Preventive Effects of Penehyclidine Hydrochloride Inhalation on Postoperative Pulmonary Complications

Study Overview
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Brief Summary
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Postoperative pulmonary complications (PPCs) are major causes of postoperative morbidity, mortality, and prolonged hospital stay.The incidence of PPCs may be as high as 41% to 75% in high-risk patients. Bronchodilator is frequently used in high-risk patients to prevent PPCs. Penehyclidine is a new anticholinergic agent which selectively block M1 and M3, but not M2 receptors. A pilot study of the investigators showed that prophylactic penehyclidine inhalation reduced the incidence of bronchospasm and the use of aminophylline in elderly patients after long-duration surgery. The purpose of this study is to investigate whether prophylactically penehyclidine inhalation could decrease the incidence of PPCs in high-risk patients after major intrathoracic and upper intraabdominal surgery.

Detailed Description
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Postoperative pulmonary complications (PPCs) are major causes of postoperative morbidity, mortality, and prolonged hospital stay. The incidence of PPCs was found to vary from 2 to 19%, but this rate might be as high as 41 to 75% in patients after intrathoracic and intraabdominal surgery. According to Canet's model, the predicted incidence of PPCs in high-risk patients (ARISCAT risk index >= 45 points) is 42.1%. Use of effective strategies to prevent PPCs is essential for these patients. Strategies that have been proved to be beneficial in decreasing PPCs include smoking cessation, proper management of chronic obstructive pulmonary disease before surgery, as well as use of lung-protective ventilation and goal-directed fluid therapy during surgery. Besides, bronchodilator inhalation is also helpful. Studies showed that, in high-risk patients undergoing intrathoracic surgery, airway resistance was increased due to bronchial hyperresponsiveness, which increased the risk of PPCs. Inhalation of anticholinergic bronchodilator can reduce the activity of vagus nerve and relieve high airway resistance, which may decrease the risk of bronchospasm and other PPCs. It has been shown that M1, M3-receptor selective blockers have better effects than β2-receptor activator in dilating bronchia. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (updated 2014) published by Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend the use of M1, M3-receptor selective blockers to relieve acute exacerbation of chronic obstructive pulmonary disease (COPD) and improve pulmonary function. Penehyclidine hydrochloride is a new anticholinergic agent, which selectively blocks M1 and M3, but not M2 receptors. Preclinical studies found that it also has anti-inflammation effects. In a pilot study of the investigators, prophylactic inhalation of penehyclidine decreased the incidence of bronchospasm and the use of aminophylline in elderly patients after long-duration surgery. The investigators propose that prophylactic inhalation of penehyclidine might decrease the incidence of PPCs in high risk patients. The purpose of this study is to investigate whether prophylactic penehyclidine inhalation could decrease the incidence of PPCs in high-risk patients after major intrathoracic and upper intraabdominal surgery.

Official Title
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Preventive Effects of Penehyclidine Hydrochloride Inhalation on Postoperative Pulmonary Complications in High-risk Patients: a Randomized, Double-blind, and Placebo Controlled Study

Conditions
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Postoperative Complications

Intervention / Treatment
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* Drug: Penehyclidine inhalation
* Drug: Placebo inhalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >50 years; Scheduled to undergo upper abdominal or noncardiac thoracic surgery with expected duration ≥2 hours. For those who undergo laparoscopic or thoracoscopic surgery, the expected length of incision must be ≥5 cm; Judged to be at high risk of PPCs according to the ARISCAT risk score (ARISCAT predictive score ≥45). Exclusion Criteria: American Society of Anesthesiologists (ASA) physical classification ≥IV or the expected survival duration ≤24 hours; Preoperative history of symptomatic hypertrophy or glaucoma; History of myocardial infarction, severe heart dysfunction (New York Heart Association functional classification ≥3) or tachyarrhythmia within one year; Inhalation of β2-receptor activator, M-receptor blockers and/or glucocorticoids within one month before surgery; Severe renal dysfunction (requirement of renal replacement therapy) or severe hepatic dysfunction (Child-Pugh grade C); History of acute stroke within three months before surgery; Refuse to participate in the study or unable to cooperate with the inhalation therapy; Participation in other clinical trial during the last month or within the six half-life periods of the study drug used in the last trial.

Ages Eligible for Study
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Minimum Age: 51 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Penehyclidine group<br>Penehyclidine inhalation will be administered (penehyclidine hydrochloride 0.5 mg/0.5 ml + normal saline 5.5 ml) once every 12 hours from the night before surgery till the second day after surgery. The total number of inhalation is seven times. Study drug inhalation will be performed with the high-flow oxygen-driven method for the non-intubated patients or with the atomizing inhalation device of ventilator for the intubated patients. | Drug: Penehyclidine inhalation<br>* Penehyclidine inhalation will be administered by inhalation (penehyclidine hydrochloride 0.5 mg/0.5 ml, mixed with normal saline 5.5 ml) once every 12 hours from the night before surgery till the second day after surgery. The total number of inhalation is seven times. Study drug inhalation is performed with the high-flow oxygen-driven method for the non-intubated patients or with the atomizing inhalation device of ventilator for the intubated patients.<br>* Other names: Penehyclidine Hydrochloride for Injection (Changtuoning);|
| Placebo Comparator: Control group<br>Placebo inhalation will be administered by inhalation (water for injection 0.5 ml + normal saline 5.5 ml ) once every 12 hours from the night before surgery till the second day after surgery. The total number of inhalation is seven times. Study drug inhalation will be performed with the high-flow oxygen-driven method for the non-intubated patients or with the atomizing inhalation device of ventilator for the intubated patients. | Drug: Placebo inhalation<br>* Placebo inhalation will be administered by inhalation (water for injection 0.5 ml, mixed with normal saline 5.5 ml) once every 12 hours from the night before surgery till the second day after surgery. The total number of inhalation is seven times. Study drug inhalation is performed with the high-flow oxygen-driven method for the non-intubated patients or with the atomizing inhalation device of ventilator for the intubated patients.<br>* Other names: Water for injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of postoperative pulmonary complications (PPCs) | PPCs indicate complications that occur in the respiratory system from end of surgery till 30 days after surgery and require therapeutic intervention. Items include respiratory failure, respiratory infection, atelectasis, pleural effusion, bronchospasm, pneumothorax and aspiration pneumonitis. | Up to 30 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to onset of PPCs | Time to onset of PPCs | From end of surgery till onset of first documented PPCs or death from any cause, whichever came first, assessed up to 30 days | 
| Number of PPCs | Items of PPCs include respiratory infection, atelectasis, pleural effusion, bronchospasm, respiratory failure, pneumothorax and aspiration pneumonitis. | Up to 30 days after surgery | 
| Incidence of extrapulmonary complications | Extrapulmonary complications indicate complications that occurred in the organs or systems other than the respiratory system and require therapeutic intervention. | Up to 30 days after surgery | 
| Length of stay (LOS) in hospital after surgery | Length of stay (LOS) in hospital after surgery | Up to 30 days after surgery | 
| All-cause 30-day mortality | All-cause 30-day mortality | Up to 30 days after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postoperative pulmonary complications, Selective anticholinergic bronchodilator, High risk patients, Postoperative period, Postoperative complications