Pneumonia, BiPAP, secretions, and HFNC: New lessons from FLORALI

Pneumonia is extremely common.  Nonetheless, there is surprisingly little evidence about supporting pneumonia patients using bi-level positive airway pressure (BiPAP) or high-flow nasal cannula (HFNC).  The recent FLORALI study offers new insight into this.  This post will explore how BiPAP and HFNC compare for pneumonia patients, prior evidence, and the FLORALI study.

BiPAP and HFNC are the primary techniques available to provide noninvasive support of oxygenation and ventilation in pneumonia.  Some important differences are as follows.  Please note that unless otherwise indicated, "BiPAP" is used here to refer to BiPAP delivered via a facial mask.

There are theoretical advantages and drawbacks of both modalities.  BiPAP can provide greater oxygenation and ventilation support.  However, BiPAP carries risks of mucus plugging, aspiration, and impaired patient monitoring.  Clinical evidence is needed to determine which technique is better. 

This was a prospective RCT of 56 patients with severe pneumonia.  41% of patients also had COPD.  All of the patients with COPD had hypercapnia, as did two patients without COPD.  Exclusion criteria included “inability to expectorate,” although it is unclear how this was determined.  Patients were randomized to BiPAP vs. conventional oxygen therapy.

BiPAP caused a reduction in intubation rates (21% vs. 50%, p=0.03) and ICU length of stay (2 days vs. 6 days, p=0.04).  This was driven primarily by the patients with COPD, among whom there was reduced mortality with the use of BiPAP (table below).  

Interpreting this study is difficult.  Generally post-hoc subgroup analysis is frowned upon.  However, the patients in this study were sharply divided:  half had COPD and were uniformly hypercapneic, whereas the other half didn't have COPD and generally were not hypercapneic.  Thus, sub-group analysis seems reasonable.  This study is often interpreted as showing a benefit among patients with COPD and pneumonia, but not among patients with only pneumonia.  

This was a prospective RCT of 105 patients with severe hypoxemic respiratory failure who were randomized to receive supplemental oxygen versus BiPAP.  Unlike Confalonieri et al., patients with hypercapnia were excluded.  Patients treated with BiPAP were allowed breaks to improve tolerance or clear secretions.  

BiPAP caused a reduction in intubation rate by about 50%, an effect which was also observed in the subgroup of patients with pneumonia (table below).  BiPAP also caused a reduction in ICU mortality. 

What accounts for the difference in results compared to Confalonieri?  One possibility is random chance (for example, if two patients in the pneumonia group had different outcomes this would have shifted the p-value to >0.05 for this subgroup).  Another possibility is that the ICUs in this study were exceptionally good at providing BiPAP.  When patients were having difficulty tolerating the BiPAP, rather than intubation patients were provided with breaks from BiPAP to facilitate secretion clearance. 

Observational studies describe mixed results for treating pneumonia with BiPAP.  Compared to other types of respiratory failure, pneumonia is often a risk factor for BiPAP failure, with failure rates often ~50% (Ferrer 2015).  Thus, the 26% failure rate reported by Ferrer et al. 2003 may not be replicable in general practice. 

Most notable is the lack of evidence regarding BiPAP for patients with pneumonia.  Confalonieri and Ferrer are the largest applicable RCTs, but even these studies combined include only 67 patients with only pneumonia.  The two studies suggest conflicting results, possibly due to different techniques in application of BiPAP.  There are no prior RCTs investigating HFNC in pneumonia. 

This is a prospective randomized trial of BiPAP vs. HFNC vs. non-rebreather facemask for patients with acute hypoxemic respiratory failure.  Inclusion criteria included respiratory rate >25 breaths/min, hypoxemia (PaO2/FiO2<300), absence of hypercapnia, absence of underlying chronic respiratory failure, hemodynamic stability, and GCS>12.  HFNC was performed using large-bore nasal prongs at 50 liters/minute flow and continued for at least 2 days.  BiPAP was applied for at least 8 hours/day for two days, with HFNC applied during breaks in the use of BiPAP. 

310 patients were recruited, of whom 82% had pneumonia.  Intubation and survival curves are shown below.  The hazard ratio for death at 90 days was 2.01 for face-mask versus HFNC (p=0.046) and 2.50 for BiPAP vs. HFNC (p=0.006).  Thus, compared to face-mask, HFNC reduced mortality by a factor of two, with an NNT of 10.  HFNC also caused a greater improvement in tachypnea, discomfort, and dyspnea scores compared to other therapies. 

Although compelling, this paper does have some weaknesses.  For example, 26 patients in the face-mask group and 14 patients in the HFNC group received BiPAP as “rescue therapy,” of whom 70% failed BiPAP and required intubation.  This was not a protocol violation, but was actually allowed within the study design.  Such cross-over may blur differences between groups, reducing observed effect size.

The primary weakness of the study may relate to precisely which diseases are being investigated.  First, it should be noted that the name of the study group is misleading (FLORALI = High FLow Nasal Oxygen in the Resuscitation of patients with Acute Lung Injury)(1).  This study is not an investigation of Acute Lung Injury (e.g. 21% of subjects had unilateral infiltrates, thus not meeting the definition of ALI).  However, many commentaries on the study have already been confused by this name, writing that this was a study of ALI.  To confuse matters further, technically the term "ALI" has now been replaced by "mild ARDS" according to the new Berlin definitions.

Nomenclature aside, this investigation is based on the assumption that all hypoxemic respiratory failure patients require the same treatment.  Which is probably wrong.  For example, patients with ARDS due to extrapulmonary sepsis may be more unstable and more likely to require intubation (Hess 2013, Ferrer 2015).  Combining heterogeneous groups of hypoxemic patients is probably not valid.  The great majority of patients had pneumonia (82%), so it is likely that these patients drove the study results.  Therefore, it might be most accurate to conceptualize this as a study of patients with severe pneumonia.  Given the low numbers of patients with each non-pneumonia diagnosis and lack of subgroup analysis, the results from this study are not necessarily generalizable to every patient with hypoxemic respiratory failure. 

Until recently, there has been little evidence upon which to base the selection of BiPAP vs. HFNC for patients with pneumonia.  FLORALI is a large RCT which constitutes the best available evidence on this topic.  In particular, it is the only RCT which provides a direct comparison between HFNC and BiPAP. 

The benefit of HFNC compared to non-rebreather facemask is not surprising.  HFNC provides powerful support of oxygenation and some support of ventilation as well.  It is extremely safe and well tolerated, with nearly no complications or contraindications.  In short, HFNC brings a lot to the table with almost no drawbacks. 

The trend towards harm from BiPAP is consistent with prior series showing a high failure rate of BiPAP in pneumonia.  This could relate to impaired secretion clearance.  It is conceivable that BiPAP via a nasal interface could perform better than BiPAP via a full facial mask, because nasal BiPAP interferes less with expectoration and communication.

Overall, the best evidence currently supports the use of HFNC as a first-line therapy for patients who have hypoxemia due to severe pneumonia and don't require immediate intubation.  This has been our practice at Genius General Hospitalfor years with good results.  Further studies are needed to confirm this and clarify exactly which patients benefit from HFNC. 

Both FLORALI and Maggiore 2014 (a RCT showing reduction in reintubation using HFNC discussed previously here) utilized HFNC at 50 liters/minute flow.  Although oxygenation may be maintained using lower flow rates, using a high flow rate provides more support for the work of breathing and perhaps some additional PEEP.

The optimal treatment for patients with a combination of COPD and pneumonia remains unclear.  The use of BiPAP in such patients is supported by a strong track record for BiPAP in COPD exacerbations, as well as evidence from Confalonieri et al.  The optimal approach may be determined on a patient-by-patient basis, depending on the dominant disease process, cough strength, and secretion volume.

BiPAP retains one unique advantage compared to HFNC in pneumonia, which is that it is more portable.  HFNC consumes an enormous amount of oxygen, typically requiring direct connection to a wall oxygen line.  BiPAP is a useful approach to support pneumonia patients temporarily during transportation.