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International Journal of Pediatric Otorhinolaryngology xxx (2014) xxx–xxx

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Recovery of vocal fold immobility following isolated patent ductus arteriosus ligation Brent G Nichols a , Jad Jabbour a , David A. Hehir b , Nancy S. Ghanayem b , David Beste a , Timothy Martin a , Ronald Woods c , Thomas Robey a, * a

Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, USA Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA c Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 14 December 2013 Received in revised form 13 May 2014 Accepted 14 May 2014 Available online xxx

Objective: Identify laryngoscopic and functional outcomes of infants with vocal fold immobility (VFI) following patent ductus arteriosus (PDA) ligation and identify predictors of recovery. Methods: Retrospective review of patients with VFI following PDA ligation from 2001 to 2012 at a single institution. Inclusion criteria were: (1) PDA ligation as only cardiac surgical procedure; (2) left VFI documented by laryngoscopy; (3) minimum follow up 120 days, with at least 2 laryngoscopies performed. Resolution of VFI was determined at follow-up laryngoscopy. Univariate logistic regression models were used to identify variables associated with VFI recovery. Results: 66 subjects were included with median follow up of 3.0 (2.1) years. The mean gestational age was 24.5  1.4 weeks, mean birth weight 673  167 g, and mean age at procedure was 18.6  14.3 days. Patients presented with respiratory symptoms (39%), dysphonia (78%) and dysphagia (55%). Resolution of VFI was observed in 2/66 (3%) patients. Recovery was documented at 20 days and 11 months respectively. Respiratory symptoms, dysphagia, and dysphonia persisted at last follow up in 11%, 47%, and 20% of patients. Conclusions: VFI associated with ligation of the ductus arteriosus has a low rate of recovery. Clinical symptoms frequently persist, and as such regular follow-up by otolaryngologists to mitigate morbidity is indicated. ã 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The incidence of a patent ductus arteriosus (PDA) in term infants has been estimated to be 57 per 100,000 live births. However, it is much more prevalent in premature infants, with one in three very low birth weight (below 10th percentile for gestational age) preterm infant being diagnosed with a PDA [1]. The indications and modalities of PDA treatment are controversial. For patients with significant left-to-right shunting that fail medical therapy, or for whom medical therapy is contraindicated surgical treatment may be considered [2]. The recurrent laryngeal nerve innervates the larynx and has a complex anatomic course, looping

* Corresponding author at: Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, 9000 W Wisconsin Avenue, Suite 540 Milwaukee, WI 53201, USA. Tel.: +1 414 266 2463; fax: +1 414 266 2693. E-mail address: [email protected] (T. Robey).

around the aortic arch on the left immediately adjacent to the ductus arteriosus before traveling superiorly toward the cricoarytenoid joint and entering the larynx. This places the left recurrent laryngeal nerve at risk of injury with surgical procedures involving the ductus arteriosus. Iatrogenic trauma to the recurrent laryngeal nerve during surgical closure of a PDA with resultant vocal fold immobility (VFI) is a well-documented complication of this procedure with incidence of left VFI following PDA ligation ranging from 8.8 to 67% [3,4]. VFI results in a wide range of symptomatology due to the role of the vocal fold in normal respiratory mechanics, airway protection from aspiration, and phonation. The degree of impairment may depend on the mechanism of injury and on whether the patient has bilateral or unilateral involvement [5]. Laryngoscopic and functional outcomes beyond hospital discharge for patients with PDA ligation-associated VFI have previously been evaluated in small case series with limited follow up [5–8]. To better understand the natural history of VFI associated with PDA ligation, we evaluated

http://dx.doi.org/10.1016/j.ijporl.2014.05.019 0165-5876/ ã 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: B.G. Nichols, et al., Recovery of vocal fold immobility following isolated patent ductus arteriosus ligation, Int. J. Pediatr. Otorhinolaryngol. (2014), http://dx.doi.org/10.1016/j.ijporl.2014.05.019

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Table 1 The demographics, presenting symptoms, and co-morbidities of patients with vocal fold immobility (VFI) following PDA ligation (N = 66) were obtained through chart review and ICD-9 diagnosis. Respiratory symptoms included stridor and/or increased work of breathing. Dysphonia was defined as a breathy or hoarse cry. Dysphagia was defined as difficulties with oral feeds. Enteral tube feeds were defined as nasogastric, gastrostomy, or gastro-jejunostomy feeding tubes. Demographics mean (STD) Presenting symptoms number (percentage)

Comorbidities number (percentage)

Birth weight (g) Gestational age (weeks) Age at procedure (days) Respiratory symptoms Dysphonia Dysphagia Enteral tube feeds Subglottic stenosis Laryngomalacia Bronchopulmonary dysplasia (no data on 8 patients) Intraventricular hemorrhage (no data on 14 patients) Retinopathy of prematurity (no data on 4 patients)

long-term outcomes of infants diagnosed with VFI after PDA ligation. Additionally, we sought to identify clinical predictors of vocal fold recovery. 2. Methods Institutional Review Board approval from Children’s Hospital of Wisconsin was obtained for retrospective study of patients with VFI diagnosed after isolated PDA ligation. Patients were identified from an approved database maintained by a pediatric otolaryngology group from July 2001 to September 2012. All patients with diagnosis of unilateral or bilateral, partial or complete “Paralysis of Vocal Cords or Larynx” (ICD 478.31–478.35), history of isolated PDA repair (no additional cardiac surgery), and greater than 120 days otolaryngology follow up after VFI diagnosis were identified. We identified 532 patients who had underwent PDA ligation during the defined period. Of these, there were 81 patients with vocal cord paralysis following PDA repair, fifteen were bilateral and were excluded and 66 were unilateral and these patients were included in the final analysis. Diagnosis of VFI was made by flexible laryngoscopy by an attending pediatric otolaryngologist. Recommended follow-up was every 3–6 months from diagnosis. Laryngoscopy was performed at irregular intervals based on clinical indications such as changes in symptoms or normalization or worsening of laryngeal function. Specific documentation of vocal fold mobility as well as the presence of other airway abnormalities diagnosed at examination including subglottic stenosis (SGS) or laryngomalacia were maintained in the VFI database. Patient characteristics including gestational age (GA), small for gestational age (SGA) status, birth weight, age at airway examination, comorbidities at presentation including bronchoplumonary dysplasia (BPD), intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP) were obtained from the medical record based on ICD-9 codes if available. Symptoms at time of VFI diagnosis and at last follow up or time of resolution were characterized as respiratory symptoms, dysphonia, or dysphagia. Respiratory symptoms included stridor and/or increased work of breathing. Dysphonia was defined as a breathy or hoarse cry. Dysphagia was defined as difficulties with oral feeds. Records were reviewed by two independent reviewers and discrepancies were resolved by the senior author. 3. Statistical analysis Patients were classified as complete recovery (normal mobility on laryngoscopic exam), or persistent VFI. Additional analysis was performed to examine predictors of dysphonia, respiratory symptoms and dysphagia at last follow up. Descriptive analysis was performed stratified by recovery. Logistic regression analysis

704.2 (185.6) 24.75 (1.6) 18.4 (13.9) 26 (39%) 51 (79%) 36 (55%) 36 (55%) 3 (5%) 25 (38%) 56 (96%) 24 (46%) 50 (84%)

was performed to identify prognostic indicators of VFI resolution. Survival analysis of time to recovery of vocal fold mobility was performed. Univariate logistic regression models were performed to evaluate risk factors for persistence of symptoms at last follow up. 4. Results 532 PDA ligations were performed during our study interval. 66 patients met inclusion criteria and were included in the analysis with median follow up of 3.0  2.1 years. The mean gestational age was 24.5  1.4 weeks, mean birth weight 673  167 g, and mean age at procedure was 18.6  14.3 days. Patients presented with respiratory symptoms (39%), dysphonia (78%) and dysphagia (55%). These patients were managed with collagen injections in 13% of cases and 55% required gastrostomy tubes for nutritional support (Table 1) Demographic and presenting symptoms of patients are listed in Table 1. We were unable to verify the presence or absence of bronchopulmonary dysplasia, intraventricular hemorrhage, or retinopathy of prematurity in 8, 14, and four patients respectively. Complete resolution of VFI was observed in 2/66 (3%) patients. Time to laryngoscopic documentation of recovery was 20 days and 11 months respectively. Thirty-three percent of patients were asymptomatic at last follow-up. Of those patients that had residual symptoms at last follow up, respiratory symptoms, dysphagia, and dysphonia persisted in 11%, 47%, and 27%, with many of the patients having more than one symptom at follow up. The majority of patients were taking all nutrition orally (Table 2). Neither of the patients that recovered vocal fold function had dysphonia, respiratory difficulties, dysphagia or gastrostomy tube dependence at last follow up. There were no statistically significant prognostic indicators of vocal fold recovery. There were significant prognostic indicators of clinical symptoms at last follow up. Respiratory symptoms at presentation, laryngomalacia, and enteral tube feeding were all positively associated with respiratory symptoms at last follow up. Dysphonia at presentation was positively associated with Table 2 Functional outcomes of patients (N = 66) with vocal fold immobility following PDA ligation at last follow up. Respiratory symptoms included stridor and/or increased work of breathing. Dysphonia was defined as a breathy or hoarse cry. Dysphagia was defined as difficulties with oral feeds. Enteral tube feeds were defined as nasogastric, gastrostomy, or gastro-jejunostomy feeding tubes. Symptoms at last follow up

Number of patients (%)

Respiratory symptoms Dysphonia Dysphagia Exclusive oral nutrition Enteral tube feeds

7 (11%) 30 (48%) 18 (27%) 44 (73%) 16 (24%)

Please cite this article in press as: B.G. Nichols, et al., Recovery of vocal fold immobility following isolated patent ductus arteriosus ligation, Int. J. Pediatr. Otorhinolaryngol. (2014), http://dx.doi.org/10.1016/j.ijporl.2014.05.019

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Table 3 Symptoms and co-morbidities at initial presentation were evaluated for association with clinical outcome at last follow up visit using univariate logistic regression models. Respiratory symptoms included stridor and/or increased work of breathing. Dysphonia was defined as a breathy or hoarse cry. Dysphagia was defined as difficulties with oral feeds. Enteral tube feeds were defined as nasogastric, gastrostomy, or gastro-jejunostomy feeding tubes. All significant associations are reported below. Outcome

Predictor

Estimate

Odds ratio

Odds ratio CI

p-value

10.80

1.21, 96.15

0.033

0.24

0.04, 1.35

0.104

0.10

0.01, 0.93

0.043

11.68

1.31, 104.19

0.028

3.91

0.96, 15.95

0.057

6.46

1.30, 32.17

0.023

1.80

0.48, 6.71

0.382

2.88

0.69, 11.97

0.147

Respiratory symptoms

Dysphonia

Dysphagia

Intercept Respiratory Symptoms Intercept Tube feed dependence Intercept G-tube placement Intercept Laryngomalacia

3.58 2.38 1.34 1.44 1.20 2.26 3.61 2.46

Intercept Dysphonia

1.20 1.36

Intercept Dysphagia Intercept Tube feed dependence Intercept G-tube placement

2.60 1.87 1.61 0.59 2.04 1.06

dysphonia at follow up. Dysphagia at presentation was associated with dysphagia at last follow up (Table 3). 5. Discussion This review presents outcomes of VFI associated with PDA ligation and demonstrates the natural history of recovery with particular attention to clinical and laryngoscopic prognosis. To our knowledge, this is the largest cohort with longest follow up of pediatric VFI patients following ligation of the patent ductus arteriosus (PDA) described in the literature. The natural history of VFI following PDA ligation in infants has not been well established. Reports regarding prognosis of VFI have been variable, though a trend toward low rates of laryngoscopic recovery is observed. Spanos et al. report laryngoscopic recovery in 2 of 6 patients at a mean follow up period of 4.5 months [4]. Both Pereira et al. [6], with follow up in 5 patients at a mean of 9 months, and Clement et al. [7], with follow up in 12 patients at a mean of 8.4 months, report a 0% rate of laryngoscopic recovery. Despite no laryngoscopic recovery, of the 17 patients followed in these 2 studies, 16 are noted to have satisfactory compensation from the normal vocal fold although this is a somewhat subjective finding [6,7]. To date, long-term laryngoscopic outcomes in patients with VFI following PDA ligation are unknown. The above studies, however, are in line with the very low (3%) rate of recovery observed in our series. The lack of vocal fold mobility suggests that the pathophysiology of VFI is likely complete disruption of the recurrent laryngeal nerve, rather than a lower grade nerve injury from stretch or compression. This contrasts with VFI following all cardiac procedures, with reported recovery rates from 35 to 82%, which suggests lower grade injuries without complete disruption of the nerve as the mechanism in some of those patients [9–11]. Our follow up period (median 3.6 years) is longer than the expected time period of recovery of axonotmesis or neurotmesis of the recurrent nerve (less than 2 years), and as such we believe the low rate of recovery represents the final outcome of recurrent nerve function in most of these patients [12]. Identifying variables associated with VFI recovery was limited by the unanticipated low incidence of recovery. Our study was under-powered to identify predictive variables of recovery of VFI secondary to PDA ligation. As such, although we performed linear regression analysis to identify predictive variables of recovery, none were identified.

Dysphonia, dysphagia and respiratory symptoms are welldescribed clinical morbidities of VFI [7,9]. Dysphonia can result from the inability to approximate the vocal folds completely resulting in a persistent glottic gap with phonation. When the contralateral vocal fold is unable to compensate or close this gap in a patient with unilateral VFI, a hoarse or breathy cry results. Similarly, if there is not adequate compensation/closure of the glottic gap with swallowing, aspiration can also result. VFI has been shown to be an independent risk factor for tube feeding dependence [13]. Furthermore, respiratory compromise in these patients can be due either to chronic aspiration contributing to worsening lung disease and/or glottic incompetence reducing the positive end expiratory pressure (PEEP) and decreasing functional residual capacity (FRC) resulting in pulmonary function decrement. Despite the low incidence of vocal fold recovery in our series, we observed encouraging clinical recovery of dysphonia, respiratory symptoms, and dysphagia in our cohort (Table 2). For example, at last follow up, 73% of our cohort was receiving exclusive oral nutrition compared to 45% at initial diagnosis. These results suggest that many patients are ultimately able to compensate for persistent VFI, as observed in previous studies [6,7]. The variables positively associated with symptoms at last follow up are not surprising and suggest that the degree of laryngeal dysfunction at presentation may predict long term clinical outcomes. For example, there were significant associations between respiratory symptoms, dysphonia, and dysphagia at presentation and their presence at the last follow up evaluation (Table 3). This supports the idea that patients with minimal laryngeal dysfunction initially will tend to have good functional outcomes, and the converse seems to be true as well. One limitation of our study is that laryngoscopy was not performed at every routine follow-up appointment. The time between laryngoscopic evaluations was variable and the decision to scope was based on changes in symptoms and clinical judgment. The intervals between laryngoscopies most likely inflated the time to laryngoscopic resolution in comparison to the physiological resolution of VFI. Our recommendations for management based on these findings are as follows: we agree with previous authors who have recommended laryngoscopic evaluation in all infants following cardiac surgery that involves manipulation of the aortic arch or the area of the ductus arteriosus [3]. When VFI is identified,

Please cite this article in press as: B.G. Nichols, et al., Recovery of vocal fold immobility following isolated patent ductus arteriosus ligation, Int. J. Pediatr. Otorhinolaryngol. (2014), http://dx.doi.org/10.1016/j.ijporl.2014.05.019

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patients should be evaluated by a multidisciplinary team including an otolaryngologist and speech pathologist to manage the commonly associated comorbidities of dysphagia, dysphonia, and respiratory symptoms. Long-term follow up should be established to manage and mitigate these morbidities until complete functional recovery occurs. Future research should be directed at identifying the outcomes of therapeutic interventions for patients with VFI following PDA ligation. With relatively small rates of spontaneous recovery, interventions that improve compensation should be pursued. Furthermore, as recovery is uncommon, research into improved techniques of ligation that minimize risk to the recurrent nerve are needed. Changes in operative technique which improve visualization of the nerve, or alternatives such as coil embolization, have the potential to reduce recurrent injuries [14,15]. Other management options to restore function, such as laryngeal re-innervation, could also be explored. 6. Conclusion In conclusion, VFI following PDA ligation has a low rate of laryngoscopic recovery, and persistence of clinical symptoms is common. Clinical recovery of laryngeal function is more common than laryngoscopic resolution of VFI, and clinical outcomes seem to be associated with the severity of dysfunction at presentation. Evaluation and long-term management of patients with VFI following PDA ligation by otolaryngologists is indicated to mitigate the associated morbidity. Furthermore, additional investigation into prevention of VFI and potential interventions to reduce morbidity is needed. References [1] N. Evans, Diagnosis of patent ductus arteriosus in the preterm newborn, Arch. Dis. Child. 68 (1 Spec No) (1993) 58–61 http://www.pubmedcentral.nih.gov/ articlerender.fcgi?artid=1029172&tool=pmcentrez&rendertype=abstract (accessed 29.10.13). [2] D.J. Schneider, J.W. Moore, Patent ductus arteriosus, Circulation 114 (17) (2006) 1873–1882 http://circ.ahajournals.org/content/114/17/1873.long (accessed 16.02.13).

[3] R.I. Zbar, A.H. Chen, D.M. Behrendt, E.F. Bell, R.J. Smith, Incidence of vocal fold paralysis in infants undergoing ligation of patent ductus arteriosus, Ann. Thorac. Surg. 61 (3) (1996) 814–816 http://www.ncbi.nlm.nih.gov/pubmed/ 8619698 (accessed 13.03.13). [4] W.C. Spanos, J.T. Brookes, M.C. Smith, et al., Unilateral vocal fold paralysis in premature infants after ligation of patent ductus arteriosus: vascular clip versus suture ligature, Ann. Otol. Rhinol. Laryngol. 118 (10) (2009) 750–753 http://www.ncbi.nlm.nih.gov/pubmed/19894404 (accessed 16.02.13). [5] J.R. Benjamin, P.B. Smith, C.M. Cotten, et al., Long-term morbidities associated with vocal cord paralysis after surgical closure of a patent ductus arteriosus in extremely low birth weight infants, J. Perinatol. 30 (6) (2010) 408–413 http:// www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2878380&tool=pmcentrez&rendertype=abstract (accessed 13.03.13). [6] K.D. Pereira, B.D. Webb, M.L. Blakely, C.S. Cox, K.P. Lally, Sequelae of recurrent laryngeal nerve injury after patent ductus arteriosus ligation, Int. J. Pediatric Otorhinolaryngol. 70 (9) (2006) 1609–1612 http://www.ncbi.nlm.nih.gov/ pubmed/16797086 (accessed 13.03.13). [7] W.A. Clement, H. El-Hakim, E.Z. Phillipos, J.J. Coté, Unilateral vocal cord paralysis following patent ductus arteriosus ligation in extremely low-birthweight infants, Arch. Otolaryngol. Head Neck Surg. 134 (1) (2008) 28–33 http://www.ncbi.nlm.nih.gov/pubmed/18209132 (accessed 16.02.13). [8] L.L. Fan, D.N. Campbell, D.R. Clarke, et al., Paralyzed left vocal cord associated with ligation of patent ductus arteriosus, J. Thorac. Cardiovasc Surg. 98 (4) (1989) 611–613 http://www.ncbi.nlm.nih.gov/pubmed/2796367 (accessed November 9.11.13). [9] M.T. Truong, A.H. Messner, J.E. Kerschner, et al., Pediatric vocal fold paralysis after cardiac surgery: rate of recovery and sequelae, Otolaryngol. Head Neck Surg. 137 (5) (2007) 780–784 http://www.ncbi.nlm.nih.gov/pubmed/ 17967646 (accessed 13.03.13). [10] S.S. Khariwala, W.T. Lee, P.J. Koltai, Laryngotracheal consequences of pediatric cardiac surgery, Arch. Otolaryngol. Head Neck Surg. 131 (4) (2005) 336–339 http://www.ncbi.nlm.nih.gov/pubmed/15837903 (accessed 2013). [11] H. Daya, A. Hosni, I. Bejar-Solar, J.N. Evans, C.M. Bailey, Pediatric vocal fold paralysis: a long-term retrospective study, Arch. Otolaryngol. Head Neck Surg. 126 (1) (2000) 21–25 http://www.ncbi.nlm.nih.gov/pubmed/10628706 (accessed 16.02.13). [12] B.N. Benjamin, S.D. Gray, C.M. Bailey, Neonatal vocal cord paralysis, Head Neck 15 (2) (2013) 169–172 http://www.ncbi.nlm.nih.gov/pubmed/8440618 (accessed 29.09.13). [13] B.A. Davidson, P.R. Knight, Z. Wang, et al., Surfactant alterations in acute inflammatory lung injury from aspiration of acid and gastric particulates, Am. J. Physiol. Lung Cell. Mol. Physiol. 288 (4) (2005) L699–708 http://www.ncbi. nlm.nih.gov/pubmed/15757954 (accessed 24.11.13). [14] R.P. Burke, Video-assisted thoracoscopic surgery for patent ductus arteriosus, Pediatrics 93 (5) (1994) 823–825 http://pediatrics.aappublications.org/content/93/5/823.short (accessed 24.11.13). [15] P.A. Cambier, W.C. Kirby, D.C. Wortham, J.W. Moore, Percutaneous closure of the small (< 2.5 mm) patent ductus arteriosus using coil embolization, Am. J. Cardiol. 69 (8) (1992) 815–816 http://www.sciencedirect.com/science/article/ pii/000291499290514Y (accessed 24.11.13).

Please cite this article in press as: B.G. Nichols, et al., Recovery of vocal fold immobility following isolated patent ductus arteriosus ligation, Int. J. Pediatr. Otorhinolaryngol. (2014), http://dx.doi.org/10.1016/j.ijporl.2014.05.019

Recovery of vocal fold immobility following isolated patent ductus arteriosus ligation.

Identify laryngoscopic and functional outcomes of infants with vocal fold immobility (VFI) following patent ductus arteriosus (PDA) ligation and ident...
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