidity in this series may be secondary to a combination of factors. First, neonatal cardiorespiratory failure may be secondary to RDS and pulmonary immaturity, rather than pulmonary vascular overload. In this case, PDA ligation would be expected to provide little postoperative benefit. Second, the surgical intervention itself, with thoracotomy and spreading of the ribs, may contribute to postoperative ventilator dependence. Left lung compression during ligation may cause intrapulmonary hemorrhage and/or prolonged atelectasis. It is well known that adult thoracotomy patients may experience prolonged postoperative pain, with its associated risk of poor respiratory effort. Third, only postsurgical patients were included in this review, and almost all had either failed multiple attempts at indomethacin closure or had contraindications to further preoperative indomethacin use. One could argue that the bsurgical patientsQ were thus
M.V. Raval et al. preselected to have poor outcomes. Indeed, the baverageQ preoperative patient was small (955 grams), premature (27 weeks GA), receiving dopamine (at 7.2 lg/kg per minute), intubated on mechanical ventilation, and on Fio2 greater than 0.50 for over eight days. Candidates for PDA ligation are usually evaluated with a variety of tests, including chest x-ray and echocardiography. These tests are thought to provide an objective measure of the impact a PDA is having on the infant. Specifically, those infants who are typically felt to have the greatest potential benefit from the operation (those with large PDAs on echocardiography, with chest x-ray evidence of pulmonary vascular overload, on pressor support with dopamine and/or dobutamine) were no more likely to extubate quickly than infants without those presumed bobjectiveQ measures of PDA significance. This study suggests that both chest radiographs and PDA size, as measured by echocardiogram, have limited predictive value in determining which infants will benefit from ligation. In this group of preterm infants who underwent PDA ligation, there were few, if any, reliable clinical predictors of a favorable outcome. Infants who were early extubators and/ or who survived without CLD were larger, had a greater GA, and were typically older at the time of surgery. In addition, these patients were receiving less ventilatory support as evidenced by lower Fio2 and fewer days with Fio2 greater than 0.5. These patients were, essentially, not as clinically bunstableQ as those who did not have favorable outcomes. However, there were no absolute bcutoffsQ in terms of variables below or above which all patients had unfavorable outcomes. This data suggests that there are no absolute contraindications to attempting PDA ligation to benefit the patient regardless of how small, how premature, and how unstable the premature infant is preoperatively. Because only postsurgical patients were included in this study, one cannot determine what would have happened to the patients if they had not undergone surgery. That is, continued nonoperative treatment might have resulted in much higher morbidity, with slower wean from mechanical ventilation, even more CLD, and even greater inhospital mortality. Indeed, in a recently reported series from a neonatal center without ready access to a pediatric surgeon (the closest surgical group was located over 2000 miles away), 98 premature infants with PDAs were studied [20]. Of the 33 patients with PDAs that did not close after 2 courses of indomethacin, 11 patients (33%) died, compared to 7 of 65 patients (11%) whose PDAs closed with indomethacin treatment. After adjustment for slightly different GAs, the relative risk of death (without surgical ligation) was 4.02. Another report examined the outcomes of 1134 extremely low-birth-weight infants in Canada, Australia, and the United States in the Trial of Indomethacin Prophylaxis in Preterms [21]. Of the 426 infants with PDAs, the death rate in the group with persistent PDAs that did not undergo surgery was 22% (71/316) vs only 14% (15/110) in those who underwent surgical closure ( P b .05). A prospective, randomized trial
Patent ductus arteriosus ligation in premature infants comparing PDA ligation to continued nonoperative treatment may be of benefit. In conclusion, this study demonstrates that morbidities associated with PDA in preterm infants are high, even after PDA ligation, and that there are few factors clearly associated with favorable outcomes.
References [1] 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;93(4):647 - 51. [2] Kitterman JA, Edmunds Jr LH, Gregory GA, et al. Patent ductus arteriosus in premature infants. Incidence, relation to pulmonary disease and management. N Engl J Med 1972;287(10):473 - 7. [3] Mikhail M, Lee W, Toews W, et al. Surgical and medical experience with 734 premature infants with patent ductus arteriosus. J Thorac Cardiovasc Surg 1982;83(3):349 - 57. [4] 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 1993;28:1137 - 9. [5] 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):1007 - 9. [6] Niinikoski J, Alanen M, Parvinen T, et al. Surgical closure of patent ductus arteriosus in very-low-birth-weight infants. Pediatr Surg Int 2001;17:338 - 41 [7] Malviya M, Ohlsson A, Shah S. Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants. Cochrane Database Syst 2003;Rev(3):CD003951. [8] Little DC, Pratt TC, Blalock SE, et al. Patent ductus arteriosus in micropreemies and full-term infants: the relative merits of surgical ligation versus indomethacin treatment. J Pediatr Surg 2003;38(3):492 - 6. [9] Palder SB, Schwartz MZ, Tyson KR, et al. Management of patent ductus arteriosus: a comparison of operative vs pharmacologic treatment. J Pediatr Surg 1983;18:835 - 41. [10] Yeo CL, Choo S, Ho LY. Chronic lung disease in very low birthweight infants: a 5-year review. J Paediatr Child Health 1997;33(2):102 - 6. [11] Soucy P, Bass J, Evans M. The muscle-sparing thoracotomy in infants and children. J Pediatr Surg 1991;26(11):1323 - 5. [12] Hines MH, Raines KH, Payne RM, et al. Video-assisted ductal ligation in premature infants. Ann Thorac Surg 2003;76:1417 - 20. [13] Quinn D, Cooper B, Clyman RI. Factors associated with permanent closure of the ductus arteriosus: a role for prolonged indomethacin therapy. Pediatrics 2002;110(1 Pt 1):e10 - 1. [14] Marshall DD, Kotelchuck M, Young TE. Risk factors for chronic lung disease in the surfactant era: a North Carolina population-based study of very low birth weight infants. Pediatrics 1999;104(6):1345 - 50. [15] Shennan AT, Dunn MS, Ohlsson A, et al. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527 - 32. [16] Truog WE, Jackson C, Badura RJ, et al. Bronchopulmonary dysplasia and pulmonary insufficiency of prematurity: lack of correlation of outcome with gas exchange abnormalities at 1 month of age. Am J Dis Child 1985;139:351 - 4 [17] Harting MT, Lally KP, Cox Jr CS, et al. Cardiac decompensation after patent ductus arteriosus ligation in premature infants. Presented at the annual meeting of the Section on Surgery of the American Academy of Pediatrics, San Francisco, CA, 2004. [18] Cassady G, Crouse DT, Kirklin JW, et al. A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N Engl J Med 1989;320:1511 - 6
75 [19] Gersony WM, Peckham GJ, Ellison RC, et al. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr 1983;102:895 - 906 [20] Brooks JM, Travadi JN, Patole SK, et al. Is surgical ligation of patent ductus arteriosus necessary? The Western Australia experience of conservative management. Arch Dis Child Fetal Neonatal Ed 2005;90(3):F235 - 9 [21] Kabra N, Schmidt B, Roberts R, et al. Surgical closure of a patent ductus arteriosus (PDA) is associated with increased neurosensory impairment in extremely low birth weight (ELBW) infants. Presented at the annual meeting of the Pediatric Academic Societies, Washington, DC;2005.
Discussion Dr Caniano, MD (Columbus, OH): A very nice study. I have one question about the timing of the ductal ligation. It was my understanding from the Vermont Oxford data that the neonatologist should consult early and that the procedure should be done within the first few days after recognition of the ductal problem. Did you find that the earlier the procedure was done, you had a better outcome versus your average at 16 days of age? Dr Raval, MD (Chapel Hill, NC) (response): The standard in our NICU is that pediatric surgery is consulted early. The data showed that the older the child was and the more days that had passed since birth, the better they did. It is an issue where you have to weigh the costs and benefits and see how the individual patient is doing. We typically followed the standard 2 courses of indomethacin, which took approximately 2 or 3 days to complete before undergoing the ligation. Dr Kosloske, MD (Sanibel, FL): You just answered the first part of my question. I think what you said just now is that all 197 patients were indomethacin failures? Dr Raval, MD (Chapel Hill, NC) (response): Either they were indomethacin failures or they had a contraindication to indomethacin such as preoperative intraventricular hemorrhage. Dr Kosloske, MD (Sanibel, FL): Well then perhaps ligation of the ductus—perhaps the surgical procedure has nothing to do with the outcome because you have selected for surgery a group of patients that would have a bad outcome anyway. Dr Raval, MD (Chapel Hill, NC) (response): That is true. Dr Kosloske, MD (Sanibel, FL): And the only way you could have comparable groups would be to do early ligation rather than indomethacin and compare groups from the start. Thank you.