Procedure volume and mortality after surgical lung biopsy in interstitial lung disease

Discussion

Previous research has shown that mortality after SLB is variable, and may be unacceptably high for some patients and in some settings [5–9]. We used multilevel modelling to demonstrate that higher hospital SLB volume was associated with lower 30-day post-operative mortality after SLB in a large cohort of patients with ILD. The stratified analysis suggested this relationship was stronger for nonelective patients and may be less likely to apply in elective situations. The highest volume quartile group was significantly associated with a lower odds of 30-day post-operative mortality, resulting in a volume threshold of 144 SLBs per hospital per year. It is likely that different volume thresholds could be safely applied to elective versus nonelective SLBs; however, we were not powered to assess this. To the best of our knowledge this is the first study to evaluate the volume–outcome relationship for SLB in ILD. The variability in post-operative mortality attributable to between-hospital differences was small, suggesting that the wide range of mortality described in the literature may be explained by patient-level factors. Specifically, nonelective procedure appears to be the most important prognosticator of post-operative outcome.

Similar volume–outcome relationships have been found with many surgeries and have been used to support the regionalisation of care for certain procedures such as lung cancer resection [11, 15]. The volume–outcome relationship is likely more complicated than purely surgical expertise and there are several factors specific to SLB in ILD patients to consider. Previous studies have suggested that an acute exacerbation of ILD (AE-ILD) may be precipitated by SLB and contribute to high mortality rates seen in this population [8, 17]. In-hospital mortality from AE-ILD is as high as 50–80% [18–20]. The trigger for an AE-ILD after SLB is unclear and may be related to factors other than surgical expertise. For example, hyperoxia and mechanical stress during ventilation of the fibrotic lung and intra-operative fluid balance have been proposed as potential aetiological factors in AE-ILD after SLB [21, 22]. Institutional factors may also influence the volume–outcome relationship, with higher-volume centres having processes in place that better equip them for the peri-operative management of these patients. The experience of support staff working in the operating room, post-operation unit, intensive care unit and surgical ward may all play a role in patient outcome. Higher-volume centres may also be more likely to have ILD experts that influence patient referral and selection for SLB. Given the volume–outcome association we observed appeared to be stronger for nonelective cases, variations on the basis of expertise within hospitals are perhaps not unexpected. However, identifying the mechanisms driving a specific volume–outcome relationship remains important for implementing system changes aimed at improving patient outcomes.

The 30-day post-operative mortality was 7.1% in our overall study cohort. Mortality was much higher for nonelective procedures (20.2%) compared with elective procedures (1.9%). These results are consistent with those seen in US administrative data, where in-hospital mortality was 6.4% for a large cohort of ILD patients undergoing SLB and mortality for nonelective procedures was much higher than for elective procedures (16.0% versus 1.7%, respectively) [9]. The authors of that study were unable to ascertain 30-day mortality, but our data on 30-day mortality would be expected to be higher than in-hospital mortality, suggesting our data are likely generalisable to other settings in North America. Interestingly, 30-day mortality after SLB for ILD in administrative data from the UK was similar to ours among elective procedures (1.5%), but lower (6.3%) in nonelective procedures [10]. This mortality difference may reflect variation in practice and nonelective patient selection patterns between the UK and North America. Regardless, a 30-day post-operative mortality rate of ∼2% for elective SLB is consistent across European and North American data.

In keeping with previous research, we also found several patient-level factors that were independently associated with 30-day post-operative mortality on multilevel modelling [9, 10]. These included older age, male sex, higher Charlson Comorbidity Index, long-term oxygen therapy, nonelective procedure and open thoracotomy. The ICC was negligible in all three of the full multilevel models (overall cohort, nonelective and elective patients). The lack of variability in outcome related to hospital variation suggests that patient characteristics are important drivers in post-operative mortality after SLB for ILD and should be carefully considered when assessing operative risk. Nonelective procedures had a strikingly higher 30-day mortality compared with elective procedures. It is difficult to know whether this finding is attributable to high baseline risk and post-operative complications or if these patients would have died regardless because of their clinical trajectory. In either case, the clear risk of SLB in nonelective patients with ILD should be carefully weighed against the potential a SLB will significantly alter treatment decisions and clinical course before deciding to proceed in such individuals.

Interestingly, while unadjusted mortality appeared to be stable over time, we found that later procedure year was associated with higher odds of SLB mortality on multilevel modelling in the overall cohort and nonelective patients. At first glance this is counterintuitive as operative mortality has fallen over time for many procedures, such as aortic valve replacement, carotid endarterectomy and several cancer resections [23, 24]. One hypothesis for the unexpected finding is that clinicians have become more aggressive with pursuing SLB over time. Our patient population appeared similar over time regarding age, sex and comorbidity burden. We were limited in our ability to determine the severity of lung disease, but the use of long-term oxygen therapy increased over time, suggesting that patients may have had progressively more severe lung disease during the study period. Several key publications on ILD occurred during our study period that may have influenced trends in pursuing SLB. In 2002, the first international guideline on the diagnosis and classification of ILDs was published jointly by the American Thoracic Society and European Respiratory Society. This guideline placed an emphasis on obtaining a SLB to aid in diagnosis in the absence of contraindications and noted that with the advent of VATS, SLB should be associated with less risk than historically seen [1]. Furthermore, this guideline stated that transbronchial biopsies were generally not useful and discouraged the traditional practice of a trial of therapy to determine prognosis rather than pursuing SLB. The authors also made note of the low SLB rate in patients with ILD at that time. In 2011, interim results from the PANTHER trial were available showing increased mortality in idiopathic pulmonary fibrosis (IPF) patients treated with prednisone, azathioprine and N-acetylcysteine [25, 26], providing further discouragement for the clinical practice of a trial of immunosuppressive therapy in situations of diagnostic uncertainty. In 2012, pirfenidone, an antifibrotic agent, was approved for use in IPF by Health Canada and, since this class of medication is not indicated in non-IPF ILD, further emphasis may have been placed on the importance of SLB after 2012 [27]. It is possible that these changes to the landscape of ILD in Canada resulted in clinicians pursuing SLB more aggressively in higher-risk patients over time and thus increasing post-operative mortality. Specifically, it is possible that patients with IPF were biopsied more frequently in recent years and were more likely to have higher post-operative mortality [9]. Expanding on the recent IPF diagnostic guidelines [28] with the development of a statement advising physicians on when SLB is contraindicated and outlining specific pre-operative considerations should be considered to avoid potentially harmful trends associated with inappropriate SLBs.

There are several limitations to our study. First, large-scale validation studies in ICES databases have not been performed for ILD codes. As a result, we were unable to assess the relationship between ILD subtype and 30-day post-operative mortality after SLB. However, we felt the specificity of an ILD diagnosis in our cohort was likely to be high, given that individuals had both a diagnostic code for ILD and underwent a SLB. Second, there is always potential for unmeasured confounding when using administrative databases for research. We were unable to ascertain lung function or intra-operative ventilator management. These may be important factors in outcome after SLB in ILD and difficult to tease out given the limitations of administrative data. Third, the stratified analysis should be interpreted with caution given an interaction term for surgical volume and nonelective versus elective procedure was nonsignificant and the sample size was not large enough to excluded a volume–outcome relationship for elective procedures. Lastly, while we showed a volume–outcome relationship between SLB and post-operative mortality, recommending system changes aimed at improving outcomes remains a challenge. We cannot be sure of the exact mechanisms behind the volume–outcome relationship. Surgical expertise is an attractive and straightforward theory which can lead to minimum volume recommendations for procedures. However, previous studies have found that increasing surgical volume does not always translate into a decrease in post-operative mortality [15], suggesting the relationship is more complicated than the research can sometimes elucidate. Despite these limitations, we were able to reliably ascertain 30-day post-operative mortality, a clinically meaningful end-point, expanding on previous administrative data that have relied on in-hospital mortality estimates.

We applied multilevel modelling to show that higher yearly hospital SLB volume is associated with lower 30-day mortality after SLB for ILD. Nonelective SLB was associated with a significantly higher mortality rate than elective SLB and should therefore be discouraged unless there is a clear indication.