Clinical trial NCT02644876: Preventive Effects of Penehyclidine Hydrochloride Inhalation on Postoperative Pulmonary Complications
Official title: Preventive Effects of Penehyclidine Hydrochloride Inhalation on Postoperative Pulmonary Complications in High-risk Patients: a Randomized, Double-blind, and Placebo Controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Postoperative Complications
Keywords: Postoperative pulmonary complications
Selective anticholinergic bronchodilator
High risk patients
Postoperative period
Postoperative complications
Lead sponsor: Peking University First Hospital
Sponsor class: OTHER
First posted: 2016-01-01
Enrollment: 864
Sex: ALL
Minimum age (years): 51
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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 β2-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.

Primary outcomes:
measure: Incidence of postoperative pulmonary complications (PPCs)
timeFrame: Up to 30 days after surgery
Secondary outcomes:
measure: Time to onset of PPCs
timeFrame: From end of surgery till onset of first documented PPCs or death from any cause, whichever came first, assessed up to 30 days
measure: Number of PPCs
timeFrame: Up to 30 days after surgery
measure: Incidence of extrapulmonary complications
timeFrame: Up to 30 days after surgery
measure: Length of stay (LOS) in hospital after surgery
timeFrame: Up to 30 days after surgery
measure: All-cause 30-day mortality
timeFrame: Up to 30 days after surgery
Other outcomes:
Locations:
city: Beijing
country: China
facility: Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital
state: Beijing
Study officials:
affiliation: Peking University First Hopital
name: Dong-Xin Wang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Canet J, Gallart L, Gomar C, Paluzie G, Valles J, Castillo J, Sabate 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.
citation: Mazo V, Sabate 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.
citation: Brooks-Brunn JA. Predictors of postoperative pulmonary complications following abdominal surgery. Chest. 1997 Mar;111(3):564-71. doi: 10.1378/chest.111.3.564.
citation: Thomsen T, Villebro N, Moller AM. Interventions for preoperative smoking cessation. Cochrane Database Syst Rev. 2014 Mar 27;2014(3):CD002294. doi: 10.1002/14651858.CD002294.pub4.
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.
citation: Celli BR. Perioperative respiratory care of the patient undergoing upper abdominal surgery. Clin Chest Med. 1993 Jun;14(2):253-61.
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(11):CD010118. doi: 10.1002/14651858.CD010118.pub2.
citation: Vestbo J, Hurd SS, Agusti 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.
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.
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.
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.
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.
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. doi: 10.3892/etm.2015.2497. Epub 2015 May 18.
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.
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.
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. No abstract available. Chinese.
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.
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. No abstract available. Chinese.
citation: Yan T, Liang XQ, Wang T, Li WO, Li HJ, Zhu SN, Wang DX. Prophylactic penehyclidine inhalation for prevention of postoperative pulmonary complications in high-risk patients: study protocol of a randomized controlled trial. Trials. 2017 Nov 28;18(1):571. doi: 10.1186/s13063-017-2315-7.