High-Intensity vs Low-Intensity NPPV in Patients With an AECOPD: The HAPPEN Trial

Effect of High-Intensity vs Low-Intensity Noninvasive Positive Pressure Ventilation on the Need for Endotracheal Intubation in Patients With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease The HAPPEN Randomized Clinical Trial

To determine whether high-intensity NPPV, compared with low-intensity NPPV, could reduce the need for endotracheal intubation during hospitalization in patients with an AECOPD and hypercapnia.

Study Overview

• Status: Terminated
• Conditions: Acute Exacerbation of Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Device: High-intensity NPPV; Device: Low-intensity NPPV

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Bayan Nur, China
    • Wuyuan Hospital of Inner Mongolia
  • Beijing, China
    • Beijing Luhe Hospital
  • Beijing, China
    • Beijing Chao-Yang Hospital
  • Beijing, China
    • Beijing Pinggu Hospital
  • Beijing, China
    • Beijing Mentougou District Hospital
  • Beijing, China
    • Beijing Fangshan Liangxiang Hospital,
  • Beijing, China
    • Beijing Jingmei Group General Hospital
  • Beijing, China
    • Beijing Zhongguancun Hospital
  • Beijing, China
    • Capital Medical University Daxing Teaching Hospital
  • Chongqing, China
    • The Second Affiliated Hospital of Chongqing Medical University
  • Dalian, China
    • Dalian Friendship Hospital
  • Dalian, China
    • Dalian Municipal Central Hospital
  • Hangzhou, China
    • Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
  • Hangzhou, China
    • Shulan (Hang Zhou) Hospital
  • Hebi, China
    • Hemei General Hospital
  • Huangshi, China
    • Huangshi Central Hospital
  • Jiaozuo, China
    • Jiaozuo People's Hospital
  • Jiaozuo, China
    • Jiaozuo Second Hospital
  • Kaifeng, China
    • Kaifeng Central Hospital
  • Kaifeng, China
    • The First Affiliated Hospital of Hanan University,
  • Luoyang, China
    • The First People's Hospital of Luoyang
  • Mianyang, China
    • The Third Hospital of Mianyang
  • Nanyang, China
    • Nanyang Central Hospital
  • Nanyang, China
    • Nanyang First People's Hospital
  • Sanmenxia, China
    • Sanmenxia Central Hospital
  • Tongliao, China
    • The Second Hospital of Tongliao
  • Urumqi, China
    • People's Hospital of Xinjiang Uygur Autonomous Region
  • Xinxiang, China
    • Xinxiang Central Hospital
  • Zhengzhou, China
    • Zhengzhou Central Hospital
  • Zhuzhou, China
    • Hunan Province Directly Affiliated TCM Hospital
  • Zibo, China
    • Zibo First Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• AECOPD confirmed by the 2019 criteria of the Global Initiative for Chronic Obstructive Lung Disease (GOLD)
• Arterial pH <7.35 and PaCO2 >45 mmHg at screening entry
• PaCO2 >45 mmHg after a 6-hour trial of low-intensity NPPV

Exclusion Criteria:

• Age <18 years
• Excessive respiratory secretions with weak cough
• Upper airway obstruction
• Recent oral, facial, or cranial trauma or surgery
• Recent gastric or esophageal surgery
• Presence of restrictive ventilatory dysfunction (eg, consolidation or removal of at least one pulmonary lobe, massive pleural effusion, chest wall deformity, continuous strapping with thoracic or abdominal bandage, or severe abdominal distension)
• Active upper gastrointestinal bleeding
• Cardiac or respiratory arrest
• Arterial oxygen tension/fraction of inspired oxygen (PaO2/FiO2) <100 mmHg
• Pneumothorax
• Obvious emphysematous bullae confirmed by chest CT scan
• Ventricular arrhythmia or myocardial ischemia
• Severe hemodynamic instability (mean arterial pressure <65 mmHg)
• Severe metabolic acidosis (pH <7.20 and bicarbonate <22 mmol/L)
• Refusal to receive NPPV or give informed consent
• Prior endotracheal intubation or tracheostomy during the current hospitalization
• A do-not-intubate order

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-intensity NPPV; Patients will receive high-intensity NPPV.	Device: High-intensity NPPV; In the high-intensity NPPV group, IPAP is initially adjusted in increments/decrements of 1-2 cmH2O, typically ranging from 20 to 30 cmH2O (or a tolerated maximum), to obtain a VT 10-15 mL/kg PBW and a respiratory rate <25 breaths/min. Subsequent adjustments to IPAP are based on the results of arterial blood gases (ABGs; up to 30 cmH2O) to achieve normocapnia (if possible), or to maximally decrease PaCO2 toward normocapnia if normocapnia can not be achieved. If PaCO2 decreases to less than 35 mmHg, IPAP will be decreased to achieve normocapnia.
Active Comparator: Low-intensity NPPV; Patients will receive low-intensity NPPV.	Device: Low-intensity NPPV; In the low-intensity NPPV group, as well as during the 6-hour trial of low-intensity NPPV, IPAP is initially adjusted in increments/decrements of 1-2 cmH2O (up to 20 cmH2O), according to patients' tolerance, to obtain a VT 6-10 mL/kg PBW and a respiratory rate <25 breaths/min. Subsequent adjustments to IPAP are based on the results of ABGs (up to 20 cmH2O) to achieve a pH of ≥7.35 and to reduce PaCO2 to a level deemed appropriate by the attending physician.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The need for endotracheal intubation during hospitalization	Defined as the proportion of patients who needed for endotracheal intubation during hospitalization after randomization	From randomization to discharge from hospital

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Actual intubation during hospitalization	Defined as the proportion of patients actually receiving intubation and invasive ventilation during hospitalization after randomization	From randomization to discharge from hospital
Need for endotracheal intubation at day 28	Defined as the proportion of patients who needed endotracheal intubation within 28 days since randomization	Within 28 days since randomization
Actual intubation at day 28	Defined as the proportion of patients receiving intubation and invasive ventilation within 28 days after randomization	Within 28 days since randomization
The composite of actual intubation or avoiding intubation by crossover to high-intensity NPPV	Defined as the incidence of patients receiving actual intubation in the high-intensity NPPV group vs the composite incidence of actual intubation or avoiding intubation by crossover to high-intensity NPPV in case of intubation criteria in the low-intensity NPPV group) during hospitalization after randomization	From randomization to discharge from hospital
NPPV weaning success	Defined as the proportion of patients with persistent disconnection of NPPV without the presence of respiratory distress within the following 72 hours during hospitalization after randomization	From randomization to discharge from hospital
Mortality in hospital		From randomization to discharge from hospital
Mortality at day 28		Within 28 days since randomization
Mortality at day 90		Within 90 days since randomization
Intensive care unit admission	Defined as the proportion of patients who transferred to ICU during hospitalization after randomization	From randomization to discharge from hospital
Live discharge from the hospital	Defined as the proportion of patients with the exception of those who died and withdrawn treatment therapy during hospitalization after randomization.	From randomization to discharge from hospital
Length of hospital stay	Defined as the number of days for the index hospitalization	From hospital admission to discharge
Length of hospital stay after randomization	Defined as the number of hospitalization days since randomization	From randomization to discharge from hospital
Invasive ventilator-free days at day 28	Defined as 28 minus the number of days with invasive ventilator (range, 0-28 days) since randomization	Within 28 days since randomization
ICU-free days at day 28	Defined as 28 minus the number of days in the ICU (range, 0-28 days) since randomization	Within 28 days since randomization
Hospital readmission at day 90	Defined as the number of hospitalization days within 90 days since randomization	Within 90 days since randomization

Collaborators and Investigators

• Sponsor: Beijing Chao Yang Hospital
• Investigators: Principal Investigator: Zujin Luo, MD, Beijing Chao Yang Hospital

Publications and helpful links

General Publications

• Luo Z, Wu C, Li Q, Zhu J, Pang B, Shi Y, Ma Y, Cao Z; HAPPEN collaboration group. High-intensity versus low-intensity noninvasive positive pressure ventilation in patients with acute exacerbation of chronic obstructive pulmonary disease (HAPPEN): study protocol for a multicenter randomized controlled trial. Trials. 2018 Nov 21;19(1):645. doi: 10.1186/s13063-018-2991-y.

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2019
• Primary Completion (Actual): January 31, 2022
• Study Completion (Actual): April 22, 2022

Study Registration Dates

• First Submitted: December 2, 2016
• First Submitted That Met QC Criteria: December 5, 2016
• First Posted (Estimated): December 7, 2016

Study Record Updates

• Last Update Posted (Actual): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 4, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease Attributes; Chronic Disease; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: BeijingCYH-ICU-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No