Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Incidence of postoperative residual neuromuscular blockade after general anesthesia: A prospective, multicenter, anesthetists-blind, observational study Yu Buwei, Ouyang Baoyi, Ge Shengjin, Luo Yan, Li Jun, Ni Dongmei, Hu Shuangfei, Xu Hui, Liu Jin, Min Su, Li Longyun, Ma Zhengliang, Xie Kangjie, Miao Changhong & Wu Xinmin To cite this article: Yu Buwei, Ouyang Baoyi, Ge Shengjin, Luo Yan, Li Jun, Ni Dongmei, Hu Shuangfei, Xu Hui, Liu Jin, Min Su, Li Longyun, Ma Zhengliang, Xie Kangjie, Miao Changhong & Wu Xinmin (2015): Incidence of postoperative residual neuromuscular blockade after general anesthesia: A prospective, multicenter, anesthetists-blind, observational study, Current Medical Research and Opinion To link to this article: http://dx.doi.org/10.1185/03007995.2015.1103213
Accepted online: 09 Oct 2015.
Submit your article to this journal
Article views: 2
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Download by: [University of California Santa Barbara]
Date: 15 October 2015, At: 08:35
Just Accepted by Current Medical Research & Opinion ORIGINAL ARTICLE Incidence of postoperative residual neuromuscular blockade after general anesthesia: A prospective, multicenter, anesthetists-blind, observational study Yu Buwei, Ouyang Baoyi, Ge Shengjin, Luo Yan, Li Jun, Ni Dongmei, Hu Shuangfei, Xu Hui, Liu Jin, Min Su, Li Longyun, Ma Zhengliang, Xie Kangjie, Miao Changhong, Wu Xinmin; on behalf of the RECITE-China Investigators doi: 10.1185/03007995.2015.1103213
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
Abstract Objective: Evidences demonstrate that postoperative residual neuromuscular blockade (rNMB) is a primary and frequent anesthetic risk factor for postoperative complications. This study was designed to mitigate the paucity of data regarding the occurrence and degree of rNMB in a reallife setting. Methods: This prospective, multicenter, anesthetists-blind, observational study enrolled 1,571 Chinese adults undergoing elective open or laparoscopic abdominal surgery lasting ≤4 hours from 32 hospitals across China. The patients received anesthesia in accordance with routine practice at the study site. Neuromuscular blockade (NMB) was monitored using acceleromyography, with rNMB defined as a train-of-four (TOF) ratio < 0.9. Results: The patients’ mean age was 46 years and 71% were female. The procedures included laparoscopic (67%), open abdominal (31%), and laparoscopic to open abdominal (2%). NMB was reversed with neostigmine in 78% of patients. The overall incidence of rNMB at extubation was 57.8%, and the proportions of participant with various TOF ratios < 0.6, 0.6~0.7, 0.7~0.8, 0.8~0.9 were 22.9%, 6.9%, 11.1% and 16.9%, respectively, immediately prior to endotracheal extubation. Age < 45 years (OR = 0.630, 95%CI = 0.496-0.801, p = 0.002), use one NMBA (OR = 0.387, 95%CI = 0.243-0.618, p < 0.0001), time from neostigmine administration to endotracheal extubation≥10min (OR = 0.513, 95%CI = 0.400-0.658, p < 0.0001) and time from last NMBA administration to endotracheal extubation≥60min (OR = 0.902, 95%CI = 0.801-0.989, p = 0411) were correlated with non-rNMB at the time of extubation. Conclusions: This observational study demonstrated that the overall incidence of rNMB at the time of endotracheal extubation was high in Chinese patients undergoing abdominal procedures, which necessitates appropriate management in current real-life practice.
© 2015 Taylor & Francis. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Taylor & Francis (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
ORIGINAL ARTICLE Incidence of postoperative residual neuromuscular blockade after general anesthesia: A prospective, multicenter, anesthetists-blind, observational study
Yu Buwei1, Ouyang Baoyi2, Ge Shengjin3, Luo Yan1, Li Jun4, Ni Dongmei5, Hu Shuangfei6, Xu Hui7, Liu Jin8, Min Su9, Li Longyun10, Ma Zhengliang11, Xie Kangjie12, Miao
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
Changhong13, Wu Xinmin5; on behalf of the RECITE-China Investigators
1
Department of Anesthesiology, Rui Jin Hospital, Shanghai Jiao Tong University School of
Medicine, Shanghai, China 2
The First Affiliated hospital of Guangzhou Medical University, Guangzhou, China
3
Zhongshan Hospital of Fudan University, Shanghai, China
4
The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
5
Peking University First Hospital, Beijing, China
6
Zhejiang Provincial People’s Hospital, Hangzhou, China
7
Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology,
Wuhan, China 8
West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
9
The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
10
China-Japan Union Hospital, Jilin University, Changchun, China
11
Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School,
Nanjing, China 12
Zhejiang Cancer Hospital, Hangzhou, China
13
Fudan University Shanghai Cancer Center, Shanghai, China
Address for correspondence: Wu Xinmin, M.D., FRCA, Department of Anesthesiology, Peking University First Hospital, No. 8 Xi Shi Ku Street, Beijing 100034, China. Tel.: +86 10 8357 2784; Fax: +86 10 8357 2784; [email protected]
Abstract Objective: Evidences demonstrate that postoperative residual neuromuscular blockade (rNMB) is a primary and frequent anesthetic risk factor for postoperative complications. This study was designed to mitigate the paucity of data regarding the occurrence and degree of rNMB in a
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
real-life setting. Methods: This prospective, multicenter, anesthetists-blind, observational study enrolled 1,571 Chinese adults undergoing elective open or laparoscopic abdominal surgery lasting ≤4 hours from 32 hospitals across China. The patients received anesthesia in accordance with routine practice at the study site. Neuromuscular blockade (NMB) was monitored using acceleromyography, with rNMB defined as a train-of-four (TOF) ratio < 0.9. Results: The patients’ mean age was 46 years and 71% were female. The procedures included laparoscopic (67%), open abdominal (31%), and laparoscopic to open abdominal (2%). NMB was reversed with neostigmine in 78% of patients. The overall incidence of rNMB at extubation was 57.8%, and the proportions of participant with various TOF ratios < 0.6, 0.6~0.7, 0.7~0.8, 0.8~0.9 were 22.9%, 6.9%, 11.1% and 16.9%, respectively, immediately prior to endotracheal extubation. Age < 45 years (OR = 0.630, 95%CI = 0.496-0.801, p = 0.002), use one NMBA (OR = 0.387, 95%CI = 0.243-0.618, p < 0.0001), time from neostigmine administration to endotracheal extubation≥10min (OR = 0.513, 95%CI = 0.4000.658, p < 0.0001) and time from last NMBA administration to endotracheal extubation≥60min (OR = 0.902, 95%CI = 0.801-0.989, p = 0411) were correlated with nonrNMB at the time of extubation. Conclusions: This observational study demonstrated that the overall incidence of rNMB at the time of endotracheal extubation was high in Chinese patients undergoing abdominal procedures, which necessitates appropriate management in current real-life practice.
Clinical Trial Registry Number: NCT01871064
Key words: Residual neuromuscular blockade − General anesthesia − Train-of-four
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
monitoring – Observational study
[Running title: Residual neuromuscular blockade in Chinese anesthetic practice]
Introduction Surgery that requires general anesthesia also necessitates the use of a neuromuscular blockade agent. Once surgical procedures are complete, the reversal of the effect of muscular relaxants is often performed to accelerate recovery from the neuromuscular blockade. At present, acetylcholinesterase inhibitors are commonly used to reverse paralysis caused by non-depolarizing neuromuscular blocking agents (NMBAs). If a patient is endotracheal extubated before the effects of the neuromuscular blocking agent have dissipated or reversed, residual paralysis occurs. Among patients who have received neuromuscular blocking agents Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
during surgery, residual neuromuscular blockade (defined as TOF ratio < 0.9) is not uncommon at endotracheal extubation or at the post-anesthetic care unit (PACU) admission, with incidences of up to 88% at the time of endotracheal extubation and up to 83% on arrival to the PACU1. Similar findings have been documented in previous studies from several countries2-4. Evidence demonstrates that residual neuromuscular blockade is associated with clinical complications including, but not limited to, hypoxemia, shortness of breath, upper airway problems, difficulty swallowing, hypercapnia, slurred speech, blurred vision and general discomfort1,5-9. Volunteer studies have described the impairment of pharyngeal function, increased risk of laryngeal penetration of contrast bolus, and impaired hypoxic ventilatory drive, among other unpleasant effects10. Clinical studies in surgical patients have demonstrated an association between rNMB and hypoxemia, upper airway obstruction, a higher risk of critical respiratory events (CREs), and other morbidities10. Data on healthcare resource utilization associated with residual neuromuscular blockade are scant, but studies have demonstrated significantly longer lengths of stay in the PACU of patients with a residual neuromuscular blockade1,11. Several patient factors and surgery types are risk factors for post-operative pulmonary complications (POPC), such as pneumonia and atelectasis. Patient factors include age ≥ 60, obesity, smoking and the American Society of Anesthesiologists (ASA) score ≥ II. Additionally, patients with chronic obstructive pulmonary disease (COPD) or chronic heart failure (CHF) and those undergoing open or upper abdominal or bariatric surgery are also at an increased risk of POPC12. This suggests that these patients and surgery types may also be at an increased risk of adverse consequences from residual neuromuscular blockade.
Despite data demonstrating potential morbidity, there is a paucity of data regarding the incidence of residual paralysis at endotracheal extubation and at the PACU admission in China. Additional evidence is required to prospectively assess the incidence, clinical consequences, impact on quality of recovery, and health care resource utilization and costs associated with residual neuromuscular blockade during routine anesthesia practice in multiple settings across China.
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
Patients and methods Patients and study design This was a prospective, multicenter, anesthetist-blind, observational trial. The study was conducted in accordance with principles of Good Clinical Practice (GCP) and approved by the appropriate Institutional Review Boards/Independent Ethics Committee at each study site of 32 participating tertiary care institutes within 16 cities across mainland of China (Supplementary Table 1) and was registered with clinicaltrial.gov (registration identifier NCT01871064). Between March and September 2013, 1,573 Chinese patients, who were scheduled for elective major abdominal operation under general anesthesia, were prospectively and consecutively screened for eligibility for this study. Patients had to be more than 18 years old with an ASA score 1-3. Patients were included in the study if they received general anesthesia and were administered non-depolarizing NMBA (rocuronium, cisatracurium, vecuronium, or atracurium) for an elective laparotomy or laparoscopic abdominal procedure that was expected to last less than 4 hours. Patients were excluded if they were receiving repeat surgery during the same hospital admission or were transferred directly to intensive care unit. Patients also were excluded if they had a procedure or condition that could interfere with the accuracy of the TOF monitoring system when attached to the ulnar nerve. All patients or legal representatives volunteered to give informed consent in writing before participating. Standard anesthesia monitors (electrocardiogram, pulse oximetry, endtidal carbon dioxide concentration, and oscillometric blood pressure) were applied as routine practices without specified intervention.
Neuromuscular monitoring Investigators carried out neuromuscular monitoring using continuous acceleromyography at the adductor pollicis muscle with TOF-Watch SX®(Organon Ireland Ltd, a subsidiary of Merck & Co., Swords, Co. Dublin, Ireland) in agreement with the guidelines for Good Clinical Research Practice in pharmacodynamics studies of neuromuscular blockade agents13,14. After induction of anesthesia but before neuromuscular relaxant administration, Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
TOF-Watch SX® was calibrated with the built-in calibration modus (CAL 2) after 5-sec 50 Hz tetanic stimulation proceeded by a repetitive TOF stimulation for 1 min. After calibration, a 3–4 min repetitive TOF stimulation was required to ensure a stable response before the administration of the neuromuscular relaxant. TOF stimulation was applied at 15 second intervals until the patient was discharged from the OR or PACU to the surgical ward or until full NMB recovery (TOF ratio>0.9). Neuromuscular monitoring data were collected by means of the TOF-Watch SX® Monitoring Program, version 2.3. After the TOF-Watch SX® set up, the neuromuscular relaxants were administered within 10 sec as a fast-running infusion. General anesthesia was induced and maintained according to each patient’s clinical need at the discretion of the clinical anesthetist. The anesthetists and PACU nurses were blinded to the results of TOF-Watch SX®. To minimize the variability of the evaluations, it was requested that the same investigator performed identical evaluations for all participants at each study site. Before initial study, all investigators received training on how to use the TOF-Watch SX®. Two consecutive TOF stimuli were used to assess residual neuromuscular blockade at the time of endotracheal extubation. If the difference between T4/T1 values did not exceed 5%, the data was used for data analysis. If the difference in the TOF ratio between the two stimuli was greater than 5%, additional TOF stimuli were applied until two subsequent, consecutive TOF readings did not differ by more than 5%. The mean value of two consecutive T4/T1 value was used for the analysis.
Data collection Patient information and clinical outcomes data were obtained from multiple sources including PACU nursing notes, anesthesia records, and surgical ward records. The study staff assessing the T4/T1 and collecting the clinical data were blind to all intraoperative information except knowing the patient had received a ND-NMBA. Clinical information collected on each patient included age, sex, and ASA physical status score. Anesthesia-specific data included anesthetic (volatile or IV), ND-NMBA (compound
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
and dose), and neostigmine administration information (dose and time-stamp). The occurrences of postoperative respiratory complications including upper airway obstruction requiring intervention, hypoxia, pneumonia, atelectasis and re-intubation were retrieved from surgical ward record. Reintubation was defined as the replacement of an endotracheal tube within 7 days of the procedure following initial endotracheal extubation in the operating room. The primary outcome was the incidence of rNMB (TOF ratio < 0.9) on the TOF-Watch ®
SX at time of endotracheal extubation. The incidence of rNMB at the time of PACU admission and healthcare resource utilization related to rNMB were also analyzed.
Statistical methods Based on an expected incidence of the residual neuromuscular blockade of approximately 30% in each region, the study should give a 95% confidence interval with a half-width of 4.6%. The sample size for each region should be 375 patients. With four regions, the total sample size would be n = 1,500 (375*4). Each site would have a recruitment goal of approximately 50 participants. All quantitative data are presented as the mean and standard deviation, and all categorical data are presented as percentages. The differences in the variables between patients at time of endotracheal extubation with and without rNMB were examined using chi-square or Fisher’s exact tests for categorical variables and one-way analysis of variance for continuous values. To evaluate the independent associations between rNMB at the time of endotracheal extubation, a multiple stepwise regression analysis was performed. Variables with significant univariate association at a level of p < 0.10 were entered into a forward stepwise logistic regression analysis in the order of their significance of their association. Statistical significance was accepted at the two-sided 0.05 level, and all confidence intervals were
computed at the 95% level. In the stepwise logistic regression model, factors with p < 0.05 were retained. Statistical analyses were performed using SAS software version 9.2 (SAS Institute, Cary, NC, USA).
Results Patients’ characteristics
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
A total of 1,573 patients were considered for recruitment from 32 hospitals, but two were excluded due to not meeting the inclusion criteria (age < 18 yrs and non-abdominal procedure). Hence, the study population consisted of 1,571 patients, of which 1,026 patients were transferred to the PACU and 545 patients were transferred to a surgical ward directly. A summary of the patient demographic characteristics, operation types, comorbidities, anesthetics, neuromuscular relaxants is provided in Table 1.
Incidence and degree of rNMB The incidence of rNMB (TOFr < 0.9) at the time of endotracheal extubation was 57.8% (Figure 2). Immediately prior to endotracheal extubation, the proportions of patients with TOF ratios < 0.6, 0.6~0.7, 0.7~0.8, and 0.8~0.9 were 22.9%, 6.9%, 11.1% and 16.9%, respectively (Figure 2). As shown in Figure 3, the incidence of rNMB (TOFr < 0.9) was 45.2%, and proportions of participant with TOF ratios < 0.6, 0.6~0.7, 0.7~0.8, and 0.8~0.9 were 23.1%, 5.1%, 6.4% and 10.6%, respectively, at PACU admission.
Factors related to rNMB occurrence Single factor regression analysis showed that age, sex, body weight, duration from endotracheal intubation to extubation, time from fascia suture to endotracheal extubation, cardiovascular diseases, muscle relaxants number (one vs. two or more), time from last dose of muscle relaxant to endotracheal extubation, and time from neostigmine administration to endotracheal extubation were associated with rNMB. In contrast, ASA score, operation type, muscle relaxant antagonism, diseases of respiratory and endocrine systems, tumor, and anesthesia type (intravenous or inhalation) were not associated with rNMB. Furthermore, age,
sex, body weight, duration from endotracheal intubation to extubation, time from fascia suture to endotracheal extubation, cardiovascular diseases, muscle relaxants number (one vs. two or more), time from last muscular relaxant administration to endotracheal extubation, time from neostigmine administration to endotracheal extubation were entered at the beginning of stepwise logistic regression. In these models, the variables listed in Table 2 were retained as independent predictors (p < 0.05) for rNMB at the time of endotracheal extubation. The following factors were significantly associated with rNMB at the time of endotracheal extubation: age (
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Incidence of postoperative residual neuromuscular blockade after general anesthesia: A prospective, multicenter, anesthetists-blind, observational study Yu Buwei, Ouyang Baoyi, Ge Shengjin, Luo Yan, Li Jun, Ni Dongmei, Hu Shuangfei, Xu Hui, Liu Jin, Min Su, Li Longyun, Ma Zhengliang, Xie Kangjie, Miao Changhong & Wu Xinmin To cite this article: Yu Buwei, Ouyang Baoyi, Ge Shengjin, Luo Yan, Li Jun, Ni Dongmei, Hu Shuangfei, Xu Hui, Liu Jin, Min Su, Li Longyun, Ma Zhengliang, Xie Kangjie, Miao Changhong & Wu Xinmin (2015): Incidence of postoperative residual neuromuscular blockade after general anesthesia: A prospective, multicenter, anesthetists-blind, observational study, Current Medical Research and Opinion To link to this article: http://dx.doi.org/10.1185/03007995.2015.1103213
Accepted online: 09 Oct 2015.
Submit your article to this journal
Article views: 2
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Download by: [University of California Santa Barbara]
Date: 15 October 2015, At: 08:35
Just Accepted by Current Medical Research & Opinion ORIGINAL ARTICLE Incidence of postoperative residual neuromuscular blockade after general anesthesia: A prospective, multicenter, anesthetists-blind, observational study Yu Buwei, Ouyang Baoyi, Ge Shengjin, Luo Yan, Li Jun, Ni Dongmei, Hu Shuangfei, Xu Hui, Liu Jin, Min Su, Li Longyun, Ma Zhengliang, Xie Kangjie, Miao Changhong, Wu Xinmin; on behalf of the RECITE-China Investigators doi: 10.1185/03007995.2015.1103213
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
Abstract Objective: Evidences demonstrate that postoperative residual neuromuscular blockade (rNMB) is a primary and frequent anesthetic risk factor for postoperative complications. This study was designed to mitigate the paucity of data regarding the occurrence and degree of rNMB in a reallife setting. Methods: This prospective, multicenter, anesthetists-blind, observational study enrolled 1,571 Chinese adults undergoing elective open or laparoscopic abdominal surgery lasting ≤4 hours from 32 hospitals across China. The patients received anesthesia in accordance with routine practice at the study site. Neuromuscular blockade (NMB) was monitored using acceleromyography, with rNMB defined as a train-of-four (TOF) ratio < 0.9. Results: The patients’ mean age was 46 years and 71% were female. The procedures included laparoscopic (67%), open abdominal (31%), and laparoscopic to open abdominal (2%). NMB was reversed with neostigmine in 78% of patients. The overall incidence of rNMB at extubation was 57.8%, and the proportions of participant with various TOF ratios < 0.6, 0.6~0.7, 0.7~0.8, 0.8~0.9 were 22.9%, 6.9%, 11.1% and 16.9%, respectively, immediately prior to endotracheal extubation. Age < 45 years (OR = 0.630, 95%CI = 0.496-0.801, p = 0.002), use one NMBA (OR = 0.387, 95%CI = 0.243-0.618, p < 0.0001), time from neostigmine administration to endotracheal extubation≥10min (OR = 0.513, 95%CI = 0.400-0.658, p < 0.0001) and time from last NMBA administration to endotracheal extubation≥60min (OR = 0.902, 95%CI = 0.801-0.989, p = 0411) were correlated with non-rNMB at the time of extubation. Conclusions: This observational study demonstrated that the overall incidence of rNMB at the time of endotracheal extubation was high in Chinese patients undergoing abdominal procedures, which necessitates appropriate management in current real-life practice.
© 2015 Taylor & Francis. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon. DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles do not necessarily reflect those of Taylor & Francis (the Publisher), the Editors or the journal. The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner. There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article. Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication.
ORIGINAL ARTICLE Incidence of postoperative residual neuromuscular blockade after general anesthesia: A prospective, multicenter, anesthetists-blind, observational study
Yu Buwei1, Ouyang Baoyi2, Ge Shengjin3, Luo Yan1, Li Jun4, Ni Dongmei5, Hu Shuangfei6, Xu Hui7, Liu Jin8, Min Su9, Li Longyun10, Ma Zhengliang11, Xie Kangjie12, Miao
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
Changhong13, Wu Xinmin5; on behalf of the RECITE-China Investigators
1
Department of Anesthesiology, Rui Jin Hospital, Shanghai Jiao Tong University School of
Medicine, Shanghai, China 2
The First Affiliated hospital of Guangzhou Medical University, Guangzhou, China
3
Zhongshan Hospital of Fudan University, Shanghai, China
4
The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
5
Peking University First Hospital, Beijing, China
6
Zhejiang Provincial People’s Hospital, Hangzhou, China
7
Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology,
Wuhan, China 8
West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
9
The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
10
China-Japan Union Hospital, Jilin University, Changchun, China
11
Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School,
Nanjing, China 12
Zhejiang Cancer Hospital, Hangzhou, China
13
Fudan University Shanghai Cancer Center, Shanghai, China
Address for correspondence: Wu Xinmin, M.D., FRCA, Department of Anesthesiology, Peking University First Hospital, No. 8 Xi Shi Ku Street, Beijing 100034, China. Tel.: +86 10 8357 2784; Fax: +86 10 8357 2784; [email protected]
Abstract Objective: Evidences demonstrate that postoperative residual neuromuscular blockade (rNMB) is a primary and frequent anesthetic risk factor for postoperative complications. This study was designed to mitigate the paucity of data regarding the occurrence and degree of rNMB in a
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
real-life setting. Methods: This prospective, multicenter, anesthetists-blind, observational study enrolled 1,571 Chinese adults undergoing elective open or laparoscopic abdominal surgery lasting ≤4 hours from 32 hospitals across China. The patients received anesthesia in accordance with routine practice at the study site. Neuromuscular blockade (NMB) was monitored using acceleromyography, with rNMB defined as a train-of-four (TOF) ratio < 0.9. Results: The patients’ mean age was 46 years and 71% were female. The procedures included laparoscopic (67%), open abdominal (31%), and laparoscopic to open abdominal (2%). NMB was reversed with neostigmine in 78% of patients. The overall incidence of rNMB at extubation was 57.8%, and the proportions of participant with various TOF ratios < 0.6, 0.6~0.7, 0.7~0.8, 0.8~0.9 were 22.9%, 6.9%, 11.1% and 16.9%, respectively, immediately prior to endotracheal extubation. Age < 45 years (OR = 0.630, 95%CI = 0.496-0.801, p = 0.002), use one NMBA (OR = 0.387, 95%CI = 0.243-0.618, p < 0.0001), time from neostigmine administration to endotracheal extubation≥10min (OR = 0.513, 95%CI = 0.4000.658, p < 0.0001) and time from last NMBA administration to endotracheal extubation≥60min (OR = 0.902, 95%CI = 0.801-0.989, p = 0411) were correlated with nonrNMB at the time of extubation. Conclusions: This observational study demonstrated that the overall incidence of rNMB at the time of endotracheal extubation was high in Chinese patients undergoing abdominal procedures, which necessitates appropriate management in current real-life practice.
Clinical Trial Registry Number: NCT01871064
Key words: Residual neuromuscular blockade − General anesthesia − Train-of-four
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
monitoring – Observational study
[Running title: Residual neuromuscular blockade in Chinese anesthetic practice]
Introduction Surgery that requires general anesthesia also necessitates the use of a neuromuscular blockade agent. Once surgical procedures are complete, the reversal of the effect of muscular relaxants is often performed to accelerate recovery from the neuromuscular blockade. At present, acetylcholinesterase inhibitors are commonly used to reverse paralysis caused by non-depolarizing neuromuscular blocking agents (NMBAs). If a patient is endotracheal extubated before the effects of the neuromuscular blocking agent have dissipated or reversed, residual paralysis occurs. Among patients who have received neuromuscular blocking agents Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
during surgery, residual neuromuscular blockade (defined as TOF ratio < 0.9) is not uncommon at endotracheal extubation or at the post-anesthetic care unit (PACU) admission, with incidences of up to 88% at the time of endotracheal extubation and up to 83% on arrival to the PACU1. Similar findings have been documented in previous studies from several countries2-4. Evidence demonstrates that residual neuromuscular blockade is associated with clinical complications including, but not limited to, hypoxemia, shortness of breath, upper airway problems, difficulty swallowing, hypercapnia, slurred speech, blurred vision and general discomfort1,5-9. Volunteer studies have described the impairment of pharyngeal function, increased risk of laryngeal penetration of contrast bolus, and impaired hypoxic ventilatory drive, among other unpleasant effects10. Clinical studies in surgical patients have demonstrated an association between rNMB and hypoxemia, upper airway obstruction, a higher risk of critical respiratory events (CREs), and other morbidities10. Data on healthcare resource utilization associated with residual neuromuscular blockade are scant, but studies have demonstrated significantly longer lengths of stay in the PACU of patients with a residual neuromuscular blockade1,11. Several patient factors and surgery types are risk factors for post-operative pulmonary complications (POPC), such as pneumonia and atelectasis. Patient factors include age ≥ 60, obesity, smoking and the American Society of Anesthesiologists (ASA) score ≥ II. Additionally, patients with chronic obstructive pulmonary disease (COPD) or chronic heart failure (CHF) and those undergoing open or upper abdominal or bariatric surgery are also at an increased risk of POPC12. This suggests that these patients and surgery types may also be at an increased risk of adverse consequences from residual neuromuscular blockade.
Despite data demonstrating potential morbidity, there is a paucity of data regarding the incidence of residual paralysis at endotracheal extubation and at the PACU admission in China. Additional evidence is required to prospectively assess the incidence, clinical consequences, impact on quality of recovery, and health care resource utilization and costs associated with residual neuromuscular blockade during routine anesthesia practice in multiple settings across China.
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
Patients and methods Patients and study design This was a prospective, multicenter, anesthetist-blind, observational trial. The study was conducted in accordance with principles of Good Clinical Practice (GCP) and approved by the appropriate Institutional Review Boards/Independent Ethics Committee at each study site of 32 participating tertiary care institutes within 16 cities across mainland of China (Supplementary Table 1) and was registered with clinicaltrial.gov (registration identifier NCT01871064). Between March and September 2013, 1,573 Chinese patients, who were scheduled for elective major abdominal operation under general anesthesia, were prospectively and consecutively screened for eligibility for this study. Patients had to be more than 18 years old with an ASA score 1-3. Patients were included in the study if they received general anesthesia and were administered non-depolarizing NMBA (rocuronium, cisatracurium, vecuronium, or atracurium) for an elective laparotomy or laparoscopic abdominal procedure that was expected to last less than 4 hours. Patients were excluded if they were receiving repeat surgery during the same hospital admission or were transferred directly to intensive care unit. Patients also were excluded if they had a procedure or condition that could interfere with the accuracy of the TOF monitoring system when attached to the ulnar nerve. All patients or legal representatives volunteered to give informed consent in writing before participating. Standard anesthesia monitors (electrocardiogram, pulse oximetry, endtidal carbon dioxide concentration, and oscillometric blood pressure) were applied as routine practices without specified intervention.
Neuromuscular monitoring Investigators carried out neuromuscular monitoring using continuous acceleromyography at the adductor pollicis muscle with TOF-Watch SX®(Organon Ireland Ltd, a subsidiary of Merck & Co., Swords, Co. Dublin, Ireland) in agreement with the guidelines for Good Clinical Research Practice in pharmacodynamics studies of neuromuscular blockade agents13,14. After induction of anesthesia but before neuromuscular relaxant administration, Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
TOF-Watch SX® was calibrated with the built-in calibration modus (CAL 2) after 5-sec 50 Hz tetanic stimulation proceeded by a repetitive TOF stimulation for 1 min. After calibration, a 3–4 min repetitive TOF stimulation was required to ensure a stable response before the administration of the neuromuscular relaxant. TOF stimulation was applied at 15 second intervals until the patient was discharged from the OR or PACU to the surgical ward or until full NMB recovery (TOF ratio>0.9). Neuromuscular monitoring data were collected by means of the TOF-Watch SX® Monitoring Program, version 2.3. After the TOF-Watch SX® set up, the neuromuscular relaxants were administered within 10 sec as a fast-running infusion. General anesthesia was induced and maintained according to each patient’s clinical need at the discretion of the clinical anesthetist. The anesthetists and PACU nurses were blinded to the results of TOF-Watch SX®. To minimize the variability of the evaluations, it was requested that the same investigator performed identical evaluations for all participants at each study site. Before initial study, all investigators received training on how to use the TOF-Watch SX®. Two consecutive TOF stimuli were used to assess residual neuromuscular blockade at the time of endotracheal extubation. If the difference between T4/T1 values did not exceed 5%, the data was used for data analysis. If the difference in the TOF ratio between the two stimuli was greater than 5%, additional TOF stimuli were applied until two subsequent, consecutive TOF readings did not differ by more than 5%. The mean value of two consecutive T4/T1 value was used for the analysis.
Data collection Patient information and clinical outcomes data were obtained from multiple sources including PACU nursing notes, anesthesia records, and surgical ward records. The study staff assessing the T4/T1 and collecting the clinical data were blind to all intraoperative information except knowing the patient had received a ND-NMBA. Clinical information collected on each patient included age, sex, and ASA physical status score. Anesthesia-specific data included anesthetic (volatile or IV), ND-NMBA (compound
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
and dose), and neostigmine administration information (dose and time-stamp). The occurrences of postoperative respiratory complications including upper airway obstruction requiring intervention, hypoxia, pneumonia, atelectasis and re-intubation were retrieved from surgical ward record. Reintubation was defined as the replacement of an endotracheal tube within 7 days of the procedure following initial endotracheal extubation in the operating room. The primary outcome was the incidence of rNMB (TOF ratio < 0.9) on the TOF-Watch ®
SX at time of endotracheal extubation. The incidence of rNMB at the time of PACU admission and healthcare resource utilization related to rNMB were also analyzed.
Statistical methods Based on an expected incidence of the residual neuromuscular blockade of approximately 30% in each region, the study should give a 95% confidence interval with a half-width of 4.6%. The sample size for each region should be 375 patients. With four regions, the total sample size would be n = 1,500 (375*4). Each site would have a recruitment goal of approximately 50 participants. All quantitative data are presented as the mean and standard deviation, and all categorical data are presented as percentages. The differences in the variables between patients at time of endotracheal extubation with and without rNMB were examined using chi-square or Fisher’s exact tests for categorical variables and one-way analysis of variance for continuous values. To evaluate the independent associations between rNMB at the time of endotracheal extubation, a multiple stepwise regression analysis was performed. Variables with significant univariate association at a level of p < 0.10 were entered into a forward stepwise logistic regression analysis in the order of their significance of their association. Statistical significance was accepted at the two-sided 0.05 level, and all confidence intervals were
computed at the 95% level. In the stepwise logistic regression model, factors with p < 0.05 were retained. Statistical analyses were performed using SAS software version 9.2 (SAS Institute, Cary, NC, USA).
Results Patients’ characteristics
Downloaded by [University of California Santa Barbara] at 08:35 15 October 2015
A total of 1,573 patients were considered for recruitment from 32 hospitals, but two were excluded due to not meeting the inclusion criteria (age < 18 yrs and non-abdominal procedure). Hence, the study population consisted of 1,571 patients, of which 1,026 patients were transferred to the PACU and 545 patients were transferred to a surgical ward directly. A summary of the patient demographic characteristics, operation types, comorbidities, anesthetics, neuromuscular relaxants is provided in Table 1.
Incidence and degree of rNMB The incidence of rNMB (TOFr < 0.9) at the time of endotracheal extubation was 57.8% (Figure 2). Immediately prior to endotracheal extubation, the proportions of patients with TOF ratios < 0.6, 0.6~0.7, 0.7~0.8, and 0.8~0.9 were 22.9%, 6.9%, 11.1% and 16.9%, respectively (Figure 2). As shown in Figure 3, the incidence of rNMB (TOFr < 0.9) was 45.2%, and proportions of participant with TOF ratios < 0.6, 0.6~0.7, 0.7~0.8, and 0.8~0.9 were 23.1%, 5.1%, 6.4% and 10.6%, respectively, at PACU admission.
Factors related to rNMB occurrence Single factor regression analysis showed that age, sex, body weight, duration from endotracheal intubation to extubation, time from fascia suture to endotracheal extubation, cardiovascular diseases, muscle relaxants number (one vs. two or more), time from last dose of muscle relaxant to endotracheal extubation, and time from neostigmine administration to endotracheal extubation were associated with rNMB. In contrast, ASA score, operation type, muscle relaxant antagonism, diseases of respiratory and endocrine systems, tumor, and anesthesia type (intravenous or inhalation) were not associated with rNMB. Furthermore, age,
sex, body weight, duration from endotracheal intubation to extubation, time from fascia suture to endotracheal extubation, cardiovascular diseases, muscle relaxants number (one vs. two or more), time from last muscular relaxant administration to endotracheal extubation, time from neostigmine administration to endotracheal extubation were entered at the beginning of stepwise logistic regression. In these models, the variables listed in Table 2 were retained as independent predictors (p < 0.05) for rNMB at the time of endotracheal extubation. The following factors were significantly associated with rNMB at the time of endotracheal extubation: age (
