Short-term respiratory outcomes of neonates with symptomatic congenital lung malformations

Short-term respiratory outcomes of neonates with symptomatic congenital lung malformations

Journal of Pediatric Surgery 54 (2019) 1766–1770 Contents lists available at ScienceDirect Journal of Pediatric Surgery journal homepage: www.elsevi...

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Journal of Pediatric Surgery 54 (2019) 1766–1770

Contents lists available at ScienceDirect

Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg

Short-term respiratory outcomes of neonates with symptomatic congenital lung malformations☆ Kevin N. Johnson a,b, Rodrigo A. Mon a,b, Samir K. Gadepalli a,b, Shaun M. Kunisaki a,⁎ a b

Section of Pediatric Surgery, Department of Surgery, Michigan Medicine, C.S. Mott, Children's and Von Voigtlander Women's Hospital, Ann Arbor, MI, USA 48109 Pediatric Surgical Critical Care, Department of Surgery, Michigan Medicine, C.S. Mott, Children's and Von Voigtlander Women's Hospital, Ann Arbor, MI, USA 48109

a r t i c l e

i n f o

Article history: Received 8 August 2018 Received in revised form 17 December 2018 Accepted 19 January 2019 Key words: Congenital pulmonary airway malformation Congenital cystic adenomatoid malformation Bronchopulmonary sequestration Neonatal surgery

a b s t r a c t Introduction: The purpose of this study was to evaluate short-term respiratory outcomes in neonates with symptomatic congenital lung malformations (CLM). Methods: Consecutive newborns who underwent surgical resection of a CLM were retrospectively reviewed. Demographic, prenatal, and outcomes data were analyzed as appropriate (p b 0.05). Results: Twenty-one neonates were managed at a median gestational age of 36.2 weeks [interquartile range (IQR), 33.8–39.0]. Endotracheal intubation was required in 14 (66.7%) for a median of 7.5 days [interquartile range (IQR), 3.0–25.8]. Three (14.3%) children underwent ex utero intrapartum treatment-to-resection, and another 14 (66.7%) had neonatal lung resections performed at a median age of 2.0 days (IQR, 0.08–19.5 days). Excluding one patient who received comfort care at birth, all neonates survived to hospital discharge with a median length of hospitalization of 36.5 days (IQR, 23.8–56.5). More than one-quarter were discharged on supplemental oxygen by nasal cannula. Based on a median follow up of 35.5 months (IQR, 19.0–80.8), CLM-related morbidity was still evident in 55.0%. Conclusion: Our study suggests a high incidence of complications and chronic respiratory morbidity after neonatal lung resection for symptomatic CLMs. These data highlight the need to provide realistic expectations in perinatal counseling discussions with families and the importance of coordinating appropriate multidisciplinary follow up for these children. Level of Evidence: Level IV. © 2019 Elsevier Inc. All rights reserved.

Congenital lung malformations (CLMs) represent a group of pulmonary lesions that include congenital pulmonary airway malformations (CPAMs), bronchopulmonary sequestrations (BPSs), and congenital lobar emphysema (CLE) [1]. The incidence of CLMs appears to be increasing over time, with more recent studies suggesting an incidence of approximately 1 in 2500 births, likely secondary to widespread prenatal screening as well as improvements in ultrasound image quality [2–4]. Although the etiology of CLMs is unclear, the inciting event may be related to transient bronchial obstruction during the canalicular phase of lung morphogenesis [5,6]. More recently, dysregulated signaling in the Ras and PI3K–AKT–mTOR pathways has been implicated [7]. The majority of children diagnosed with a CLM have small lesions and are asymptomatic at birth [8,9]. In these patients, elective pulmonary resection later in infancy is well tolerated and associated with minimal long-term morbidity [10,11]. Conversely, there remains a small but distinct subset of children, usually with larger CLMs, who have early ☆ Funding: No sources of support ⁎ Corresponding author at: Johns Hopkins Children's Center, 1800 Orleans Street, Suite 7353, Baltimore, MD 21287-1005. Tel.: +410 955 9012; fax: +410 502 5314. E-mail address: [email protected] (S.M. Kunisaki). https://doi.org/10.1016/j.jpedsurg.2019.01.056 0022-3468/© 2019 Elsevier Inc. All rights reserved.

symptomatic disease, manifesting as significant respiratory distress at birth or as hydrops in utero secondary to mass effect on the heart and normal lung parenchyma [12,13]. These patients may be candidates for fetal intervention and often require intensive resuscitation in the delivery room, supplemental oxygen, mechanical ventilation, and rarely, extracorporeal membrane oxygenation (ECMO) [14,15]. To date however, there has been relatively little focus on the postoperative course, extent of pulmonary morbidity, and risk factors of chronic respiratory disease in these symptomatic children [16–19]. In this study, we sought to evaluate the hospital course and early postoperative morbidity in neonates with symptomatic CLMs resected at a major tertiary care referral center. Our group hypothesized that children born with symptomatic CLMs, much like their counterparts with congenital diaphragmatic hernia (CDH) [20,21], incur substantial pulmonary morbidity in the first several years of life despite operative resection performed in the newborn period. 1. Methods This study was approved by the University of Michigan Institutional Review Board (#51132). We performed a retrospective chart review on

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prospectively collected data within an institutional CLM database at the C.S. Mott Children's Hospital in Ann Arbor, Michigan. Between January 2002 and June 2017, consecutive pediatric patients (n = 102) were identified. All newborns with symptomatic respiratory disease (defined as tachypnea, need for additional respiratory support) secondary to the CLM were further analyzed. The critical care management and operative indications in these children have been described by our group and others [22–24]. Recorded data included patient demographics, preoperative, intraoperative, and postoperative data (namely hospital length of stay, complications, readmissions, and reinterventions). The CPAM volume ratio (CVR) was prospectively measured throughout the pregnancy as previously detailed [17]. Hydrops was defined as the presence of fluid in two or more spaces, including ascites, pleural effusion, pericardial effusion, or skin edema, with fetal echocardiographic evidence to support heart dysfunction as reported elsewhere [25]. The pathologic diagnosis was confirmed in all resected specimens. Patients with ongoing respiratory symptoms were followed in an interdisciplinary fashion as outpatients by neonatology, pediatric surgery, and pediatric pulmonary specialists until clinical resolution. Data were expressed as mean ± standard deviation unless specified otherwise. Comparisons were made using Fisher's exact test for ordinal variables, Mann–Whitney test for continuous variables, and Spearman correlation as appropriate using the SPSS software package (IBM, Chicago, IL). Significance was defined as p b 0.05. 2. Results 2.1. Demographic data Of 102 consecutive CLM patients managed over 15.5 years, 21 (20.6%) had symptomatic disease in the newborn period. One neonate was made comfort care at birth owing to multiple other anomalies (i.e., bilateral multicystic dysplastic kidneys, lung hypoplasia) and subsequently died within 24 h of delivery. This patient was excluded from further analysis. Basic demographic data are shown in Table 1. No other major anomalies were identified except for one syndromic child who was ultimately diagnosed with Wolf–Hirschhorn syndrome. The median gestational age at birth for the entire symptomatic cohort was 36.2 weeks [interquartile range (IQR), 33.8–39.0 weeks]. The mean birthweight was 2.77 ± 0.86 kg. Fourteen (70%) were inborn deliveries.

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Table 2 Prenatal characteristics of neonates with symptomatic lung lesions (n = 16). Initial CVR, mean ± SD

1.4 ± 1.0

Maximum CVR, mean ± SD Mediastinal shift Macrocystic disease Hydrops Maternal betamethasone Fetal procedures Open resection Thoracoamniotic shunt Ex utero intrapartum treatment-to-resection Gestational age at birth, median (IQR) Birthweight, mean kg ± SD Pathologic diagnosis CPAM Hybrid lesion, CPAM with feeding vessel Intralobar bronchopulmonary sequestration Extralobar bronchopulmonary sequestration Congenital lobar emphysema

2.2 ± 1.3 14 (87.5%) 6 (37.5%) 7 (43.8%) 8 (50.0%) 0 (0.0%) 2 (12.5%) 3 (18.8%) 36.2 wks (34.9–39.0) 3.0 ± 0.75 9 (56.3%) 2 (12.5%) 2 (12.5%) 2 (12.5%) 1 (6.3%)

Abbreviations: CVR, congenital pulmonary airway malformation volume ratio; CPAM, congenital pulmonary airway malformation.

of the symptomatic masses that were first identified after delivery were CLE. Mediastinal shift was evident in fourteen (88%). The mean initial CVR of 1.4 ± 1.0 at a median gestational age of 25.6 weeks (IQR, 22.0–29.8), and the mean maximum CVR was 2.2 ± 1.3 at a median gestational age of 29.9 weeks (IQR, 25.0–32.9). Both the initial CVR and maximum CVR were significantly increased in symptomatic neonates when compared to CVR values in asymptomatic neonates (initial: 0.58 ± 0.46, p = 0.013 and maximum: 0.86 ± 0.81, p = 0.007). Seven (43.8%) symptomatic neonates developed hydrops (mean maximum CVR, 2.1 ± 1.1), and this was statistically significant when compared to the hydrops rate in asymptomatic neonates (2.0%, p b 0.001). Two doses of maternal betamethasone were administered in the setting of an elevated CVR and/or hydrops in eight (50%) fetuses with respiratory symptoms at birth. There were no open fetal resections, two (12.5%) thoracoamniotic shunts for macrocystic lesions with a dominant cyst (mean maximum CVR, 1.9), and three (18.8%) ex utero intrapartum treatment (EXIT)-to-resections for large microcystic masses (mean maximum CVR, 3.1) with or without hydrops. The median gestational age at EXIT was 36.4 months (IQR, 35.0–39.0). 2.3. Postnatal hospital course

2.2. Prenatal management Prenatal data are shown in Table 2. Sixteen (80%) symptomatic newborns were initially diagnosed by fetal ultrasound. Whereas all symptomatic CPAM, BPS, and hybrid lesions were diagnosed prenatally, all Table 1 Basic demographics on neonates with symptomatic lung lesions (n = 20). Female gender

7 (35.0%)

Left-sided mass Lobe involved Right upper Right middle Right lower Left upper Left lower Extralobar Pathologic diagnosis CPAM Hybrid lesion, CPAM with feeding vessel Intralobar bronchopulmonary sequestration Extralobar bronchopulmonary sequestration Congenital lobar emphysema Gestational age at birth, median weeks (IQR) Birthweight, mean kg ± SD

17 (85.0%)

Abbreviation: CPAM, congenital pulmonary airway malformation.

0 (0.0%) 1 (5.0%) 2 (10.0%) 5 (25.0%) 10 (50.0%) 2 (10.0%) 9 (45.0%) 2 (10.0%) 2 (10.0%) 2 (10.0%) 5 (25.0%) 36.2 (33.8–39.0) 2.77 ± 0.86

Fourteen (70%) symptomatic neonates required endotracheal intubation and mechanical ventilation for a median length of 7.5 days (IQR, 3.0–25.8). Two (10%) were difficult to manage on conventional ventilators but were eventually stabilized using a high frequency jet ventilator. Four (20%) received supplemental oxygen via nasal cannula but required no additional respiratory support. Two (10%) newborns with small CLMs presented with an ipsilateral pneumothorax shortly after birth and were successfully managed with a chest tube followed by delayed thoracoscopic resection at a median age of 6.0 months. Overall, 18 (90%) lobectomies and two (10%) extralobar sequestration excisions were performed in 20 children. Fourteen (70%) patients with demonstrated mediastinal mass effect on imaging studies (i.e., plain radiograph ± CT scan) underwent neonatal thoracotomy and lung resection at a median age of 2.0 days (IQR, 0.1–19.5 days). In one child undergoing a lobectomy, a bronchogenic cyst was also removed. Six (42.9%) of these had persistent parenchymal air leaks in the postoperative period requiring prolonged chest tube drainage. Six (30%) symptomatic neonates developed pulmonary hypertension based on echocardiographic criteria. Five (25%) were supported on venovenous or venoarterial ECMO for a median of 10.0 days (IQR, 5.5–14.5). All but one ECMO run was initiated after lung resection. Major complications occurring during the hospitalization included hemorrhagic stroke (n = 1, 5%), failure to thrive (n = 2, 10%), severe

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Fig. 1. Univariate analyses of neonates with symptomatic lung malformations showing the relationship between selected patient characteristics (x-axis) and hospital number of days (yaxis). (A) XY plot when correlated with gestational age at birth (in months, Spearman correlation: p = 0.001). (B) XY plot when correlated with birthweight (in kilograms, Spearman correlation: p = 0.002). (C) Bar graph shows no significant association in hospital duration based on prenatal hydrops status (Mann-Whitney, p = 0.35). (D) Bar graph demonstrates no significant association in hospital duration based on extracorporeal membrane oxygenation (ECMO) utilization (Mann-Whitney, p = 0.10). Note: all bar graph values expressed as the median with interquartile range.

gastroesophageal reflux disease requiring pyloric feeding or fundoplication (n = 2, 10%), and transient renal failure (n = 1, 10%). All children survived to hospital discharge at a median length of hospitalization of 36.5 days (IQR, 23.8–56.5). Symptomatic neonates had significantly longer hospital stays when compared to hospital stays in asymptomatic neonates who underwent delayed elective resection (4.5 days, p b 0.001). Among symptomatic neonates, univariate analyses revealed a significant correlation between length of hospitalization and gestational age at birth (p = 0.001) as well as birthweight (p = 0.002, Fig. 1A, B). There was no association between length of hospitalization and other patient characteristics, including hydrops status, CVR, ECMO utilization, and pathologic diagnosis (Fig. 1C, D). Six (30%) infants were discharged on supplemental oxygen (1/4 l) by nasal cannula. The median length of hospitalization in this subgroup on nasal cannula was 46.0 days (IQR, 35.0–90.3). 2.4. Respiratory follow up The pulmonary status of each child was successfully followed at least once as an outpatient. Based on a median follow up of 35.5 months (IQR, 19.0–80.8), all children had completely weaned off of supplemental oxygen. However, CLM-related chronic morbidity was evident in 11 (55%) children, with 50% requiring once or twice daily inhaled bronchodilators to manage ongoing asthma and chronic lung disease. Both the maximum CVR and ventilator duration were significant predictors of respiratory morbidity (p = 0.02 and 0.04, respectively; Table 3). Two (10%) patients were subsequently diagnosed with pectus excavatum. The lone syndromic child in our study died at 27 months of age following an acute episode of aspiration pneumonia. 3. Discussion Based on several published cohort studies, it is estimated that 10%– 25% of children with CLMs managed at tertiary care hospitals are

symptomatic at birth [9,19,26,27]. Most of these cases are identified prenatally by ultrasound screening during the fetal anatomic survey at 18–20 weeks' gestation, and the likelihood of having neonatal respiratory symptoms can be predicted based on mass size, as measured by serial CVR measurements throughout the pregnancy [9,28]. Specifically, our group has shown that a maximum CVR less than 1.0 in nonhydropic fetuses with a CLM has a greater than 95% likelihood of having no respiratory distress at birth [9]. The majority of asymptomatic children can be safely discharged 24–48 h after delivery and can be counseled as Table 3 Univariate analysis of post-operative respiratory morbidity in neonates undergoing lung malformation resection (n = 20). Variable

Morbidity n = 11 (55%)

No Morbidity n = 9 (45%)

p value

Prenatal diagnosis Hydrops Initial CVR, mean ± SD Maximum CVR, mean ± SD Maternal steroids Fetal procedure (shunt, EXIT) Gestational age, median weeks, (IQR) Birthweight, mean kg ± SD Ventilator use, median days, (IQR) ECMO Pathologic diagnosis CPAM BPS, CPAM with feeding vessel Congenital lobar emphysema

9 (81.8%) 6 (54.5%) 1.5 ± 1.3 2.8 ± 1.3 5 (45.5%) 3 (27.3%) 35.0 (33.4–39.0)

7 (77.8%) 1 (11.1%) 1.3 ± 0.8 1.6 ± 0.9 3 (33.3%) 2 (22.2%) 36.4 (32.5–39.0)

1.00 0.07 0.94 0.02* 1.00 1.00 0.81

2.8 ± 0.8 13.0 (3.0–35.0)

2.8 ± 1.0 4.0 (2.5–7.5)

0.62 0.04*

4 (36.4%)

1(11.1%)

0.32

5 (45.5%) 4 (36.4%)

4 (44.4%) 2 (22.2%)

1.00 0.64

2 (18.2%)

3 (33.3%)

0.62

Abbreviations: CVR, congenital pulmonary airway malformation volume ratio; EXIT, ex utero intrapartum treatment; ECMO, extracorporeal membrane oxygenation; CPAM, congenital pulmonary airway malformation; BPS, bronchopulmonary sequestration; * p b 0.05 (Fisher's exact test).

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outpatients regarding the advantages of prophylactic CLM resection (e.g., reduce pneumonia risk, compensatory lung growth) when compared to nonoperative management [29–32]. Although the overall safety, short hospital length of stay, and low morbidity following elective lung surgery are well established by most groups [10,11,33–36], clinical outcomes in neonates presenting soon after birth with larger, symptomatic lesions have largely focused on the role of fetal intervention and overall mortality as opposed to postnatal morbidity [13,18,37,38]. As a result, the respiratory sequelae in these children have not been well defined. In this study, we sought to evaluate the hospital course and early respiratory morbidity in a contemporary cohort of neonates with symptomatic CLMs resected at a major referral center. Analogous to the consequences of herniated abdominal viscera on lung development and postnatal morbidity in CDH [39], the mass effect of a large fetal CPAM or BPS lesion has been associated adverse consequences, including lung hypoplasia, pulmonary hypertension, and reactive airways disease [14,40,41]. One major finding from this study was that roughly half of symptomatic neonatal CLMs were CPAMs whereas one-quarter had either BPS on components or CLE based on pathologic data on resected specimens. Critically, all symptomatic CPAMs and BPSs were prenatally diagnosed, thereby suggesting the very high sensitivity of fetal ultrasound for the detection of these lesions compared to CLE, a lesion that usually has similar echogenicity to that of normal fetal lung tissue [42]. We also found that the maximum CVR, as determined by serial sonographic measurements, was confirmed to be a significant and useful predictor for identifying neonates who are more likely to have symptomatic respiratory disease at birth. The utility of the maximum CVR as a prenatal sonographic predictor of disease symptomatology at birth was described by our group in 2013 [9] and has been corroborated by studies in recent years by others [28,43,44]. In contrast to the short length of hospitalization and low morbidity observed in infants following elective resection of an asymptomatic CLM [10,11,33,34], our study also confirmed that newborns with symptomatic respiratory disease have substantially more difficult clinical courses, often requiring considerable neonatal intensive care unit resources, including postoperative invasive mechanical ventilation support for one or more weeks and ECMO support in up to one-quarter of symptomatic infants to facilitate management of severe pulmonary hypertension. Although postoperative respiratory failure, pulmonary hypertension, and ECMO have been well documented after neonatal CLM resection [18,24], their exact incidence has been difficult to quantify secondary to CLM disease heterogeneity, referral bias inherent in studies from quaternary centers focused on fetal surgery, and lack of standardized clinical follow up in this patient population. Despite having a cohort of patients with almost half developing signs of hydrops, our study suggests low mortality rates under an aggressive management strategy that employs maternal steroids, thoracoamniotic shunts, and EXIT-to-resection for the highest risk lesions. The data revealed a median length of hospitalization for these neonates of approximately five weeks. As expected, gestational age at birth and birthweight were significantly correlated with length of hospitalization. In this patient population, several case series have reported a median invasive mechanical ventilator duration between 6 and 30 days and a median length of hospitalization ranging from 13 to 60 days [17,18]. Furthermore, in contrast to the experience in infants undergoing elective lung resection for asymptomatic disease as documented elsewhere [34], our study shows that symptomatic neonates appear to have a high incidence of postoperative complications and chronic respiratory morbidity, including discharge to home on supplemental oxygen by nasal cannula in one-fourth of children. Based on a median follow-up age of three years, we found that all symptomatic children status post CLM resection as neonates were able to wean off of supplemental oxygen. These data are consistent with

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gradual respiratory symptom resolution in preschool aged children as reported elsewhere [19]. However, respiratory morbidity many years after lung resection was still evident in more than half of our patients, as shown by inhaled bronchodilator use to manage chronic lung disease and asthma symptoms. According to recent data from the Centers for Disease Control, the overall incidence of asthma in children between age 0 and 11 years is 8% [45]. The finding that the respiratory morbidity is often not relieved by resecting the affected lung has been supported by other investigators, who have demonstrated relatively high rates of asthma after pulmonary resection in the range of 17%–40% [16,36]. Unlike one study that suggested that CLE patients are at increased risk for long-term respiratory morbidity [19], the statistical analysis presented in Table 3 does not support the notion that disease pathology influences respiratory morbidity. Instead, we found that the maximum CVR and ventilator duration were significant predictors of respiratory morbidity. Whether the observed reactive airways disease in CLMs tends to worsen or improve over time remains unknown and therefore warrants further study. Despite the aforementioned data presented here, several caveats deserve mention. First, this was a retrospective, single institution series with a relatively short median follow-up of 36 months. There may still be a potential for referral bias, in which less symptomatic CPAMs may have been managed elsewhere and had more benign clinical courses. Alternatively, the most severe CLMs may have developed frank hydrops and may have not been referred to our center prior to in utero demise. Larger multicenter collaborative studies may be better able to delineate factors that can predict respiratory symptomatology and morbidity in these patients. Second, we did not use an age-matched control group, namely asymptomatic neonates who underwent surgical resection, in our respiratory outcomes analysis since elective neonatal resection is not the standard of care in most pediatric surgical practices [46,47]. Moreover, because there is much less controversy regarding the excellent short-term respiratory morbidity of asymptomatic children with CLMs who undergo delayed operative resection outside of the neonatal period [10,11,33,34], we abstained from a formal comparative analysis of respiratory outcomes with older CLM resection patients. A third limitation is that we have yet to establish a formal, standardized protocol for the long-term follow up of these patients at fixed time points. As a result, the medical management of these patients may be susceptible to individual provider practice patterns. Unfortunately, we did not obtain objective measures of lung function (e.g., pulmonary function testing) in the majority of our patients as has been described elsewhere for infants and preschool aged children in a long-term follow-up study [48]. Finally, although beyond the scope of the current study, we also did not evaluate other morbidities that may be associated with this patient population, including gastrointestinal, nutritional, orthopedic, and neurodevelopmental issues, as described by others [49]. Nevertheless, we believe that our data are informative, particularly in terms of highlighting the need to provide realistic expectations in counseling discussions with families at birth and the importance of coordinating appropriate multidisciplinary follow up for these infants.

Acknowledgments The authors wish to thank Jeannie Kreutzman, RN, MSN, CPNP, and George B. Mychaliska, MD, of the Fetal Diagnosis and Treatment Center at Michigan Medicine for their assistance with the early data collection and analysis.

Conflict of interest The authors indicate no potential conflicts of interest.

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