Pratik Doshi: So, for disclosures for our trial, it was sponsored by Vapotherm, who makes the high-velocity nasal cannula that we utilized for this study. None of the authors have any conflict of interest other than the sponsored trial itself and the money that was given for the trial. Two of the authors were employed by Vapotherm at the time, and they were involved in study design as well as analysis and manuscript writing, and therefore they were the authors under the study by ICMJ guidelines. None of the other authors have any other conflicts of interest. I received funding for Zole for co-coordinating on this clinical trial during this time as well.
Dyspnea and respiratory failure are among the top five reasons for patient presentation to the emergency departments. Tools available to us for management of these patients includes simple oxygen therapy, non-invasive positive pressure ventilation, and then subsequently endotracheal intubation, and mechanical ventilation.
Over the last decade, we have seen the increased utilization of high-flow nasal cannula in variety of forms. That has allowed us to actually provide greater support than simple oxygen therapy, and it is felt that it is not as great as support as non-invasive positive pressure ventilation. It can provide 100% oxygen via nasal cannula. It does provide mild distending pressure up to three to five centimeters of water. It actually improves ventilation efficiency by extra-thoracic dead space washout with the flow that is generated. Previous studies using high-flow nasal cannula in the management of hypoxic patients were specifically not hypercapnic.
High Velocity Nasal Insufflation is a form of high-flow nasal cannula, which utilizes a small bore nasal cannula compared to the large bore that was previously studied in the hypoxic patients. The small bore configuration allows for more efficient dead space washout with resultant improvement in ventilatory efficiency. As emergency physicians, when were looking at a tool that may be helpful to us … Its very difficult when the patient shows up in severe respiratory distress to determine if they’re just purely hypoxic. Are they hypoxic and hypercapnic? Are they hypercapnic? We see a lot of work of breathing that’s difficult. For me, the question really comes down to is this a tool that can be utilized in the emergency department at the level of non-invasive positive pressure ventilation.
The hypothesis of our trial was high velocity nasal insufflation is non-inferior to non-invasive positive pressure ventilation in the treatment of undifferentiated respiratory failure starting in the emergency department. It was a prospective, multi-center, randomized controlled trial of two non-invasive ventilatory modalities. HVNI vs. non-invasive positive pressure ventilation using a non-inferiority model. We conducted a trial around five centers across Southeastern United States. Two of them were academic centers and three of them were community centers just to provide the heterogeneity clinical practice, and as well as be able to translate the results to say it is effective in all settings not just in academic tertiary care centers.
Our inclusion criteria was straightforward as an adult patient that shows up with respiratory failure that the treating clinician deems requires non-invasive positive pressure ventilation. Once that was deemed, the patients were randomized to either get high-flow high velocity nasal insufflation versus non-invasive positive pressure ventilation. Our exclusion criteria were suspected drug overdose, cardiovascular instability, end stage cancer, life expectancy less than six months, significant respiratory depression with a GCS of less than nine, cardiac or respiratory arrest on presentation, and known or suspected stroke on ST elevation MI that require other interventions, and patients with increased risk of pulmonary aspiration [inaudible 00:03:26] with high velocity nasal insufflation that aspiration risk is not there. We’re going to be randomizing these patients and we felt that the aspiration risk with non-invasive positive pressure ventilation would be a contraindication to put these patients on that. Those were the exclusion criteria for the trial.
Our primary endpoint was treatment failure. This is an important part. Treatment failure was defined as a requirement of endotracheal intubation. However, if you are going to conduct a clinical trial looking at respiratory failure in the emergency department, consent becomes a big issue. Safety also becomes a big issue for these patients. We actually built in a crossover arm within the trial to allow for if they were randomized to a primary therapy and then bedside clinician felt that the primary therapy was not working, they had a choice of either crossing over to the other therapy or to proceed with endotracheal intubation and mechanical ventilation.
Our primary endpoint become co-primaries. One is requirement of endotracheal intubation and mechanical ventilation, as well as failure of primary assigned therapy which was built in more from safety perspective than the actual endpoint. Our power analysis and all calculations were based on rates of intubation that was present for non-invasive positive pressure ventilation. Such data does not exist for high-flow nasal cannula or high-velocity nasal insufflation.
Our secondary endpoints were ability of high-velocity nasal insufflation versus non-invasive positive pressure ventilation to affect indices of breathing, specifically PCO2, respiratory rate, heart rate, and saturation. Patient perception of dyspnea was evaluated by visual analog scale and modified Borg score. We also collected data on the treating physician’s perception of efficacy recorded at the end of the first four hours or the end of the emergency department stay for the patient. Disposition and length of stay in any unit was reported to determine any differences between groups.
The patients were monitored for 72 hours after randomization for the primary endpoint. In our mind that was because we felt that if the patient’s condition continued to be worse at that point, or recurred for things like COPD or CHF, it was not the primary reason and if the intubation happens subsequent to that, it would not mean that the the primary treatment did not work if it worked for three days and then they subsequently required intubation. Final disposition and length of stay data for the entire hospitalization was collected. A sample size of 204 patients was calculated such that we would have a significant .05 significance level with 90% power based on an intubation rate of 16.1%.
This is also worth discussing for a moment. 16.1% comes from the Cochran Review for COPD exacerbations treated with non-invasive positive pressure ventilation. That had a wide conference interval. For CHF, that number is about 15%. If you looked at hypoxic respiratory failure, that number is much higher. Up to 40 or 50% of those patients require intubation. We chose the 16% because choosing the higher rate is easy because I need less patients to potentially show something, but we wanted to be conservative and we wanted to make sure that whatever we showed in this clinical trial was meaningful and was appropriate to come to the conclusions that we were hoping to come to. That’s where the 204 patient sample size was calculated.
This is our consort diagram. There were 546 patients that were escalated to non-invasive positive pressure ventilation during the study period which was a two-year period, October 2014 to September 2016. Out of these, 228 patients were randomized, and 204 were enrolled finally. The number from 546 to 228, majority of it is anytime any of us that run clinical trials, we realize that just getting the people to the bedside in a timely fashion to be able to enroll them is difficult. The majority of the patients were actually just logistic reasons why we couldn’t get to the patient in a timely fashion.
From the 228 to 204, there were 24 patients that were excluded after randomization. 10 of them actually met exclusion criteria. Six of them did not consent to the study after being randomized, and two of the physicians refused continuation in the trial itself. That’s how we get to 204 in the HVNI group and 100 in the non-invasive ventilation group. These are our baseline characteristics. I hope they project well. Average age in both arms was 63. The body mass index was 32 as we were just discussing, so we were Southeast United States. We’re big people and that’s what we expected to find, and that’s what we did see. Average [inaudible 00:07:38] score, which we did purely to make sure the severity of illness was similar between the two groups was surprisingly high. It was 31 in both groups, which is a very high severity of illness overall.
Then the second part of this algorithm is the presenting condition and the discharge diagnosis. We were trying to assess what the reason for respiratory failure was at the time of enrollment. Then we went back at discharge to see what the final discharge diagnosis was for the patient, to be able to have more correct information. Sometimes patients that face three or four CHF and COPD, they come in as respiratory distress, and it’s not completely clear what the reason for their respiratory distress is. We did both, and about a third of our patients were …