Disclosure: This post is unusually full of hearsay and conjecture. Like a secondary endpoint that flirts with statistical significance it should be viewed purely as hypothesis generating. For a more reasoned and experienced view of the following data please read Josh Farkas’s wonderful post on pulmcrit.org.
Damage control ventilation is not a novel concept. It functions under the premise that positive-pressure ventilation intrinsically possesses few curative properties and rather acts as a bridge until a more suitable state of ventilatory well-being can be achieved. As such, we should view its utilization as a necessary evil and endeavor not to correct the patient’s pathological perturbations but rather limit its iatrogenic harms. Since the publication of the ARDSNet protocol in 2000 we have known that striving to achieve physiological normality leads to greater parenchymal injury and downstream mortality (1). Later research demonstrated that even in patients without fulminant ARDS, a protective lung strategy is beneficial (2). Understandably we are reticent to initiate mechanical ventilation unless absolutely necessary. Because of its abilities to delay and even prevent more invasive forms of ventilatory support, non-invasive ventilation (NIV) has long been the darling of the emergent management of most respiratory complaints. It is a rare respiratory ailment that cannot be remedied with a tincture of positive-pressure ventilatory support delivered via a form-fitting face mask. Its widespread implementation is primarily borne from NIV’s capacity to provide a bridge to a more definitive form of therapeutic support. Due in part to NIV’s ability to decrease the rate of intubation in patients presenting with COPD and CHF exacerbations, it is more readily being utilized in a subgroup of patients where a definitive destination is far less assured, a group of patients where the cause of their current dyspnea is not so readily correctable. A bridge, if you permit me a moment of sensationalism, to nowhere…
Although the efficacy for the use of NIV in COPD exacerbations and acute cardiogenic pulmonary edema are well documented (3,4,5,6,7), the evidence for its use in managing other forms of hypoxic failure, such as pneumonia and ARDS, is far less robust. In fact there is some less than perfect evidence demonstrating that in these populations, NIV fails to prevent intubation and in this subset of patients, who are unsuccessful in their trial of non-invasive ventilatory support, the mortality is higher than in those patients who were initially intubated (8,9). And so the authors of the “Clinical Effect of the Association of Non-invasive Ventilation and High Flow Nasal Oxygen Therapy in Resuscitation of Patients with Acute Lung Injury (FLORALI)” trial hoped to examine whether NIV was superior to standard face mask oxygenation therapy in patients with acute hypoxic respiratory failure (10). Frat et al examined two forms of non-invasive ventilatory strategies in patients admitted to the ICU with non-hypercapneic, non-cardiogenic hypoxic respiratory failure. The first was the traditional bi-level positive pressure ventilation, more commonly known as BPAP. The second was high-flow (50 L/min) humidified oxygen delivered via nasal cannula. Using a 1:1:1 ratio the author’s randomized 313 patients too either BPAP, high-flow NC or standard facemask support. The authors enrolled a relatively sick spectrum of patients. In order to be enrolled patients were required to have a respiratory rate of more than 25 breaths per minute, a PaO2/FiO2 of 300 mg Hg or less while on 10 L of supplementary O2, have a PaCO2 of no higher than 45 mm Hg with no history of underlying chronic respiratory disease. Additionally patients were excluded if they presented with an exacerbation of asthma or COPD, cardiogenic pulmonary edema, severe neutropenia, hemodynamic instability, use of vasopressors, a GCS of 12 or less, any contraindication to non-invasive ventilation, an urgent need for intubation or DNI orders. Given these stringent inclusion and exclusion criteria it is no surprise that out of the 2506 patients to present to one of the 23 participating ICUs, only 525 met the criteria for inclusion. Of these 313 underwent randomization and 310 were included in the final analysis (10).
The cause of hypoxia in the vast majority (75.5%) of these patients was due to pneumonia. The authors’ primary endpoint was the number of patients in each group who underwent endotracheal intubation within 28-days of enrollment. Although the authors found no statistical difference in the rate of intubation between the three groups, it is difficult not to infer a clinically important difference that was statistically overlooked due to the limited power generated by an n of 310. The 28-day intubation rate in the high-flow O2 group was 37% compared to 47% and 50% in the face-mask and BPAP groups respectively (an absolute difference of 10% and 13% respectively). When the more severely hypoxic patients were examined (those with a PaO2/FiO2 < 200), this absolute difference increased to 18% and 23% respectively. Additionally patients randomized to high-flow O2 had lower mortality rates, compared to either the facemask or BPAP groups. ICU mortality was 11%, 19% and 25% respectively and 90-mortality was 12%, 23%, and 28% respectively. In the patients with a more pronounced hypoxia these differences in mortality became even more pronounced. In patients with an PaO2/FiO2 < 200 the ICU mortality was 12%, 21.6% and 28.4%, while the 90-day mortality was 13.2%, 27.0% and 32.1%. Although the primary endpoint of this trial was negative (p= 0.18), there is a clear and consistent improvement in outcomes of patients randomized to high-flow O2 compared to the other two non-invasive strategies (10).
This trial is nowhere near perfect. The sample size is far too small to confidently rule out statistical whimsy’s causal responsibility for these findings. Additionally it is difficult to discern whether high-flow O2 was beneficial in this subgroup of patients or rather BPAP was deleterious. Most importantly it fails address the question of primary concern for the Emergency Physician. Is non-invasive ventilation preferable to early endotracheal intubation? Frey et al compared high-flow O2 and BPAP therapy to standard face-mask oxygenation, which does not help us differentiate whether NIV is superior to early invasive ventilator support. Furthermore this trial examines the use of NIV in ICU patients over prolonged periods (median time to intubation was 17-27 hours), it does not tell us whether the use of BPAP is detrimental while patients are managed in the Emergency Department. Given these shortcomings how should we view these data?
Technically from a Frequentist’s viewpoint these statistically significant secondary endpoints are just hypothesis building and additional studies are required to validate these preliminary findings. But what if for a moment, we were to take a Bayesian perspective and examine this very same paper from an alternative vantage? How then would this data appear? Bayesian statistics takes an inductive perspective when examining data. Simply put it asks how does this data affect the prior scientific belief? Given the data presented in this trial, what is the most probable hypothesis that explains these results (12)? How do these results change the current scientific belief that was held prior to this study being conducted? Alternatively, when using Frequentist statistics we employ deductive methodology to address one question and utilize a predetermined statistical threshold to either accept or reject the null-hypothesis. All other questions examined in the paper are essentially exploratory and, due to the single minded nature of the p-value, are simply hypothesis generating (11).
Examining the data published by Frat et al, one would conclude the most probable hypothesis that would explain these events is:
In patients with non-hypercapnic, non-cardiogenic, hypoxic respiratory failure high-flow oxygen therapy decreases both mortality and the rate of intubation when compared to face-mask oxygenation. Additionally the use of BPAP does not decrease the rate of intubation and may in fact increase mortality in a subset of the sickest patients.
How does this effect the prior scientific belief of the efficacy of NIV in patients with hypoxic respiratory failure? Frat et al certainly supports the prior evidence demonstrating that BPAP therapy is detrimental in this subset of patients with hypoxic respiratory failure. In fact the rate of endotracheal intubation (50%) is essentially identical to rates cited in prior cohorts (8). It also highlights that these negative effects may in fact be due to the therapy itself rather than the delay to definitive airway management as was previously hypothesized. Though there was a non-significant increase in the median time to intubation in the BPAP group compared to patients receiving face-mask therapy alone, the time to intubation between the BPAP and high-flow O2 groups were identical. And yet despite these minimal differences in time to intubation, the patients who underwent intubation in the BPAP group had an increased mortality when compared to those randomized to either face-mask and high-flow oxygen (10). Patients in the BPAP group, with the help of positive pressure, achieved average tidal volumes of 9cc/kg. As the ARDSNET trial group demonstrated when administering positive pressure ventilation, a lung protective strategy, tidal volumes of 6cc/kg, led to significant improvement in outcomes in patients with ARDS (1). Determann et al demonstrated that even in patients without ARDS, lung protective strategies led to improved outcomes when compared to more traditional physiological lung volumes (2). Until now we have cognitively absolved positive pressure delivered in a non-invasive form as a causative agent of such complications. The findings of Frat et al have, for the first time, cast a shadow of doubt on the innocence of NIV.
As far as the spectacular results demonstrated by the high-flow O2 group, given the size of the population studied and a paucity of previous science with which to compare, it is hard to know how much credence to place in these results. What is clear is we should no longer view high-flow O2 as a substandard option, reserved only for patients who have failed to tolerate the more traditional forms of NIV. Rather high-flow O2 may provide a unique form of respiratory support that is not accounted for by our prior understanding of NIV (10).
We have known for some time that the use of positive pressure ventilation is the result of being forced to choose between the lesser of two evils. Although it provides a means of ventilatory support, it itself possesses little inherent therapeutic benefits. In fact, positive-pressure ventilation comes at the cost of hemodynamic compromise, iatrogenic lung injury, nosocomial infections, and sedation protocols that leave the patients confused and delirious. As such, a damage control strategy is typically employed to limit these downstream harms until the patients own ventilatory capacity has returned. Until now these strategies have been limited to invasive forms of ventilatory support. The Frat et al data suggests that, to some degree, non-invasive ventilatory support may be associated with similar iatrogenic harms. Although the current data is incomplete, it should remind us that if we intend to construct a bridge, we should have some understanding of where this intended conduit will lead and if this is a healthier destination then where we started.
1. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome: the Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301?8.
2. Determann RM, Royakkers A, Wolthuis EK, et al. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care 2010;14(1):R1.
3. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacer- bations of chronic obstructive pulmonary disease. N Engl J Med 1995;333:817-22.
4. Keenan SP, Sinuff T, Cook DJ, Hill NS. Which patients with acute exacerbation of chronic obstructive pulmonary disease ben- efit from noninvasive positive-pressure ventilation? A systematic review of the lit- erature. Ann Intern Med 2003;138:861-70.
5. Lightowler JV, Wedzicha JA, Elliott MW, Ram FS. Non-invasive positive pres- sure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ 2003;326:185.
6. Masip J, Roque M, Sánchez B, Fernán- dez R, Subirana M, Expósito JA. Noninva- sive ventilation in acute cardiogenic pul- monary edema: systematic review and meta-analysis. JAMA 2005;294:3124-30.
7. Gray A, Goodacre S, Newby DE, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008;359(2):142-51.
8. Carrillo A, Gonzalez-diaz G, Ferrer M, et al. Non-invasive ventilation in community-acquired pneumonia and severe acute respiratory failure. Intensive Care Med. 2012;38(3):458-66..
9. Delclaux C, L’Her E, Alberti C, et al. Treatment of acute hypoxemic nonhyper- capnic respiratory insufficiency with con- tinuous positive airway pressure delivered by a face mask: a randomized controlled trial. JAMA 2000;284:2352-60.
10. Frat JP, Thille AW, Mercat A, et al. High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. N Engl J Med. 2015;
11. Goodman SN. Toward evidence-based medical statistics. 1: The P value fallacy. Ann Intern Med. 1999;130(12):995-1004.
12. Goodman SN. Toward evidence-based medical statistics. 2: The Bayes factor. Ann Intern Med. 1999;130(12):1005-13.
University of Georgetown
Resuscitation and Critical Care Fellowship Graduate