Association of anesthetic and surgical risk factors with outcomes of initial diagnostic biopsies in a current cohort of children with anterior mediastinal masses

Introduction

Diagnostic biopsies of anterior mediastinal masses (AMMs) carry significant operative and anesthetic risk.1 The mass effect of these tumors can lead to tracheal or bronchial compression and to interruption of venous return or cardiac output, with potentially catastrophic consequences.2 However, while these biopsies are high-risk procedures, they cannot be avoided for many AMMs because histological and molecular analyses are still required for the prescription of appropriate therapy.

Well-described clinical and radiographic risk features have been highlighted as red flags for potential procedural mortality, especially tracheal compression.3 4 Following the initial recognition of these procedural risk factors in the 1970s, general anesthesia (GA) and invasive ventilation had traditionally been strictly avoided.5 Yet, conducting these procedures solely under local anesthesia is difficult in children due to their anxiety and inability to cooperate with invasive procedures when awake.6 In more recent literature, strategies such as upright posturing, newer anesthetic drugs and better selections of drug combinations have been shown to mitigate these risks.7 Thus, with evolving awareness of historical procedural risk factors, accurate estimation of individual patients’ risk level and appropriate selection of perioperative approaches may facilitate safe conduct of these biopsies without strictly precluding the use of GA. However, the outcomes of these procedures performed with current day management strategies have not been reviewed in recent literature.

Thus, we aimed to study the association of airway risk factors with choices of anesthetic and surgical approaches and the resulting procedural and survival outcomes, in a current cohort of pediatric patients with AMMs undergoing initial diagnostic biopsies.

Materials and methods

Results

We identified 35 children with AMMs: 23 (65.7%) were male and 12 (34.3%) were female; diagnoses included lymphoma (N=19), neuroblastoma (N=5), germ cell tumor (N=4) and other masses (N=7) that included tuberculosis, Langerhans cell histiocytosis, pleuropulmonary blastoma, aneurysmal bone cyst, congenital pulmonary airway malformation, leukemia and bacterial lymphadenitis. In total, 23 (65%) underwent GA and 12 (35%) had sedation. No procedures were performed only with local anesthesia. Biopsy approach was percutaneous in 19 (54%), open in 12 (34%), and thoracoscopic in 4 (11%) cases. Digital PACS measurements could be performed on CT scans of 25 patients. Among them, 13 (52%) had >50% reduction in tracheal anteroposterior diameter and 10 (40%) had tracheal deviation.

Significantly more patients with >50% tracheal anteroposterior compression had a diagnosis of lymphoma (11 (85%%) vs 4 (33%), p=0.026), received sedation (9 (69%) vs 3 (25%), p=0.047), and were positioned upright (6 (46%) vs 0, p=0.015) compared with patients with ≤50% compression (table 1). Among them, nine patients (69%) were either spontaneously ventilated and/or put in a sitting position (figure 1). These anesthetic measures did not differ significantly with presence or absence of tracheal deviation (table 1).

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Among patients who underwent biopsies under sedation, supportive measures commonly employed included preprocedural counseling of family and patients, bedside mock rehearsals of anticipated conscious procedures, use of pre-induction topical anesthesia at intended biopsy and intravenous cannulation sites, and intravenous anxiolysis (figure 2).

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In total, 4 of 35 (11.4%) patients encountered procedural adverse events: 2 underwent thoracoscopic biopsy; 3 received GA; all 4 were CTCAE grade 1 and 2 events. Notably, these patients were not placed upright for their biopsies, with three of four in the lateral position (table 2). The first patient, a 10-year-old with lymphoma and a history of asthma, developed laryngospasm after induction with intravenous thiopentone but thereafter successfully underwent thoracoscopic biopsy in a right lateral position. The second patient, a 3-year-old with lymphoma, presented with superior vena cava obstruction. Following inhalational induction with sevoflurane, he developed laryngospasm and desaturated, then was deepened with propofol. He then underwent an open biopsy in a supine position. The third patient, a 12-year-old with lymphoma, presented with mediastinal and tracheal deviation. He had transient desaturation during inhalational induction with sevoflurane but therafter could be ventilated uneventfully, and a thoracoscopic biopsy was performed under GA in lateral position. The fourth patient with pleuropulmonary blastoma presented with tracheal deviation and >50% tracheal compression. She underwent percutaneous biopsy in lateral position under ketamine sedation but during attempted central line insertion desaturated and was intubated. She failed extubation, later requiring high-frequency oscillatory ventilation and then extracorporeal membrane oxygenation (ECMO). She died 1 month post-biopsy due to ECMO-related complications.

Overall incidence of procedural-related adverse events did not differ with airway risk factors but was significantly higher in patients who had morphine and sevoflurane (p<0.001) and in those with thoracoscopic biopsies (p=0.035) (table 3). No direct surgical complications were encountered. Regarding long-term survival, in total, four deaths were encountered: three were delayed and related to disease progression and one (patient 4) was temporally related to the biopsy procedure (table 2). Among the study variables analyzed, only tracheal deviation was significantly associated with long-term survival outcome (p=0.017) (table 3).

Discussion

In our current experience with initial diagnostic biopsies of pediatric patients with AMM, airway risk factors, such as anteroposterior tracheal compression, were not associated with increased incidence of procedural adverse events. Increased adverse events were instead observed with thoracoscopic biopsies and with the use of sevoflurane and morphine. Our findings suggest that with greater awareness of airway risk factors, appropriate patient selection and risk-avoidance practices may effectively obviate the procedural mortality historically associated with these procedures.

Predictive risk factors for mortality from AMM biopsies have evolved during recent decades. The association of anesthetic risk with CT-detected tracheal cross-sectional area was first identified in the 1980s, with avoidance of GA recommended for all children with <50%–66% normal tracheal area.3 10 In the 1990s, recognition of significant risk factors for periprocedural mortality evolved to include <50% predicted peak expiratory flow rate (PEFR) and reduced tracheal cross-sectional area, together termed as ‘Shamberger’s box’.11 12 In patients with mediastinal lymphoma, the presence of clinical symptoms was additionally associated with increased anesthetic complications.8 This study found that anesthetic and surgical management choices of managing teams reflected appropriate risk-based considerations, and procedural morbidities that were historically associated with patients with these risk factors correspondingly decreased. More recent literature is consistent with our experience and may reflect more current trends in anesthetic and surgical practice, particularly that clinical symptoms and PEFR correlate poorly with the actual extent of anatomical airway obstruction and eventual complications.13 Interestingly, we observed that long-term survival was correlated with tracheal deviation, which could be a radiographic risk feature that might indicate more aggressive tumor behavior or greater tumor burden.

Our practice experience supports the benefits of multidisciplinary management of these complex cases.14–16 Preoperative assessments and formulation of multidisciplinary plans have been shown to effectively guide management in such patients and to prevent overall morbidity and mortality.17 If anesthetic or surgical expertise is insufficient to provide the required support for an AMM biopsy, safer alternative sites, such as bone marrow, pleural fluid and extrathoracic lymph nodes, can be considered instead.18 However, they are associated with false negative or inaccurate histological results,19–22 with diagnostic yields as low as 32% reported in bone marrow aspirates and 86% from lymph node biopsies in Hodgkin’s disease.23 In lymphoblastic lymphoma, even less invasive means such as pleural fluid analysis can be used to further mitigate risks.24

Aggressive surgical interventions, such as the use of cardiopulmonary bypass or attempts at upfront resection, have very limited utility and need to be employed with caution. Given the success of the more conservative initial diagnostic approaches that we demonstrated, these more radical maneuvers may hold even less relevance in current practice and if so, only in a few selected scenarios.25 However, empirical upfront treatment also can lead to dramatic tumor shrinkage, which may make AMMs inaccessible for biopsy or potentially alter the histomorphology.18 In pediatric patients with mediastinal lymphoma, pre-biopsy steroids have been associated with compromised pathological diagnosis in up to 22% of cases26 but should be considered particularly in patients presenting with critical life-threatening airway obstruction.27 Pre-biopsy radiation can also distort cellular morphology and compromise accurate histological diagnosis and should be considered with caution.28

Historically, GA has been strictly discouraged in patients with AMMs because of the risk of precipitating complete airway obstruction due to tracheal collapse,29 30 with up to 7%–20% encountering complications, ranging from transient hypotension to complete cardiorespiratory collapse.31 In our study, at-risk patients with >50% reduction in tracheal anteroposterior diameter had significantly greater use of sedation over GA, with corresponding reduction of procedural morbidities. This supports recommendations to maintain muscle tone and spontaneous ventilation in such patients.32 Also, in our study, procedural adverse events were significantly higher in those who positioned supine. This supports the use of upright posturing to decrease anteroposterior pressure on the trachea, thereby avoiding critical airway collapse. In the event of inadvertent intraprocedural deterioration, possible contingencies can include increasing fractional inspired oxygen, repositioning, continuous positive airway pressure or intermittent positive pressure ventilation, rigid bronchoscopy or reducing anesthetic depth.33 34

During the study period, we observed changing trends in the use of sedative agents in our practice. There was an increase in the use of ketamine from 2007 onwards, possibly due to increased experience with its use in patients with AMM and to increased awareness of its advantages, namely maintenance of intercostal muscle function and chest wall tone, which prevent respiratory collapse.35 Also, we noted an increase in the use of dexmedetomidine, which also caused minimal respiratory depression.36 However, to date, there has been little published experience with the use of dexmedetomidine in pediatric AMMs.36–39 Increasingly, we have been combining dexmedetomidine with ketamine, for their complementary analgesic and sympatholytic effects.

This study was limited as a single-center experience and by the small patient numbers, which limited the extent of statistical analysis, particularly precluding multivariable analysis. The wide range of diagnoses included in the study may limit the interpretability of long-term survival data, though it would be expected to have less direct impact on immediate procedural outcomes compared with the anatomical configuration of the tumor and resulting airway compromise. While guided by current evidence, choice of specific procedural measures was not enforced among individual anesthetists and surgeons. The duration of the study period could have contributed to temporal bias and to selection bias due to inclusion of only digitized CT studies. Using risk-based algorithms and guidelines for multidisciplinary teams, future research could study the impact of protocol-based treatment plans in these high-risk procedures. Additionally, future studies could evaluate recently described novel predictive risk factors, including standardized tumor volume and mediastinal mass ratio, which is the CT-measured proportion of maximal widths of mass over mediastinum.40

In conclusion, through a more selective approach to using GA, traditionally high-risk patients with >50% anteroposterior tracheal compression could safely undergo initial diagnostic biopsies of AMMs. Increased appreciation of radiographic risk factors for airway-related procedural morbidity and risk-adapted perioperative management may help to reduce the adverse outcomes historically associated with pediatric AMM biopsies.