Exacerbations of chronic obstructive pulmonary disease (ECOPD) are clinically important events in the course of the disease,1 representing a great burden of morbidity and mortality.2,3 Standard medical care consists of supplemental oxygen, bronchodilators, systemic corticosteroids, and antibiotics.1 Noninvasive positive pressure ventilation (NIPPV) is the recommended treatment for hypercapnic ECOPD after optimal medical management.4 NIPPV is supported by a number of randomized controlled trials (RCT) that have shown a reduction in intubation rates,5–7 mortality,5,6,8 and length of hospital stay.5,7 As a consequence, the use of NIPPV for ECOPD has increased steadily in the last decade whereas invasive mechanical ventilation (IMV) use has declined.9,10 This was accompanied by an increase in the absolute number of patients transitioning from NIPPV to IMV, whose in-hospital mortality appeared to be worsening over time.10 In previous research, concerns were raised that NIPPV might delay intubation leading to a worse outcome.11,12 On the other hand, a dedicated NIPPV team was associated with a lower risk of death or intubation in subjects with ECOPD.13 Therefore, we decided to examine the outcomes of subjects with ECOPD treated according to current recommendations in a “real-life” scenario. In this context, subjects might have different responses to treatment not captured in traditional RCT which usually evaluate the performance of an intervention under ideal and controlled circumstances.14

The Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (GOLD)1 has presented recommendations for hospital and intensive care unit (ICU) admission, NIPPV and IMV. However, less evidence is available on their use in routine practice in the emergency department (ED) setting in Brazil, a practice that is becoming more common with increasing participation of physical therapists.

Therefore, the aim of the present study was to compare clinical outcomes according to initial ventilatory support indication in subjects with ECOPD in a “real-life” ED and investigate predictors of successful NIPPV. Secondly, baseline COPD severity and physiological parameters at ED admission were compared in patients initially selected to receive NIPPV without the subsequent need for IMV (Group A: successful NIPPV), those transitioning from NIPPV to IMV (Group B: failed NIPPV), and patients who presented an immediate need for IMV (Group C).

472 subjects were admitted to the ED with ICD-10 codes related to COPD over the 18-month study period. Of these, there were 93 subjects without the need for ventilatory support, 198 without a previous spirometry test, and 64 patients who had a previous spirometry test without a COPD diagnosis who did not meet the inclusion criteria. NIPPV was used in 109 of the 117 subjects (93%) who required ventilatory support at admission, while the remaining subjects (8/117; 7%) received initial IMV without prior NIPPV (Group C). Among the 109 subjects receiving NIPPV, 13 (12%) required transition from NIPPV to IMV (Group B) (Fig. 1). The difference in previous functional and clinical characteristics, domiciliary oxygen therapy, and continuous NIPPV, as well as Manchester risk classification at ED admission were not statistically significant between Groups A (successful NIPPV) and B, yet in Group C, an increased FEV1/FVC ratio was found (Table 1). Notwithstanding these findings, Group B showed worse clinical outcomes: higher ICU admission, longer length of hospital stay, longer length of ICU stay, and greater in-hospital mortality (Table 2). Poisson regression analyses showed that Group B had a 245% higher risk of mortality when compared to Group A (Exp(B): 3.45; 95% CI: 1.74–6.84; p<0.001). In addition, subjects initially subjected to IMV (n=8) showed higher in-hospital mortality (4/8; 50%) and length of ICU stay (15.8 SD 13.3 days) when compared to Group A (p<0.05), however, no significant difference from Group B was reported (Table 2).

Figure 1.

Flowchart of 117 studied subjects.

Definition of abbreviations: ED, emergency department; ICD, international classification of diseases; COPD, chronic obstructive disease; IMV, invasive mechanical ventilation; NIPPV, noninvasive positive pressure ventilation.

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Our study evaluated clinical outcomes on subjects with ECOPD in a real practice ED setting according to ventilatory support indication based on current recommendations.1 The main findings of the present study were: (1) subjects who failed after an initial NIPPV attempt (Group B) presented higher ICU admission, in-hospital mortality, length of hospital stay and length of ICU stay compared to subjects with successful NIPPV (Group A); (2) although subjects in Group B were significantly more tachycardic when compared to Group A, there were no identifiable physiological parameters at admission to predict a transition from NIPPV to IMV. In fact, the significant parameters for predicting NIPPV failure were intolerance to NIPPV and lower reduction in PaCO2 (i.e. parameters available only after administration of ventilatory support); (3) no difference in prior clinical characteristics were found between Groups A and B, including COPD severity, previous home oxygen therapy and prevalence of comorbidities. Nonetheless, it is important to highlight that because of the size of our study, further research may be necessary to detect significant differences in baseline characteristics between Groups A and B. The use of NIPPV has revolutionized the management of ECOPD18 with a shift from invasive to noninvasive ventilation. Therefore, it is considered reasonable the description of the effectiveness of any proven intervention in a real-life scenario where disease severity, comorbidities and the real practice of health assistance may interfere with outcomes. Furthermore, the study of a specific scenario (in this case, a Brazilian tertiary care ED) is useful for the local evaluation of quality assistance, comparison with other institutions as well as present local/regional results. Our data showed a higher percentage of subjects who required a transition from NIPPV to IMV (13/109; 12%) when compared to a report from an extensive database including over 7.5 million ECOPD admissions (5%)10 or a recent observational study (8%).19 Nonetheless, another extensive database study including more than 723,000 ECOPD hospitalizations reported a 17% NIPPV failure rate9 while another recent observational study showed a 20% rate of those patients transitioning from NIPPV to IMV.20 Therefore, our figures show a NIPPV failure rate within the literature range.

In addition, as previously reported,10 the study found that subjects transitioning from NIPPV to IMV (Group B) presented significantly worse clinical outcomes. Nevertheless, they were not significantly different from those patients initially receiving IMV since initial ED admission (Group C). Further studies are necessary to support this finding because a larger sample is necessary to detect differences between Groups B (n=13) vs. C (n=8) and a type II error could be present. In fact, the above-mentioned extensive database with millions of ECOPD admissions10 suggested that patients who failed NIPPV and transitioned to IMV experienced significantly higher mortality than patients who were immediately submitted to IMV, in addition to the longest and most expensive hospitalizations for COPD exacerbations. Finally, as expected and previously described,21 NIPPV was associated with better results than IMV for ECOPD in a real-world setting.

The identification of predictors of NIPPV failure is not a new concept, and it has been the focus of several previous works resulting in variable findings.16,18,22–24

Unfortunately, no variable capable of predicting NIPPV failure at admission was found. In fact, the only parameters obtained after 1h of NIPPV treatment such as improvement in PaCO2 levels and interface tolerance were significantly associated with success. Subjects who were recommended for noninvasive ventilation (and without a contra-indication) should be re-evaluated after 1h of ventilatory support. A PaCO2 reduction higher than 6.5mmHg was identified as the optimal threshold for success. Although some seminal pioneer RCTs demonstrating the clinical benefits of noninvasive ventilation in ECOPD did not show a significant difference in PaCO2 reduction compared to standard therapy,6,7 other studies have demonstrated a significant higher PaCO2 reduction associated with NIPPV.5,8 Accordingly, the overall combination of seminal RCTs18 and current observational studies19,24 demonstrated higher PaCO2 values after 1h of noninvasive ventilation in the usual medical care group and in the group who subsequently needed IMV, respectively. In fact, the optimal threshold identified in the present study to predict NIPPV success resembled the ∼9mmHg difference in PaCO2 reduction between groups (i.e. NIPPV vs. control) in a previous classical RCT.8 Therefore, NIPPV intolerance and/or absence of reduction in PaCO2 should be considered as meaningful predictors when considering the early transition from NIPPV to IMV in ECOPD. This information has important clinical implications: while a subject with higher likelihood of NIPPV failure with subsequent IMV is best managed in the ICU, a subject who is likely to be successfully treated with noninvasive ventilation can be appropriately managed in less intensive settings. Furthermore, tachycardia at baseline16,19 and persistence of tachycardia after 1h of noninvasive ventilation treatment19 were previously identified as independent predictors of NIPPV failure. Accordingly, despite not remaining in our multivariate analysis (possibly due to our underpowered sample), HR at baseline was significantly higher in patients with NIPPV failure (Table 3). The presence of tachycardia at admission might represent a possible marker of NIPPV failure and deserves further investigation. Finally, low pH value at admission, usually identified as NIPPV failure predictor19,24 was not a significant independent predictor in our multivariate analysis, in accordance with another study showing that ECOPD with severe acidosis (pH≤7.25) could be successfully treated with NIPPV at intermediate care units.25

The strength of the present approach is that all COPD cases were confirmed using spirometry (Fig. 1), whereas in the majority of previous studies5,6,19,21,26–28 this approach was not used for the COPD diagnosis.1 Furthermore, other clinical conditions than COPD that could be responsible for acute respiratory failure and represented potential confounding elements in previous works were not included.29–32 One of the few studies describing spirometric measurements in nearly 90% of the subjects found significantly lower FVC in patients with NIPPV failure,22 which was not observed in our study. Nevertheless, a low statistical power due to the sampling cannot be ruled out. In addition, this study has intrinsic limitations due to its retrospective nature besides the higher probability of protocol violations in real practice and emergency settings. These aspects justify the lack of some potential interesting analyses such as hospital admission comparison among groups (i.e. all patients were admitted to the hospital) and the effect of NIPPV length prior IMV in Group B (due to lack of trustworthy registers).

In conclusion, COPD patients with subsequent transition to IMV (Group B: NIPPV failure) had higher ICU admissions, longer ICU stays, and greater in-hospital mortality compared to those who had successful NIPPV (Group A) in a real practice ED scenario. NIPPV tolerance and higher PaCO2 reduction after 1h of NIPPV were the only predictors of successful NIPPV. These results should be further confirmed in a randomized controlled trial.

The authors declare no conflicts of interest.