The randomized control trial has proven to be the ideal method to account for non-random error or bias. The concept is simple, any confounders that exist in the cohort will be equally distributed between groups. And while randomization is our best strategy to control for non-random error, its strengths are dependent on the efficacy of the randomization process. As the sample size grows larger, the random variation between the groups becomes less pronounced. In undersized trials, where the total number of patients randomized is small, the risk of random deviations significantly affecting the resulting cohort is high.
It is with this in mind that we turn to a recent trial published in JAMA by Patel et al examining the role of non-invasive positive pressure ventilation (NIPPV) in patients with ARDS (1). The authors enrolled 83 patients with ARDS presenting to a single ICU in Chicago. The authors compared NIPPV using a standard facemask to a novel positive pressure helmet(see fig.1).
The trial was stopped prior to the 206 patient preplanned sample size due to an overwhelming benefit demonstrated in the patients randomized to the helmet arm. The intubation rate was 61%in the standard facemask group vs only 18% in the helmet group. This 43.3% ARR crossed the predetermined threshold for stoppage with a p-value of <0.001 (95% CI -62.5% to -24.3%). Additionally, patients randomized to the helmet group had significantly more ventilator free days at 25.5 vs 12.5 and demonstrated a significantly decreased mortality rate (34.1% vs 56.4%, p value 0,02) when compared to those who received NIPPV using a traditional facemask. Adverse events were minimal in both groups and primarily limited to pressure related ulcers (3 in each group), involving the respective device interfaces with the patients’ skin.
The authors offer a number of suggestions to account for why this novel method of applying NIPPV may have resulted in such impressive benefits when compared to the traditional approach. Because of a more efficient seal created at the interface between the patient and the device, patients randomized to receive NIPPV via the helmet were able to be ventilated with higher levels of PEEP (8 cm H2O compared to 5 cm H2O). The authors infer that these higher PEEP values allow for increased alveolar recruitment and in turn improve lung mechanics. Additionally, the helmet apparatus utilizes high flow oxygen with rates of at least 100 L/m to ensure washout of excess CO2 that tends to accumulate in the helmet. These flow rates may have led to a wash out of the residual CO2 in the upper airway allowing for more efficient ventilations, in turn decreasing the overall work required from the patients. These suppositions are at least in part supported the data. The patients randomized to NIPPV via the helmet had lower respiratory rates and higher oxygen saturation despite requiring lower levels of inhaled oxygen. The authors also reported that the patients randomized to the helmet group were far less likely to require intubation for respiratory failure when compared to patients in the standard face-mask group (37.5 vs 83.3%).
And while such physiologic reasoning seems plausible and may be the underlying foundation for this trial’s success, it may in reality be due to simple chance errors in the randomization process. The results demonstrated by Patel et al are intriguing. It is a shame the study was stopped prior to completing enrollment. If such a prominent effect size remained after enrolling 206 patients these conclusions would be far more convincing. As it stands, given the early stoppage and diminutive sample size it is difficult to imagine clinicians modifying their practice based on these limited results.
It is important to question whether traditional NIPPV using a facemask is the appropriate control with which to compare this novel helmet. A great deal of late has been published on the use of NIPPV in the treatment of ARDS. Most of these endeavors have demonstrated that a large portion of patients placed on non-invasive positive pressure ventilation will fail, requiring subsequent intubation and mechanical ventilation. Most recently the FLORALI trial published by Frat et al in the NEJM, demonstrated that patients who were randomized to BiPAP, when compared to standard face-mask or high-flow nasal cannula, more frequently required mechanical ventilation (50%,47% 38%) (2). More importantly, in the subset of patients who failed non-invasive measures, those who received NIPPV prior to intubation demonstrated higher mortality rates (49% compared to 45% and 30% in the facemask and high-flow groups respectively). The authors suggest the high tidal volumes delivered when using NIPPV may be responsible for these observations. The median tidal volume observed in the NIPPV group while on BiPAP was 9 cc/kg, which is higher than the 6 cc/kg we traditionally consider lung protective ventilation (4).
The role of tidal and NIPPV failure in patients with acute hypoxic respiratory failure was recently examined in an observation study published in Critical Care Medicine by Carteaux et al. The authors enrolled 62 patients with hypoxic respiratory failure initially managed using NIPPV. 76% met criteria for acute respiratory distress syndrome (ARDS) and 51% of patients failed NIPPV and required intubation. In the analysis of the exhaled tidal volume obtained during NIPPVthey found that despite adjusting pressure support to target volume between 6-8 ml/kg of predicted body-weight (PBW), the median tidal volume obtained during trials of NIPPV in the entire cohort was 9.8 mL/kg PBW. The mean tidal volume and minute ventilation in patients who failed NIPPV were significantly higher than in those who did not (10.6 mL/kg vs 8.5 mL/kg and 21 L/min vs 17 L/min respectively). Patients with a PaO2/FiO2 ratio ? 200 mm Hg with a mean tidal volume ?9.5 mL/kg at 4 hours had a higher probability of NIPPV failure. Despite targeting low tidal volumes with minimal pressure support (median value 7 cm H2O), 77% of patients still had unsafe mean tidal volumes ?8ml/kg PBW.
The non-randomized and observational nature of the data presented by Carteaux et al prohibits us from reaching causative conclusions. Whether NIPPV in patients with hypoxic respiratory failure is intrinsically deleterious or failure of NIPPV is simply a marker for worsening underlying disease is unclear. However, these findings are consistent with previous literature suggesting potential harm with the use of NIPPV in patients with ARDS. It is evident that a large portion of patients with ARDS on NIPPV require subsequent intubation, and that the uncontrolled tidal volumes perpetuated by NIPPV may intrinsically worsen lung injury. The patient-centered gains achieved through the avoidance of early intubation may be offset by the injurious ventilatory pattern promoted by NIPPV. As such, NIPPV using a traditional facemask, may not be the ideal control group with which to compare these novel forms of NIV. Rather, a more important clinical comparison may be the analysis of these novel therapies in contrast to early intubation and lung protective mechanical ventilation.
- Patel BK, Wolfe KS, Pohlman AS, Hall JB, Kress JP. Effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2016;
- Frat JP, Thille AW, Mercat A, et al. High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. N Engl J Med. 2015;
- Carteaux G, Millán-Guilarte T, de Prost N, et al.: Failure of Noninvasive Ventilation for De Novo Acute Hypoxemic Respiratory Failure: Role of Tidal Volume. Critical Care Medicine 2016; 44:282–290
- 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.