Tracheobronchomalacia diagnosed by tracheobronchography in ventilator-dependent infants

Abstract

Background

Tracheobronchomalacia prevalence in premature infants on prolonged mechanical ventilation is high.

Objective

To examine the prevalence of tracheobronchomalacia diagnosed by tracheobronchography in ventilator-dependent infants, and describe the demographic, clinical and dynamic airway characteristics of those infants with tracheobronchomalacia.

Materials and methods

This retrospective review studies 198 tracheobronchograms performed from 1998 to 2011 in a cohort of 158 ventilator-dependent infants <2 years of age. Dynamic airway assessment during tracheobronchography determined the optimal positive end-expiratory pressure to maintain airway patency at expiration in those infants with tracheobronchomalacia.

Results

Tracheobronchograms were performed at a median age of 52 weeks post menstrual age. The primary diagnoses in these infants were bronchopulmonary dysplasia (53%), other causes of chronic lung disease of infancy (28%) and upper airway anomaly (13%). Of those with bronchopulmonary dysplasia, 48% had tracheobronchomalacia. Prematurity (P=0.01) and higher baseline - pre-tracheobronchogram positive end-expiratory pressure (P=0.04) were significantly associated with tracheobronchomalacia. Dynamic airway collapse during tracheobronchography showed statistically significant airway opening at optimal positive end-expiratory pressure (P < 0.001). There were no significant complications noted during and immediately following tracheobronchography.

Conclusion

The overall prevalence of tracheobronchomalacia in this cohort of ventilator-dependent infants is 40% and in those with bronchopulmonary dysplasia is 48%. Infants born prematurely and requiring high pre-tracheobronchogram positive end-expiratory pressure were likely to have tracheobronchomalacia. Tracheobronchography can be used to safely assess the dynamic function of the airway and can provide the clinician the optimal positive end-expiratory pressure to maintain airway patency.

Introduction

Tracheobronchomalacia is a disease characterized by excessive airway collapsibility during expiration due to diffuse or focal softening of the tracheobronchial cartilaginous rings and associated hypotonia of the soft-tissue myoelastic elements [1]. Tracheobronchomalacia may arise congenitally from disorders associated with impaired cartilage maturation or may be acquired secondary to prolonged mechanical ventilation. Chronic lung disease of infancy is a heterogeneous group of respiratory diseases that begin in the neonatal period. Bronchopulmonary dysplasia is a form of chronic lung disease of infancy that develops after a prolonged exposure to oxygen and/or mechanical ventilation for respiratory distress syndrome in surfactant-deficient preterm newborns. In addition to bronchopulmonary dysplasia, conditions that have resulted in chronic lung disease of infancy include pneumonia or sepsis, meconium aspiration syndrome, pulmonary hypoplasia, persistent pulmonary hypertension of the newborn, congenital diaphragmatic hernia, tracheoesophageal fistula, congenital cardiac disease and congenital neuromuscular disorders. Bronchopulmonary dysplasia is the most common cause of chronic lung disease of infancy [2]. Between 16% and 50% of selected infants with bronchopulmonary dysplasia show evidence of tracheobronchomalacia by endoscopy [3].

Diagnosing tracheobronchomalacia in infants and children is difficult due to the small lumen of the airway and the rapid respiratory rate. Tracheobronchography involves the radiographic assessment of the airways after the introduction of nonionic water-soluble contrast media into the airways [4]. It is usually considered a more sensitive investigation for diagnosing tracheobronchomalacia compared with bronchoscopy, as it is not affected by stenting and distortion of the airways. Tracheobronchography can delineate the anatomy and any anomalous geometry of abnormal airway segments and can rapidly and accurately assess the dynamic airway function of the tracheobronchial tree throughout the entire respiratory cycle [5–7]. An important therapeutic aspect of tracheobronchography is the addition of continuous positive airway pressure in the airway circuit, which can guide the clinician in the management of the patient’s airway disease [8]. Although radiation exposure presents a risk, the level of radiation associated with tracheobronchography can be on par with or less than that of CT imaging [9]. It is generally accepted that the diagnosis of tracheobronchomalacia by tracheobronchography requires both dynamic assessment of the trachea and bronchi throughout a respiratory cycle and demonstration of a reduction in a cross-sectional area of at least 50% on expiration [10].

The purpose of this study is to determine the prevalence of tracheobronchomalacia diagnosed by tracheobronchography in a cohort of ventilator-dependent infants with chronic lung disease of infancy and bronchopulmonary dysplasia, and to identify demographic and clinical characteristics that may predict the likelihood of tracheobronchomalacia. We hypothesize that the prevalence of tracheobronchomalacia in ventilator-dependent infants is high and, if tracheobronchomalacia is present, tracheobronchography would estimate the optimal positive end-expiratory pressure to keep the airway open throughout the respiratory cycle.

Materials and methods

Subjects

In 2011, our Institutional Review Board approved this retrospective review of 198 tracheobronchograms performed in a cohort of 158 ventilator-dependent infants <2 years of age at the hospital’s radiology department from January 1998 to July 2011. Of the 158 infants, 123 had 1 tracheobronchogram each and 35 had more than one tracheobronchogram (31 infants had two, 3 infants had three and 1 infant had four tracheobronchograms) performed during the study period, for a total of 198 studies. Only the initial tracheobronchogram in each case (n=158) was included in the data analysis. Clinical suspicion of tracheobronchomalacia was raised by any of the following: 1) the inability to wean from invasive mechanical ventilation; 2) need for high positive end-expiratory pressure; 3) episodes of profound oxygen desaturation and bradycardia while on the ventilator usually precipitated by agitation thought to be bronchopulmonary dysplasia spells and/or bronchospasm, or 4) the need for ventilator support that seemed disproportionate to the infant’s parenchymal lung disease.

Data collection

For demographic and clinical data, the National Institute of Child Health and Human Development severity-based definition of bronchopulmonary dysplasia was used to identify infants with severe bronchopulmonary dysplasia and chronic lung disease of infancy [11]. The timing of each tracheobronchography was recorded as post menstrual age in weeks. The results of tracheobronchograms were abstracted from the medical records. Respiratory parameters including mean airway pressure, peak inspiratory pressure, positive end-expiratory pressure, partial pressure of carbon dioxide, and percent of inspired oxygen over the previous 48 h and 48 h following tracheobronchography were collected. If there were multiple values, the closest one prior to and after performing the tracheobronchography was recorded for each parameter.

Tracheobronchography procedure and technique

At our institution, tracheobronchography was originally performed by one interventional radiologist, but in the past 7 years, five additional interventional radiologists have joined the hospital’s radiology department. Relative to this study, all the tracheobronchograms until 2008 were performed by one interventional radiologist (n=95), while the studies that were performed from 2009 to July 2011 were shared by all interventional radiologists (n=63). Since 2009, conventional bronchograms have been performed an average of 28 times per year (or 6 bronchograms per radiologist per year). Once the tracheobronchogram was scheduled, the patient was transported to the radiology department while on the ventilator by the intensive care nurse and respiratory therapist. The patient was on continuous cardiorespiratory and oxygen saturation monitors during transport and throughout the entire fluoroscopy procedure. A pediatric or neonatal intensive care physician was present and adjusted the level of positive end-expiratory pressure until the optimal level was reached as determined by the radiologist’s fluoroscopic assessment of airway collapse.

During tracheobronchography, infants were investigated while awake, supine and on assisted ventilation either through an endotracheal or a tracheostomy tube. A 5-Fr Bern catheter was passed into the breathing tube and aliquots of 0.5 ml to a maximum of 2 ml of nonionic radiopaque contrast medium (Optiray 240, Mallinckrodt, USA) were injected into the distal trachea to delineate the tracheobronchial tree. The volumes of the contrast used during the procedure were selected by the interventional radiologist on the basis of opacifying the necessary tracheobronchial anatomy to yield a diagnostic study. The contrast was not diluted to isosmolar due to the small volume of contrast injected and low volume of possible fluid shift into the airway. Additionally, the diluted contrast would result in diminished ability to visualize pertinent radiographic findings. The initial positive end-expiratory pressure was recorded and used as the baseline. Cine image sets were obtained through several cycles of inspiration and expiration in posteroanterior projections at baseline and incremental level of positive end-expiratory pressure until the maximum opening of the collapsed airway during expiration was demonstrated. Pulsed fluoroscopy was used at a rate of 10 frames per second. Lateral projections were not employed after initial experience demonstrating suboptimal visualization of airway structures due to overlying tissues and support apparatus. The additional radiation dose associated with posteroanterior and lateral fluoroscopy was not deemed to be of enough diagnostic benefit to warrant the additional dose. Fluoroscopy time (fraction of a minute) and radiation dose (mSv) were recorded in the more recent tracheobronchograms performed. Static images were reviewed with accurate airway measurements taken during inspiration and expiration and the percentage of airway collapse at varying positive end-expiratory pressures during expiration was reported. At the conclusion of each cine loop and at the conclusion of the entire procedure, contrast was suctioned from the airway by a respiratory therapist. Figure 1 shows examples of static images at baseline positive end-expiratory pressure at inspiration, at expiration showing >50% collapse, and at optimal positive end-expiratory pressure during expiration.

Fig. 1

A 3-month-old boy who was born at 29 weeks’ gestation developed severe bronchopulmonary dysplasia and tracheobronchomalacia: (a) tracheobronchogram during inspiration at baseline positive end-expiratory pressure of 9 cm H₂O, (b) during expiration at the same positive end-expiratory pressure of 9 cm H₂O showing >50% collapse of both main stem bronchi and (c) during expiration at increased positive end-expiratory pressure of 14 cm H₂O with maximum opening of the airways

Statistical analysis

SAS version 9.2 (Cary, NC, and SPSS version 18, Chicago, IL) was utilized for all statistical calculations. Proportions (%), chi-square and Fisher exact tests compared the groups on categorical variables. Group comparisons on continuous variables were attained reviewing means and standard deviations, medians and ranges, t-tests and Wilcoxon rank sum tests (when appropriate). Logistic regression with stepwise selection was used to look at the collection of variables that may be predictive of tracheobronchomalacia in this cohort. A P value of <0.05 was considered statistically significant.

Results

Patient demographics

The cohort consisted of 158 ventilator-dependent infants: 94 males (59%) and 64 females (41%). Ninety-three (59%) were Caucasian, 45 (28%) were African-American and 20 (13%) were either Hispanic or Asian. The mean gestational age was 32.9 weeks (23–41 weeks; standard deviation (SD) ± 5.9) and 55 (35%) were born at less than 29 weeks’ gestation. The mean birth weight was 2.1 kg (0.46–4.47 kg; SD ±1.2), and 58 (37%) had a birth weight of less than 1.5 kg. Eighty-seven (55%) were born small for gestational age. All infants were ventilator-dependent for a minimum of 10 weeks, either through an endotracheal or tracheostomy tube at the time of tracheobronchogram. The median age at tracheobronchogram was 52 weeks’ post menstrual age (range: 33–135 weeks). Of the 158 infants, 84 (53%) had bronchopulmonary dysplasia as the primary diagnosis, 44 (28%) had other forms of chronic lung disease of infancy, 21 (13%) had congenital or acquired upper airway anomalies and 9 (6%) had congenital diaphragmatic hernia with pulmonary hypoplasia as shown in Table 1. There was one infant who was born premature and had esophageal atresia with distal tracheoesophageal fistula and tetralogy of Fallot and subsequently developed severe bronchopulmonary dysplasia and tracheobronchomalacia.

Table 1 Demographic and clinical characteristics of study infants

Patients with tracheobronchomalacia

Tracheobronchomalacia was found in 40% (63 of 158 infants). When infants with tracheobronchomalacia were compared to those without tracheobronchomalacia, no difference in the proportion of male infants was observed; however, there was a significantly higher proportion of Caucasian patients and lower proportion of Hispanic/Asian patients in those infants with tracheobronchomalacia (P = 0.044). There was no significant difference in the mean birth weight (P = 0.10) between the groups. The tracheobronchomalacia group was significantly more premature (mean of 31 weeks +/− 5.9 vs. 33.6 weeks +/− 5.6, P < .0066), but the proportion of small for gestational age infants was the same for both groups (P=0.54).

In this cohort, the prevalence of tracheobronchomalacia in infants with bronchopulmonary dysplasia was 48% (40/84). Conversely, bronchopulmonary dysplasia was the primary diagnosis in 64% (40/63) of infants with tracheobronchomalacia compared to 46% (44/95) in those without tracheobronchomalacia. Other forms of chronic lung disease of infancy were less common in infants with tracheobronchomalacia (P = 0.049). The proportions of infants with upper airway anomalies and congenital diaphragmatic hernia/pulmonary hypoplasia were similar in both groups as shown in Table 1.

The pre-tracheobronchogram mean airway pressure, peak inspiratory pressure, positive end-expiratory pressure, partial pressure of carbon dioxide and fraction of inspired oxygen were not significantly different among those with or without tracheobronchomalacia, while the post-tracheobronchogram mean airway pressure and positive end-expiratory pressure were significantly higher in those infants with tracheobronchomalacia, P = 0.042 and P < 0.0001, respectively, as shown in Fig. 2, presumably based on adjustments made to correct the airway collapse shown by tracheobronchogram.

Fig. 2

Pre-tracheobronchogram (a) and post-tracheobronchogram (b) fraction of inspired oxygen, mean airway pressure in cm H₂O, partial pressure of carbon dioxide in mmHg, positive end-expiratory pressure in cm H₂O and peak inspiratory pressure in cm H₂O in infants without tracheobronchomalacia compared to those with trachebronchomalacia. FiO₂ fraction of inspired oxygen, MAP mean airway pressure, pCO₂ partial pressure of carbon dioxide, PEEP positive end-expiratory pressure, PIP peak inspiratory pressure, TBG tracheo-bronchogram, TBM tracheobroncho-malacia

A logistic regression model included all demographic variables (gender, race, gestational age, birth weight, indicator of small for gestational age and primary diagnosis) as well as the pre-tracheobronchogram parameters (indicators for high mean airway pressure, peak inspiratory pressure, positive end-expiratory pressure, partial pressure of carbon dioxide and fraction of inspired oxygen). Chi-square tests were used to examine these variables individually and showed prematurity and need for high pre-tracheobronchogram positive end-expiratory pressure were significantly associated with tracheobronchomalacia with P = 0.011 and P = 0.046, respectively. When high pre-tracheobronchogram mean airway pressure and positive end-expiratory pressure were excluded from this model due to small sample sizes, stepwise-selection resulted in a model containing only prematurity as a significant predictor of tracheobronchomalacia with an odds ratio of 2.4 (95% confidence interval: 1.2–4.7).

Dynamic airway assessment in patients with tracheobronchomalacia

The dynamic airway measurements using the severity criteria of tracheobronchomalacia [12, 13] showed a statistically significant difference in the pre- and post-tracheobronchogram mean airway pressures (MAP) in cm H₂O (median: 14, range: 7–19 vs. median: 17, range: 7–25, P=0.0002), peak inspiratory pressures (PIP) in cm H₂O (median: 25, range: 15–43 vs. median: 27, range: 13–46, P=0.0039), positive end-expiratory pressures (PEEP) in cm H₂O (median: 9, range: 5–16 vs. median: 11, range: 5–18, P < 0.0001) in those infants with tracheobronchomalacia as shown in Fig. 3. In this study, the optimal positive end-expiratory pressure was defined as the maximum positive end-expiratory pressure at which there was no further improvement in airway opening at expiration. Fraction of inspired oxygen was significantly lower post-tracheobronchogram (median: 35, range: 21–100 vs. median: 30, range: 21–100, P=0.015), while pre- and post-tracheobronchogram partial pressure of carbon dioxide were similar (median: 56, range: 37–95 vs. median: 55, range: 28–82, P=0.49) as shown in Fig. 4.

Fig. 3

The post-tracheobronchogram mean airway pressure in cm H₂O (P=0.0002) and peak inspiratory pressure in cm H₂O (P=0.0039) were significantly higher than the pre-tracheobronchogram measurements in infants with tracheobronchomalacia. MAP mean airway pressure, PEEP positive end-expiratory pressure, PIP peak inspiratory pressure

Fig. 4

The post-tracheobronchogram fraction of inspired oxygen (P=0.015) was significantly lower, while the pre- and post-tracheobronchogram partial pressure of carbon dioxide in mm Hg (P=0.49) were similar in infants with tracheobronchomalacia. FiO₂ fraction of inspired oxygen, pCO₂ partial pressure of carbon dioxide

Complications during tracheobronchography included transient bradycardia, desaturation and agitation in less than 3% of infants. These infants required increased oxygen, suctioning of the airways and extra breaths from the ventilator to improve and return to baseline status. Sampling of 20 cases from where the fluoroscopy time and radiation dose were reported showed that the average time was 0.8 min and the average radiation dose was 1.3 mSv. This radiation dose is lower than the 1.7 mSv for dynamic pulmonary CT reported by Greenberg [9].

Discussion

This study reports the use of tracheobronchography in infants younger than 2 years of age, who have been ventilator-dependent for at least 10 weeks, and finds that tracheobronchomalacia is present in 40% (63/158). The majority of these infants have bronchopulmonary dysplasia (64%) and are males, Caucasians and small for gestational age with one-third born very preterm (<29 weeks’ gestation). All of these are known risk factors for the development of bronchopulmonary dysplasia. In those with bronchopulmonary dysplasia, we found that the prevalence of tracheobronchomalacia is 48% (40/84). This finding confirms the incidence of tracheobronchomalacia is high in infants with bronchopulmonary dysplasia. Our incidence is higher than the 36% and 16% reported by Boogaard et al. [14] and by Downing and Kilbride [15], respectively. In our cohort, tracheobronchograms were obtained at least several months after being chronically ventilated. These infants who were ventilator-dependent were suspected of having concomitant airway disease in addition to parenchymal pulmonary disease, compared to previous reports where ventilated preterm infants were evaluated within the first weeks of life. More importantly, tracheobronchography was used to investigate for the presence of tracheobronchomalacia in contrast to bronchoscopy or flexible fiber optic endoscopy. This finding further confirms the claim that the latter methods underestimate the degree of airway collapse because airflow dynamics and assessment of airway reactivity are affected by the presence of the instrument within the airways [8, 10, 16]. Additionally, improved imaging techniques, increased awareness of the condition among clinicians and overall increased survival of very premature infants with bronchopulmonary dysplasia may have contributed to the higher incidence [2, 11, 17].

When we compared infants with and without tracheobronchomalacia, we found no clinical factors predictive of tracheobronchomalacia. However, there were significantly more infants with bronchopulmonary dysplasia in the tracheobronchomalacia group. The pathophysiology of tracheobronchomalacia in infants with bronchopulmonary dysplasia is unclear. It had been postulated to be secondary to airway deformation and immaturity [15], but it remains unknown whether tracheobronchomalacia was a consequence of long-term mechanical ventilation. It has been suggested that acquired tracheobronchomalacia may consist of a combination of abnormal development of airway and supporting structures, aggravated by injury from prolonged mechanical ventilation [17, 18]. However, it has not been proven whether the development of tracheobronchomalacia is a form of arrest in airway development similar to alveolar and vascular arrest in the pathogenesis of the “new” bronchopulmonary dysplasia [11, 19]. This concept of airway developmental dysgenesis and arrest in oversimplified lung in bronchopulmonary dysplasia has not been studied, but potentially could explain the association between bronchopulmonary dysplasia and tracheobronchomalacia.

In addition to known bronchopulmonary dysplasia risk factors, we reviewed pre- and post-tracheobronchogram respiratory parameters to predict the likelihood of tracheobronchomalacia in our cohort. Post-tracheobronchogram parameters demonstrated that both mean airway pressure and positive end-expiratory pressure were significantly higher in infants with tracheobronchomalacia. Respiratory support for these infants was increased based on tracheobronchogram findings. Demographic and clinical parameters in a logistic regression model showed prematurity and high positive end-expiratory pressure likely identifies bronchopulmonary dysplasia infants with tracheobronchomalacia. However, step-wise selection regression model identified prematurity as the only significant predictor of tracheobronchomalacia, i.e. premature infants are 2.4 times more likely to have tracheobronchomalacia (95% CI: 1.217–4.685). Jacobs et al. [20] found a similar relationship in a study of 50 infants, with 52% having acquired tracheobronchomalacia and 96% born premature with respiratory distress syndrome and required prolonged mechanical ventilation.

Continuous positive airway pressure has been used in the treatment of infants with tracheobronchomalacia. Panitch et al. [21] demonstrated that assessment of forced expiratory flow reflects the amount of continuous positive airway pressure necessary to prevent airway collapse in infants with tracheobronchomalacia. Bronchoscopy and fluoroscopy have shown that continuous positive airway pressure maintains airway patency during tidal breathing. By creating a pneumatic stent, continuous positive airway pressure prevents the collapse of the airway throughout the respiratory cycle. An important advantage of using tracheobronchography is direct observation of changes in airway patency on expiration at varying positive end-expiratory pressure levels while the infant is awake and breathing spontaneously.

Our study demonstrates a significant increase in post-tracheobronchography mean airway pressure and positive end-expiratory pressure in those infants with tracheobronchomalacia. These findings are expected because patients with excessive collapsibility during tracheobronchogram had their positive end-expiratory pressure levels increased until their airways were open at expiration. However, the post-tracheobronchogram fraction of inspired oxygen is significantly lower and there is no change in partial pressure of carbon dioxide. These findings suggest that with optimal positive end-expiratory pressure, airway patency is achieved with improvement in oxygenation and maintenance of adequate ventilation, at least within the 48 h following tracheobronchography. There were no significant acute complications seen following the installation of nonionic contrast media directly into the patient’s airways. In a previous study of safety of tracheobronchography, Kanter et al. [22] used up to 19 cm H₂O pressure and with the aid of esophageal measurement, found that esophageal pressure did not exceed 3 cm H₂O and circulation was not compromised. This method needs to be validated and may be used to help determine objectively that the high level of positive end-expiratory pressure required by these infants to open their airway on expiration does not necessarily affect their hemodynamic status.

Our study has several limitations. This is a retrospective review of tracheobronchograms performed during a period of 13 years. The earlier studies were performed by one interventional radiologist while the latter ones were performed by a number of pediatric interventional radiologists, with either the pediatric or neonatal intensive care physician in attendance, who titrated the amount of positive end-expiratory pressure required to open the collapsible airway. This approach is open to subjective bias as assessments were not blinded to the clinical status and management of these infants. In general, data deficiencies are present with retrospective review. Fluoroscopy time and the radiation dose used in the tracheobronchograms performed in the early years of the study period are important data we did not have. Additionally, our population was drawn from a level IV regional referral center, with its attendant selection bias; therefore, we may overestimate the prevalence of tracheobronchomalacia in infants with bronchopulmonary dysplasia. Lastly, although several studies have shown that tracheobronchography is a better investigation for diagnosing tracheobronchomalacia and determining opening pressures in ventilator-dependent infants, the diagnostic criteria have not been validated. Nevertheless, we speculate that the short-term clinical validity of its use is important and requires further study.

Conclusion

We found that the prevalence of tracheobronchomalacia in this cohort of ventilator-dependent infants is 40% and in those with bronchopulmonary dysplasia it is 48%. This is higher than previously reported. Tracheobronchomalacia frequently complicates the clinical condition of premature infants with bronchopulmonary dysplasia requiring a high level of positive end-expiratory pressure. Tracheobronchography can be used to safely assess the dynamic function of the airway and assist the clinician in determining optimal positive end-expiratory pressure to maintain patency of the airway at expiration.