Preventive Effects of Penehyclidine Hydrochloride Inhalation on Postoperative Pulmonary Complications

Postoperative Complications Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02644876
• Other study ID #: 2015[06]
• Secondary ID: ChiCTR-IPC-15006
• Status: Completed
• Phase: Phase 4
• Start date: September 1, 2015
• Est. completion date: December 10, 2018

Study information

• Verified date: November 2020
• Source: Peking University First Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 864
• Est. completion date: December 10, 2018
• Est. primary completion date: November 8, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 51 Years and older

Eligibility

Inclusion Criteria:

1. Age >50 years;

2. 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;

3. Judged to be at high risk of PPCs according to the ARISCAT risk score (ARISCAT predictive score =45).

Exclusion Criteria:

1. American Society of Anesthesiologists (ASA) physical classification =IV or the expected survival duration =24 hours;

2. Preoperative history of symptomatic hypertrophy or glaucoma;

3. History of myocardial infarction, severe heart dysfunction (New York Heart Association functional classification =3) or tachyarrhythmia within one year;

4. Inhalation of ß2-receptor activator, M-receptor blockers and/or glucocorticoids within one month before surgery;

5. Severe renal dysfunction (requirement of renal replacement therapy) or severe hepatic dysfunction (Child-Pugh grade C);

6. History of acute stroke within three months before surgery;

7. Refuse to participate in the study or unable to cooperate with the inhalation therapy;

8. 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.

Related Conditions & MeSH terms

• Postoperative Complications

Intervention

Drug:
• Penehyclidine inhalation
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.
• Placebo inhalation
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.

Locations

Country	Name	City	State
China	Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital	Beijing	Beijing

Sponsors (1)

Lead Sponsor	Collaborator
Peking University First Hospital

Country where clinical trial is conducted

China, 

References & Publications (18)

Brooks-Brunn JA. Predictors of postoperative pulmonary complications following abdominal surgery. Chest. 1997 Mar;111(3):564-71. — View Citation

Canet J, Gallart L, Gomar C, Paluzie G, Vallès J, Castillo J, Sabaté S, Mazo V, Briones Z, Sanchis J; ARISCAT Group. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010 Dec;113(6):1338-50. doi: 10.1097/ALN.0b013e3181fc6e0a. — View Citation

Celli BR. Perioperative respiratory care of the patient undergoing upper abdominal surgery. Clin Chest Med. 1993 Jun;14(2):253-61. Review. — View Citation

Cui J, Li CS, He XH, Song YG. Protective effects of penehyclidine hydrochloride on acute lung injury caused by severe dichlorvos poisoning in swine. Chin Med J (Engl). 2013;126(24):4764-70. — View Citation

Hulzebos EH, Smit Y, Helders PP, van Meeteren NL. Preoperative physical therapy for elective cardiac surgery patients. Cochrane Database Syst Rev. 2012 Nov 14;11:CD010118. doi: 10.1002/14651858.CD010118.pub2. Review. — View Citation

Kroenke K, Lawrence VA, Theroux JF, Tuley MR. Operative risk in patients with severe obstructive pulmonary disease. Arch Intern Med. 1992 May;152(5):967-71. — View Citation

Liu XB, Pan S, Yang XG, Li ZW, Sun QS, Zhao Z, Ma HC, Cui CR. Effect of penehyclidine hydrochloride on heart rate variability in hysteroscopy. Exp Ther Med. 2015 Jul;10(1):181-186. Epub 2015 May 18. — View Citation

Ma TF, Zhou L, Wang Y, Qin SJ, Zhang Y, Hu B, Yan JZ, Ma X, Zhou CH, Gu SL. A selective M1 and M3 receptor antagonist, penehyclidine hydrochloride, prevents postischemic LTP: involvement of NMDA receptors. Synapse. 2013 Dec;67(12):865-74. doi: 10.1002/syn.21693. Epub 2013 Jul 24. — View Citation

Mazo V, Sabaté S, Canet J, Gallart L, de Abreu MG, Belda J, Langeron O, Hoeft A, Pelosi P. Prospective external validation of a predictive score for postoperative pulmonary complications. Anesthesiology. 2014 Aug;121(2):219-31. doi: 10.1097/ALN.0000000000000334. — View Citation

Shi H, Dong CM. [The effect of penehyclidine hydrochloride on the expression of inflammatory factor in rat with sepsis-associated lung injury]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2009 Nov;21(11):685-7. Chinese. — View Citation

Thomsen T, Villebro N, Møller AM. Interventions for preoperative smoking cessation. Cochrane Database Syst Rev. 2014 Mar 27;(3):CD002294. doi: 10.1002/14651858.CD002294.pub4. Review. — View Citation

Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013 Feb 15;187(4):347-65. doi: 10.1164/rccm.201204-0596PP. Epub 2012 Aug 9. Review. — View Citation

Wang KW, Lin HQ, Wang JR. [Effect of penehyclidine hydrochloride as preoperation drug for elder on HRV]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2008 Feb;24(1):28-9, 128. Chinese. — View Citation

Wu GM, Mou M, Mo LQ, Liu L, Ren CH, Chen Y, Zhou J. Penehyclidine hydrochloride postconditioning on lipopolysaccharide-induced acute lung injury by inhibition of inflammatory factors in a rodent model. J Surg Res. 2015 May 1;195(1):219-27. doi: 10.1016/j.jss.2014.12.018. Epub 2014 Dec 17. — View Citation

Wu XJ, Xia ZY, Wang LL, Luo T, Zhan LY, Meng QT, Song XM. Effects of penehyclidine hydrochloride on pulmonary contusion from blunt chest trauma in rats. Injury. 2012 Feb;43(2):232-6. doi: 10.1016/j.injury.2011.10.009. Epub 2011 Nov 4. — View Citation

Xiao H, Liao Z, Meng X, Yan X, Chen S, Mo Z. Effects of the selective muscarinic receptor antagonist penehyclidine hydrochloride on the respiratory tract. Pharmazie. 2009 May;64(5):337-41. — View Citation

Xiao HT, Liao Z, Tong RS. Penehyclidine hydrochloride: a potential drug for treating COPD by attenuating Toll-like receptors. Drug Des Devel Ther. 2012;6:317-22. doi: 10.2147/DDDT.S36555. Epub 2012 Nov 1. Review. — View Citation

Yan T, Wang D. [Effects of penehyclidine inhalation on postoperative pulmonary complications of elderly patients after long-duration surgery]. Zhonghua Yi Xue Za Zhi. 2014 Jan 14;94(2):122-6. Chinese. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Length of stay (LOS) in hospital after surgery	Length of stay (LOS) in hospital after surgery	Up to 30 days after surgery
Secondary	All-cause 30-day mortality	All-cause 30-day mortality	Up to 30 days after surgery