The RAMER Reviews: The HAPPEN Randomized Clinical Trial
Written by: Thomas Sanchez, MD; Edited by: Timothy Khowong, MD, MSED
The Trial:
This Randomized control trial conducted in China across 30 centers in non-ICU wards aimed at the study question: Do high intensity settings for Noninvasive Positive Pressure Ventilation (NPPV) decrease the need for endotracheal intubation in patients with exacerbations of COPD?
The study was designed with two groups to evaluate for differences in outcomes. The groups were with Low intensity settings (5-10 mL/kg of tidal volume) vs High intensity settings (10-15 ml/kg of tidal volume). The primary outcome was the need for endotracheal intubation during hospital stay. There were >15 secondary outcomes. The attending physicians and primary investigators were not blinded.
The included patients had an acute exacerbation of COPD and a Paco2 level greater than 45 mm Hg after receiving 6 hours of low-intensity NPPV. They were then informed of the study and elected to participate before being randomized to high or low intensity.
The exclusion criteria included: being younger than 18; having excessive respiratory secretions/upper airway obstruction; having recent oral, facial, or cranial trauma/ surgery; having recent gastric or esophageal surgery; having restrictive ventilatory dysfunction; having active Upper GI bleed; having recent cardiac or respiratory arrest; having a ratio of Pao2 to fraction of inspired oxygen (Fio2) of less than 100 mm Hg; having pneumothorax; having emphysematous bullae confirmed by a CT scan; having ventricular arrhythmia or myocardial ischemia; having severe hemodynamic instability (mean arterial pressure <65 mm Hg); having severe metabolic acidosis (pH level <7.20 and bicarbonate level <22 mmol/L); refusing to receive NPPV or give informed consent; having received prior endotracheal intubation or having undergone a tracheostomy during the current hospitalization; or having a do-not-intubate order.
Investigators determined that in order to properly generate statistical significance of a decrease in intubation rates between the two groups, they would need a sample size of 480. They designed the study to obtain 600 participants across the 30 centers to account for estimated 20% dropout. The two groups were quite similar, though 68% of the participants were male. The primary analyses followed an intention-to-treat approach. Dichotomous primary, secondary, and safety outcomes were compared using either a χ² test or Fisher’s exact test. Continuous secondary outcomes were analyzed using a nonparametric Mann-Whitney test. Absolute differences in rates and their 95% confidence intervals (CIs) were calculated using Wald asymptotic or exact (Clopper-Pearson) methods. For continuous secondary outcomes, differences in median times and their 95% CIs were estimated using 5000-bootstrap resampling. To assess the effects of high-intensity NPPV compared to low-intensity NPPV on primary, secondary, and safety outcomes, univariable and multivariable logistic regression or Cox proportional hazards models were employed.
An interim analysis, as planned, was conducted after primary outcome data were collected for 300 patients at discharge. The analysis revealed a significant difference in the primary outcome—endotracheal intubation—with a between-group difference of 9.0% (1-sided P = .004) based on a simple test of superiority without a predefined margin. In response to these findings, the data and safety monitoring board, along with the trial steering committee, decided to terminate the trial. This decision was influenced by the significant interim results and the logistical and ethical challenges posed by the COVID-19 pandemic, which made continuation of the trial impractical.
The primary outcome, defined as the need for endotracheal intubation based on prespecified criteria, was observed in 7 out of 147 patients (4.8%) in the high-intensity NPPV group compared to 21 out of 153 patients (13.7%) in the low-intensity NPPV group. This represented an absolute difference of −9.0% (95% CI, −15.4% to −2.5%; 1-sided P = .004) and a rate ratio of 0.35 (95% CI, 0.14 to 0.76) (Table 2). After accounting for factors such as respiratory tract infection, time from exacerbation to randomization, pH at randomization, and Pao2:Fio2 ratio at randomization, the difference between the groups remained statistically significant, with an adjusted rate ratio of 0.30 (95% CI, 0.11 to 0.69).
The outcomes are statistically and clinically significant! The rates of intubation were clearly lower in the high intensity group. However, this study has several limitations. It was prematurely halted after enrolling half the intended participants due to significant differences in the primary outcome found during a prespecified interim analysis and challenges like slow recruitment and disruptions from the COVID-19 pandemic. This may skew numbers as they did not complete their initial plan. Treatment allocation was unblinded to investigators and physicians, potentially introducing bias. Randomization was not stratified by center, potentially causing unbalanced characteristics at some sites, though overall baseline characteristics were similar. Lastly, findings may not apply to patients with emphysematous bullae or restrictive ventilatory dysfunction, and others who were excluded.
These results have moderate external validity and generalizability. The ages and other comorbidities were appropriately similar between the two groups. Though further studies with enough power and participants should be conducted in the US in order to have more applicable data to our populations.
Given these results are congruent with current practice, this is practice reaffirming information. It fits the current knowledge well. Many patients with hypercapnic acidosis from COPD exacerbations require NPPV in order to assist in effort and increase Minute Ventilation via Tidal Volume control. This study reaffirms the belief in tidal volume as a main contributor to correction of Paco2 and pH to stave off need for intubation. While an imperfect study, there is statistical significance with the obtained results! Think about using high intensity settings and even consider “AVAPS” mode the next time you have a patient with a COPD exacerbation and respiratory acidosis!