Background

Postoperative pulmonary complications are common. Aging and respiratory disease provoke airway hyperresponsiveness, high-risk surgery induces diaphragmatic dysfunction, and general anesthesia contributes to atelectasis and peripheral airway injury. This study therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces the incidence of pulmonary complications in high-risk patients over the initial 30 postoperative days.

Methods

This single-center double-blind trial enrolled 864 patients age over 50 yr who were scheduled for major upper-abdominal or noncardiac thoracic surgery lasting 2 h or more and who had an Assess Respiratory Risk in Surgical Patients in Catalonia score of 45 or higher. The patients were randomly assigned to placebo or prophylactic penehyclidine inhalation from the night before surgery through postoperative day 2 at 12-h intervals. The primary outcome was the incidence of a composite of pulmonary complications within 30 postoperative days, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis.

Results

A total of 826 patients (mean age, 64 yr; 63% male) were included in the intention-to-treat analysis. A composite of pulmonary complications was less common in patients assigned to penehyclidine (18.9% [79 of 417]) than those receiving the placebo (26.4% [108 of 409]; relative risk, 0.72; 95% CI, 0.56 to 0.93; P = 0.010; number needed to treat, 13). Bronchospasm was less common in penehyclidine than placebo patients: 1.4% (6 of 417) versus 4.4% (18 of 409; relative risk, 0.327; 95% CI, 0.131 to 0.82; P = 0.011). None of the other individual pulmonary complications differed significantly. Peak airway pressures greater than 40 cm H2O were also less common in patients given penehyclidine: 1.9% (8 of 432) versus 4.9% (21 of 432; relative risk, 0.381; 95% CI, 0.171 to 0.85; P = 0.014). The incidence of other adverse events, including dry mouth and delirium, that were potentially related to penehyclidine inhalation did not differ between the groups.

Conclusions

In high-risk patients having major upper-abdominal or noncardiac thoracic surgery, prophylactic penehyclidine inhalation reduced the incidence of pulmonary complications without provoking complications.

Editor’s Perspective
What We Already Know about This Topic
  • Postoperative pulmonary complications account for substantial morbidity and mortality

  • It remains unknown whether prophylactic bronchodilator therapy reduces complications in high-risk patients who have major noncardiac and thoracic surgery

What This Article Tells Us That Is New
  • In this study, 864 noncardiac surgical patients at high risk of pulmonary complications were randomized to inhaled penehyclidine, a long-acting muscarinic antagonist bronchodilator

  • Patients assigned to penehyclidine had 28% fewer composite pulmonary complications, although most complications were minor

  • Penehyclidine or similar antimuscarinic bronchodilators, such as tiotroprium, may reduce pulmonary complications in high-risk patients

Postoperative pulmonary complications are common1–3  and associated with prolonged hospitalization, increased hospital cost,2,4  perioperative mortality,2,4  and reduced long-term survival.5  The Assess Respiratory Risk in Surgical Patients in Catalonia study reported that the incidence of pulmonary complications is 1 to 3% in low-risk patients (scores less than 26), 6 to 13% in intermediate-risk patients (scores of 26 to 44), and 38 to 45% in high-risk patients (score of 45 or higher).1,3 

Advanced age, smoking history, obesity, asthma, and obstructive sleep apnea all provoke airway hyperresponsiveness and complications in surgical patients.6–8  Surgery per se provokes inflammation, pain, and diaphragmatic dysfunction, especially upper-abdominal and thoracic surgery. Consequent reductions in pulmonary compliance, ventilation function, and secretion retention contribute to pulmonary complications.9–11  General anesthesia also contributes to complications, including atelectasis and peripheral airway injury.11–13  Tidal airway closure and atelectasis occur when the closing volume exceeds the end-expiratory lung volume. Indeed, the reported incidence of pulmonary complications is 10 to 16% after upper-abdominal operations and 23 to 38% after thoracic surgeries.1–4,14 

Strategies thought to prevent perioperative pulmonary complications include smoking cessation for more than 4 to 8 weeks,15  preoperative respiratory training,16  neuraxial anesthesia,17  lung-protective ventilation,18  restricted fluid administration,19  laparoscopic surgical approaches,20  postoperative use of continuous positive airway pressure,21  and early mobilization after surgery.22  Another potential preventive measure is inhalation of long-acting muscarinic agonists, which are first-line treatments for chronic obstructive pulmonary disease (COPD).23  For example, tiotropium inhalation reduces closing volume and improves ventilation homogeneity in patients with COPD.24  When used in COPD patients having thoracic and abdominal surgery, tiotropium inhalation reduces airway resistance and improves pulmonary function.25–28  However, perioperative pulmonary complications are hardly restricted to patients with COPD; aging patients with various comorbidities are also at high risk, especially when scheduled for major upper-abdominal or intrathoracic surgery.1,3,29  Perioperative muscarinic antagonists may therefore improve pulmonary function and reduce pulmonary complications in broader surgical populations.30 

Penehyclidine is a long-acting muscarinic antagonist with high selectivity for the M3 receptor, a receptor subtype that mediates airway smooth muscle contraction induced by acetylcholine. In both clinical and experimental studies, the drug also moderates infectious and noninfectious inflammation within the respiratory system, possibly by inhibiting Toll-like receptors.31–34  Penehyclidine is effective for treatment of acute exacerbations of COPD and acute respiratory distress syndrome, possibly by dilating bronchioles, improving pulmonary compliance, and inhibiting airway inflammation. We therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces a composite of pulmonary complications in high-risk noncardiac surgical patients over the initial 30 postoperative days.

This single-center trial was performed in Peking University First Hospital (Beijing, China). The study protocol was approved by the local clinical research ethics committee (approval No. 2015[06] on April 15, 2015; principal investigator: D.-X.W.) and registered with the Chinese Clinical Trial Registry (www.chictr.org.cn, ChiCTR-IPC-15006603; May 14, 2015) and ClinicalTrials.gov (NCT02644876; January 1, 2016). Written informed consent was obtained from the participating patients.

The original protocol and changes to the trial methods and outcomes are detailed in Supplemental Digital Content 1 (http://links.lww.com/ALN/C798). An important change was that we adopted the Clavien–Dindo Classification to categorize pulmonary and extrapulmonary complications; those of grade II or above were used to calculate the incidences. This made the diagnoses of complications more definitive. All changes were made before the trial data were accessed. The rationale and design of the study were previously published.35 

Participants

We included patients who (1) were more than 50 yr old; (2) were scheduled for upper-abdominal or noncardiac thoracic surgery expected to last at least 2 h and have at least a 5-cm-long incision; and (3) had an Assess Respiratory Risk in Surgical Patients in Catalonia score of 45 or higher and were thus at high risk of pulmonary complications.1 

We excluded patients who (1) were unable to cooperate during inhalational therapy; (2) had moderate-to-severe symptomatic prostatic hypertrophy or narrow-angle glaucoma; (3) used inhaled β2-agonists, muscarinic antagonists, and/or glucocorticoids within 1 preoperative month; (4) had a stroke within 3 months; (5) had a previous myocardial infarction, severe heart dysfunction (New York Heart Association classification higher than 3), or tachyarrhythmia within 1 yr; (6) required renal replacement therapy; (7) had severe hepatic dysfunction (Child–Pugh grade C); (8) were designated American Society of Anesthesiologists (Schaumburg, Illinois) Physical Status of IV or higher or were expected to survive 24 h or less; or (9) participated in other drug trials within 1 preoperative month.

Randomization, Masking, and Study Drug Administration

Random allocations were generated in a 1:1 ratio without stratification in blocks of six by an independent statistician using SAS 9.2 software (SAS Institute, USA). Penehyclidine hydrochloride (1 mg) and water placebo were provided as clear aqueous solutions in identical 1-ml ampoules (Chengdu List Pharmaceutical Co., Ltd., China). Treatment allocations were sealed in sequentially numbered opaque envelopes that were opened as necessary by a pharmacist who was not otherwise involved in the trial. Consequently, investigators, clinicians, and patients were fully blinded to treatment.

Trial drugs (penehyclidine hydrochloride 0.5 mg/0.5 ml or water for injection 0.5 ml) were diluted with normal saline to 6 ml, added to nebulizers, and provided for inhalation. Patients were asked to inhale the entire volume seven times at 12-h intervals starting at 7:00 pm the evening before surgery. The inhaled trial drug was given with a jet nebulizer (DNA100, Chongren Medical Equipment Co., Ltd., China) with an oxygen flow rate at 5 to 8 l/min for nonintubated patients or a vibrating mash nebulizer (Agrogen Professional Nebulizer System, AG-AP6000CH, Aerogen Ltd., Ireland) for patients who remained intubated after surgery.

Preparation, Anesthesia, and Perioperative Management

Preoperative preparation was performed according to routine practice. Respiratory symptoms were normally well controlled before anesthesia. Intraoperative monitoring included electrocardiogram, pulse oxygen saturation, noninvasive blood pressure, airway pressure, end-tidal concentration of carbon dioxide and inhalational anesthetics, nasopharyngeal temperature, urine output, and Bispectral Index. Intraarterial pressure (and derivative parameters such as stroke volume variation) and central venous pressure were monitored when necessary. No anesthetic premedication was provided. Prophylactic antibiotics (usually a first- or second-generation cephalosporin, with or without metronidazole, or cephamycins) were given 30 to 60 min before the surgical incision.

General endotracheal anesthesia was induced with intravenous propofol and/or etomidate, sufentanil, and rocuronium or cisatracurium. Anesthesia was maintained with intravenous propofol, remifentanil and/or sufentanil, and rocuronium or cisatracurium, with or without sevoflurane and/or nitrous oxide. Some patients were given both rocuronium and cisatracurium, usually rocuronium for induction and cisatracurium for maintenance but not simultaneously. Target Bispectral Index values were between 40 and 60. Anesthetic management was performed at the discretion of anesthesiologists and included epidural or peripheral nerve blocks when practical.

Patients were mechanically ventilated at a tidal volume of 6 to 8 ml/kg during two-lung ventilation or 5 to 7 ml/kg during one-lung ventilation, a positive end-expiratory pressure of 0 to 5 cm H2O, and an inspired oxygen of 50% or less (mixed with nitrous oxide or air). Oxygen concentration was increased as necessary during one-lung ventilation to maintain oxyhemoglobin saturation greater than 90%. Fluid management was per clinical routine, and packed red blood cells were transfused as necessary to keep hemoglobin greater than 7 g/dl.

At the end of surgery, patients were extubated when deemed ready and transferred to the postanesthesia care unit for at least 30 min before being transferred to a surgical ward or intensive care unit. Extubated patients were given low-flow supplemental oxygen as necessary, usually until the evening of surgery.

For patients who were transferred to the intensive care unit while intubated, propofol and/or dexmedetomidine sedation were provided along with opioid analgesia. Postoperative mechanical ventilation was provided with bilevel ventilation mode with a low level from 3 to 5 cm H2O, a high level between 13 and 16 cm H2O, and a trigger flow at 2 to 3 l/min (PB 840 ventilator, Puritan-Bennett Corp., Ireland). Patients were extubated when they regained consciousness and airway protective reflexes, had normal circulatory status and temperature, and were fully recovered from paralysis per clinical assessment. For patients with acute respiratory failure, high-flow nasal cannula oxygen therapy or noninvasive positive pressure ventilation was used to promote early extubation or to avoid reintubation. When patients required mechanical ventilation for more than 24 h, a ventilator weaning protocol was used to speed up extubation.35 

Patient-controlled intravenous or epidural analgesia was provided for up to 3 days after surgery. The target was to maintain numeric pain scores 3 or lower on an 11-point scale where 0 equaled no pain and 10 equaled the worst pain. Nonsteroidal anti-inflammatory drugs were given as appropriate. Other routine management included chest physiotherapy, early mobilization, removal of nasogastric tube, parenteral or enteral nutrition, expectorants, intravenous respiratory medications such as theophyllines, and glucocorticoids.

Prophylactic inhalation of nonstudy respiratory medications was prohibited. However, patients who developed postoperative pulmonary complications were treated per routine practice including inhalational therapies. Clinicians were allowed to adjust study drug dose or discontinue treatment if deemed necessary.

Data Collection and Outcome Assessment

Baseline data included demographic and morphometric characteristics, surgical diagnosis, diagnoses of and treatments for preoperative comorbidities, and smoking and alcohol history, along with results of relevant laboratory tests and physical and other examinations. Intraoperative data included type and duration of anesthesia, types and doses of anesthetics/medications, mechanical ventilation settings, fluid balance and blood transfusion, as well as type and duration of surgery.

Patients were evaluated once daily (7:00 to 8:00 am) for the first 6 postoperative days, once weekly thereafter until hospital discharge, and 30 days after surgery. Patients were interviewed via telephone after hospital discharge. Pain intensity was assessed and the types and doses of administered analgesics were recorded during the first 3 postoperative days. Sufentanil equivalent dose was calculated.36  Delirium was assessed with the Confusion Assessment Methods for the Intensive Care Unit37  within 6 days by trained investigators. Pulmonary and extrapulmonary complications were evaluated until 30 days after surgery. For patients who withdraw trial consent, available data were used for analysis.

The primary outcome was the incidence of a collapsed composite of postoperative pulmonary complications that occurred within 30 postoperative days. Pulmonary complications were defined by established criteria and included respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis (table S1 in Supplemental Digital Content 2, http://links.lww.com/ALN/C799),1,35,38  and classified as grade II or above on the Clavien–Dindo classification (table S2 in Supplemental Digital Content 2, http://links.lww.com/ALN/C799).39  Postoperative pulmonary complications were defined by the presence of any components of grade II or higher. Diagnoses were based on patient interviews, physical examinations, laboratory and imaging results, and consultation with attending surgeons. Pulmonary complications were independently confirmed by at least two investigators, including a senior intensivist (T.Y.), all of whom were blinded to treatment. Differences were adjudicated by a senior pulmonologist (K.-Y.Y.).

Secondary outcomes included the postoperative time to onset of pulmonary complications, the number of individual pulmonary complications within 30 days, the incidence of extrapulmonary complications within 30 days, the length of hospital stay after surgery, and 30-day all-cause mortality. Postoperative extrapulmonary complications were defined as new events outside the respiratory system that occurred within 30 days after surgery, had adverse effects on patients’ recovery, and required therapeutic intervention; that is, grade II or greater in the Clavien–Dindo classification.39  Exploratory outcomes included intensive care unit (ICU) admission after surgery; and, for patients admitted to ICU, the duration of mechanical ventilation and ICU stay.

We considered adverse events potentially related to initial inhalation of the study drug from the evening before surgery until the third postoperative morning. Potential adverse events during anesthesia/surgery included difficult airway (failed intubation attempt more than three times), desaturation (Pao2 less than 60 mmHg or oxygen saturation measured by pulse oximetry less than 90%), high airway pressure (peak airway pressure greater than 40 cm H2O), hypercapnia (Paco2 greater than 50 mmHg), hypotension (systolic blood pressure less than 90 mmHg or a decrease of more than 30% from ward baseline), hypertension (systolic blood pressure greater than 180 mmHg or an increase of more than 30% from baseline), bradycardia (heart rate less than 40 beats per minute), tachycardia (heart rate greater than 100 beats per minute), massive hemorrhage (estimated blood loss greater than 1,000 ml) and new-onset arrhythmia requiring therapy. We also recorded nausea, vomiting, dry month, palpation, dizziness, cough, and flushing.

Statistical Analysis

Sample Size Estimation

In a pilot trial, prophylactic inhalation of penehyclidine reduced bronchospasm in elderly patients after surgery lasting at least 3 h (1 of 30 [3.2%] with penehyclidine, 1 of 31 [3.2%] with ipratropium, and 6 of 29 [20.7%] with normal saline; P = 0.025).40  In patients similar to ours, with Assess Respiratory Risk in Surgical Patients in Catalonia scores 45 or greater, the reported incidences of pulmonary complications ranged from 42 to 45%.3  In previous studies of COPD patients, perioperative inhalation of tiotropium reduced the incidence of pulmonary complications by 16 to 32%.27,28 

We therefore assumed that the incidence of postoperative pulmonary complications would be 42% in the placebo group patients, and that prophylactic penehyclidine inhalation would reduce the incidence of postoperative pulmonary complications by an absolute 10% (i.e., to 32%). The calculated sample size that would provide 80% power to detect this difference at a two-sided significance level of 0.05 was 365 patients per group. Considering a dropout rate of about 15%, we planned to enroll 432 patients in each group. No interim analyses were planned for effectiveness or futility.

Data Analysis

Compliance and completeness of data were monitored by an independent committee from Peking University Clinical Research Institute. The trial database was locked on June 12, 2019, after which data were unmasked and statistical analyses performed.

Outcome analyses were based on modified intent-to-treat; that is, all patients were analyzed in the group to which they were randomized, excluding those whose surgery was canceled. For the primary outcome, analysis was also performed in the per-protocol population, excluding patients who dropped out of the trial. Safety outcomes were analyzed in the safety population, consisting of all randomized patients who received at least one trial drug inhalation.

Baseline balance was assessed using absolute standardized difference, calculated as the absolute difference in means, medians, or proportions divided by the pooled SD. Baseline variables with an absolute standardized difference 0.147 or greater (i.e., 1.96×(n1+n2)/(n1×n2)) were considered imbalanced, where n1 and n2 were the number of patients in each randomized group.

Our primary outcome, the incidence of pulmonary complications within 30 postoperative days, was compared with a chi-square test, with differences between groups expressed as relative risk and 95% CI. The number needed to treat was estimated as the reciprocal of the absolute risk reduction. Similar analyses were performed for the per-protocol population. Post hoc exploratory analyses were performed to assess heterogeneity of the primary outcome in predefined subgroups including age, sex, body mass index, respiratory disease, respiratory symptoms in last month, cigarette smoking, type of anesthesia, location of surgery, and type of surgery. Treatment-by-covariate interactions were assessed separately for each subgroup factor using logistic regression.

For secondary outcomes, categorical variables were analyzed with chi-square, continuity-corrected chi-square, or Fisher exact tests. Time-to-event results were analyzed with Kaplan–Meier survival analyses, with differences between groups tested using log-rank tests; univariable Cox proportional hazards models were used to calculated hazard ratios and 95% CIs. Patients who died within 30 days were censored at the time of death. Discrete variables were analyzed with the Mann–Whitney U test; median difference (and 95% CI) was calculated with the Hodges–Lehmann estimator. The missing data were not replaced.

Quantitative results with normal distribution are presented as means ± SDs; those with nonnormal distribution were presented as medians (interquartile ranges). Qualitative results are presented as numbers (percentages). For all hypotheses, two-tailed P values of less than 0.05 were considered statistically significant. For the treatment-by-covariate interaction in predefined subgroup analyses, P < 0.10 was considered statistically significant. The final statistical analysis plan, except exploratory analysis, was completed after the end of enrollment but before unblinding group assignment and outcome analysis. Statistical analyses were performed with the SPSS 25.0 (IBM SPSS Inc., USA) software package.

Patients

Between September 1, 2015, and November 8, 2018, a total of 1,647 patients were screened for eligibility. Among them, 1,136 met inclusion/exclusion criteria; 864 were enrolled and randomized to penehyclidine (n = 432) or placebo (n = 432). All enrolled patients received at least one study drug dose and were included in the safety analysis. However, 38 surgeries were canceled, 7 patients withdrew consent, 12 patients dropped out because of adverse events, and there were 49 protocol deviations. There were thus 826 patients included in intention-to-treat analysis and 758 patients in the per-protocol analysis (fig. 1; table S3 in Supplemental Digital Content 2, http://links.lww.com/ALN/C799). The last patient follow-up was performed on December 10, 2018.

Fig. 1.

Trial profile. See also table S3 in Supplemental Digital Content 2 (http://links.lww.com/ALN/C799).

Fig. 1.

Trial profile. See also table S3 in Supplemental Digital Content 2 (http://links.lww.com/ALN/C799).

Close modal

Baseline and Perioperative Data

The two groups were well matched on baseline characteristics, except that lung tumors were slightly more common and esophageal/mediastinal tumors were slightly less common in patients randomized to penehyclidine (table 1; table S4 in Supplemental Digital Content 2, http://links.lww.com/ALN/C799). Intraoperative and postoperative variables were also well balanced between the groups, except that more patients assigned to penehyclidine were given patient-controlled intravenous analgesia after surgery (tables 2 and 3; table S5 in Supplemental Digital Content 2, http://links.lww.com/ALN/C799).

Table 1.

Demographic and Baseline Data

Demographic and Baseline Data
Demographic and Baseline Data
Table 2.

Intraoperative Data

Intraoperative Data
Intraoperative Data
Table 3.

Postoperative Data

Postoperative Data
Postoperative Data

Effectiveness Outcomes

The fraction of patients with composite pulmonary complications within 30 days after surgery was significantly lower in the penehyclidine group than in the placebo group: 18.9% (79 of 417) versus 26.4% (108 of 409; relative risk, 0.72; 95% CI, 0.56 to 0.93; P = 0.010; number needed to treat, 13). The same difference was found by the per-protocol analysis: 18.9% (69 of 378) versus 26.3% (100 of 380; relative risk, 0.69; 95% CI, 0.53 to 0.91; P = 0.008; table 4; fig. 2). In subgroup analyses, we found a significant interaction for the primary outcome between treatment and age and body mass index; specifically, the effect of penehyclidine inhalation on postoperative pulmonary complications was disproportionately beneficial in patients age 63 yr or younger and body mass index less than 24 kg/m2 (fig. 3). There were no significant interactions between treatment group and other predefined factors.

Table 4.

Effectiveness Outcomes

Effectiveness Outcomes
Effectiveness Outcomes
Fig. 2.

Probability of postoperative pulmonary complications by day 30 after surgery.

Fig. 2.

Probability of postoperative pulmonary complications by day 30 after surgery.

Close modal
Fig. 3.

Forest plot assessing the effect of penehyclidine inhalation versus placebo inhalation in predefined subgroups. Logistic models were applied for assessment of treatment-by-covariate interactions. Treatment-by-covariate interactions were assessed separately for each subgroup factor, including age, sex, body mass index, respiratory disease, respiratory symptoms in the last month, preoperative cigarette smoking, type of anesthesia, location of surgery, and type of surgery.

Fig. 3.

Forest plot assessing the effect of penehyclidine inhalation versus placebo inhalation in predefined subgroups. Logistic models were applied for assessment of treatment-by-covariate interactions. Treatment-by-covariate interactions were assessed separately for each subgroup factor, including age, sex, body mass index, respiratory disease, respiratory symptoms in the last month, preoperative cigarette smoking, type of anesthesia, location of surgery, and type of surgery.

Close modal

Among secondary outcomes, time to onset of pulmonary complications was significantly longer (median, 30 days [interquartile range, 30 to 30] vs. 30 days [10 to 30]; hazard ratio, 0.69; 95% CI, 0.52 to 0.92; P = 0.009), postoperative bronchospasm was significantly less common (1.4% [6 of 417] vs. 4.4% [18 of 409]; relative risk, 0.327; 95% CI, 0.131 to 0.82; P = 0.011), and the number of pulmonary complications was significantly less (125 complications in 79 patients given penehyclidine vs. 161 complications in 108 patients given placebo; P = 0.016) in penehyclidine patients. There were no significant differences in ICU admissions, the incidence of extrapulmonary complications within 30 days, the duration of hospitalization, or all-cause 30-day mortality. In exploratory analyses, the incidence of pulmonary complications, except for bronchospasm, was lower in patients given penehyclidine inhalation, although not significantly so (18.7% [78 of 417] vs. 23.7% [97of 409]; relative risk, 0.79; 95% CI, 0.61 to 1.03; P = 0.078); the incidence of pulmonary complications in the subgroup with patient-controlled intravenous analgesia was significantly lower in those given penehyclidine inhalation (17.3% [67 of 388] vs. 25.6% [93 of 363]; relative risk, 0.67; 95% CI, 0.51 to 0.89; P = 0.005; table 4; table S6 and fig. S1 in Supplemental Digital Content 2, http://links.lww.com/ALN/C799).

Safety Outcomes

Significantly fewer penehyclidine patients had high intraoperative airway pressures than in the placebo group: 1.9% (8 of 432) versus 4.9% (21 of 432; relative risk, 0.381; 95% CI, 0.171 to 0.85; P = 0.014). No other complications differed by statistically significant or clinically meaningful amounts. No severe adverse outcomes were attributed to the study drugs (table 5).

Table 5.

Safety Outcomes

Safety Outcomes
Safety Outcomes

Among high-risk patients having upper-abdominal and noncardiac thoracic surgery, prophylactic perioperative inhalation of penehyclidine reduced pulmonary complications by about a quarter. The results were largely consistent across a wide variety of preplanned subgroup analyses. Penehyclidine inhalation also reduced the incidence of intraoperative high airway pressure episodes without promoting adverse events.

Respiratory infections were the most common postoperative pulmonary complication in our patients, with an incidence of 19.0%, which was well within the reported range in high-risk patients.41–43  This was followed by atelectasis (5.7%), pleural effusion (4.6%), bronchospasm (2.9%), respiratory failure (2.2%), and pneumothorax (0.2%). Most (84%) pulmonary complications occurred within the first 5 days with a median onset on postoperative day 2, as might be expected from the acute effects of surgery and anesthesia.44,45  Prophylactic penehyclidine inhalation reduced respiratory infection by 17% and atelectasis by 33%, but the CI values were wide and not individually statistically significant. The biggest difference was in bronchospasm, which was reduced by about two thirds.40 

Current evidence regarding the use of inhaled muscarinic antagonists in perioperative patients mainly comes from patients with COPD. For COPD patients, inhalation of muscarinic antagonists improves pulmonary function and activity tolerance, with long-acting drugs providing the most benefit.46  The same is true in high-risk COPD patients having surgery.25,26  In a retrospective study of 104 lung cancer patients with moderate to severe COPD, perioperative tiotropium inhalation was associated with fewer postoperative cardiopulmonary complications.27 

We recruited patients at high risk for pulmonary complications as predicted by the Assess Respiratory Risk in Surgical Patients in Catalonia model, but only 12% had a history of respiratory diseases, and only 2% had comorbid COPD. Our results therefore considerably extend previously limited data about perioperative inhalation of muscarinic antagonists. Specifically, we show that penehyclidine inhalation substantially reduces pulmonary complications even in patients with little or no preexisting COPD, although a substantial fraction did have other respiratory diseases or symptoms, thus extending benefit to a much larger population. Our results are consistent with a trial in 84 gastric cancer patients with mild to moderate COPD that suggested benefit from perioperative tiotropium inhalation, although those results were underpowered.28 

Pulmonary complications are common in patients recovering from thoracic and upper-abdominal surgery, even when they do not have serious preexisting respiratory disease.1,3,29  Major contributors to postoperative respiratory complications include decreased diaphragm function and increased airway reactivity, which together reduce vital capacity by 50 to 60%, decrease functional residual volume by 30%, and increase airflow resistance, all of which ultimately diminish coughing and airway clearance.9–11  Other potential reasons include peripheral airway injury resulting from tidal airway closure, which is common during general anesthesia.11–13 

The mechanisms by which penehyclidine inhalation provides pulmonary protection remain uncertain, but it seems likely that bronchodilation and reduced respiratory resistance contribute.31  These effects might also have resulted in less peripheral airway collapse during anesthesia and thus less ventilator-induced lung injury.24  Indeed, penehyclidine inhalation reduced intraoperative high airway pressure episodes and postoperative bronchospasm in our patients, possibly explaining why a muscarinic antagonist reduced pulmonary complications in a mainly non-COPD and nonasthmatic patient population.

The incidence of postoperative pulmonary complications was 26%, which was less than the 42% we anticipated, possibly because half of our patients had thoracoscopic or laparoscopic surgery. Despite a lower than expected complication incidence in the placebo group, we had sufficient power to conclude that prophylactic penehyclidine inhalation significantly reduces pulmonary complications.

The benefit of penehyclidine was especially prominent in patients 63 yr of age or younger with a body mass index of less than 24 kg/m2, perhaps because the acetylcholine-induced airway response decreased with age47  and the potential benefit was diminished by unfavorable respiratory mechanics in obese patients.7,48  Other clinical outcomes were not significantly improved, including ICU admission, length of hospital stays, and 30-day all-cause mortality. A possible explanation is that while pulmonary complications were reduced by prophylactic penehyclidine inhalation, extrapulmonary complications remained common and similar in each group. Importantly, however, our trial was not powered for these outcomes, making these results essentially uninformative.

Adverse reactions are common after intravenous anticholinergics and include dry mouth, flushing, dizziness, palpitation, urinary retention, delirium, and others. However, such complications are uncommon after aerosolized inhalation because so little of the drug is systemically absorbed. As might thus be expected, inhalation of 0.5 mg penehyclidine did not promote adverse events, including delirium or even dry mouth, in our patients. Long-term inhalation of anticholinergics is associated with cardiovascular death, myocardial infarction, and stroke among patients with COPD,49  but such complications seem unlikely with short-term perioperative use, and none was observed.

A limitation of our trial is that it was single-center, excluded patients who already used inhaled drugs, and was largely restricted to high-risk patients. The benefits of inhaled penehyclidine will presumably differ in other populations. Treatment was restricted to penehyclidine (or placebo) inhalation twice daily for 4 days (1 day before, 1 day during, and 2 days after surgery) because most of our patients did not have chronic respiratory disease and required little if any postoperative mechanical respiratory support. Presumably the results would vary with other penehyclidine dosing; however, it seems unlikely that the observed reduction in pulmonary complications depends critically on how the drug is administered. Our trial was designed to detect differences in a composite of endpoints. It was not powered for individual complications, and on a component basis, only bronchospasm differed significantly. We excluded 38 (4.4%) patients from the intention-to-treat analysis due to canceled surgeries unrelated to group assignment (which was blinded). We also excluded 68 (7.9%) patients from per-protocol analysis mainly due to physician-related protocol deviations, which did not seem to result in bias. As might therefore be expected, the results were similar for each analysis. Penehyclidine is not approved by the U.S. Food and Drug Administration (Silver Spring, Maryland). A similar drug, tiotropium, is available in the United States, although it is not labeled for prophylactic use.

Experimental and clinical studies report that penehyclidine ameliorates acute lung injury by alleviating inflammation.31–33,50  For example, retrospective analyses report that patients who inhaled tiotropium have lower leukocyte counts and lower C-reactive protein concentrations.27  It is therefore possible that penehyclidine provides additional lung protection by reducing inflammation, although we did not evaluate this mechanism. Nor did we evaluate the effects of penehyclidine inhalation on pulmonary and diaphragmatic function.

In summary, prophylactic penehyclidine inhalation meaningfully reduced the incidence of pulmonary complications in high-risk patients recovering from major upper-abdominal or noncardiac thoracic surgery without provoking complications. Inhalation of penehyclidine may be helpful in surgical patients who are at high risk of pulmonary complications.

Acknowledgments

The authors gratefully acknowledge Mei-Xia Shang, M.S. (Department of Biostatistics, Peking University First Hospital, Beijing, China), for generating the random numbers and labeling the study drugs and Dong-Liang Mu, M.D. (Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital), for his help with delirium assessment training.

Research Support

Supported by grant No. 2018YFC2001800 from the National Key R&D Program of China (Beijing, China), grant No. 2015QN025 from a scientific research fund at Peking University First Hospital (Beijing, China), and grant No. 2017-01 from the Chinese Society of Cardiothoracic and Vascular Anesthesiology (Beijing, China). The study drugs were manufactured and supplied by Chengdu List Pharmaceutical Co., Ltd. (Sichuan, China). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Competing Interests

Dr. Sessler is a consultant for Edwards Lifesciences (Irvine, California), Mercury Medical (Cleveland, Ohio), and Pacira Biosciences (Parsippany, New Jersey). He serves on advisory boards and has equity interests in Calorint (Philadelphia, Philadelphia), Transtronics (Philadelphia, Philadelphia), the Health Data Analytics Institute (Boston, Massachusetts), Medasense (Tel Aviv, Israel), Serenno (Tel Aviv, Israel), Sensifree (Cupertino, California), Perceptive Medical (Newport Beach, California), and Neuroindex (Tel Aviv, Israel). He serves on the board of the Foundation for Anesthesia Education and Research (Schaumburg, Illinois). The other authors declare no competing interests.

Reproducible Science

Full protocol available at: dxwang65@bjmu.edu.cn. Raw data available at: dxwang65@bjmu.edu.cn.

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