POSTOPERATIVE respiratory impairment may be

Transcription

1 Residual Neuromuscular Blockade Affects Postoperative Pulmonary Function Gopalaiah Venkatesh Kumar, M.B.B.S., D.N.B.,* Anita Pramod Nair, M.B.B.S., D.N.B., Hanuman Srinivasa Murthy, M.B.B.S., M.D., Koppa Ramegowda Jalaja, M.B.B.S., D.N.B., Karnate Ramachandra, M.B.B.S., M.D., Gundappa Parameshwara, M.B.B.S., M.D. This article has been selected for the Anesthesiology CME Program. Learning objectives and disclosure and ordering information can be found in the CME section at the front of this issue. ABSTRACT Background: Residual neuromuscular blockade () is known to be associated with respiratory complications in the postoperative period after muscle relaxant usage. The authors hypothesized that causes reductions in pulmonary function test (PFT) parameters in the immediate postoperative period. Methods: An open-label prospective randomized cohort study was conducted comparing reductions in PFT parameters due to among different neuromuscular blocking agents. One hundred and fifty patients were randomized to receive vecuronium, atracurium, or rocuronium. After reversal of neuromuscular blockade and extubation, train-of-four ratio was measured every 5 min until the train-of-four ratio of 0.9 or greater was attained. PFTs were performed preoperatively and postoperatively when the patients were willing and fit. The train-of-four ratio, measured at PFT, was used to classify patients into absent and present. was defined as a train-of-four ratio less than 0.9. Results: Thirty-nine patients had at the time of performing PFT. There was no statistically significant difference in the postoperative reductions in PFT parameters in patients with among different neuromuscular blocking agents. Patients were regrouped as absent * Senior Resident, Specialist, Consultant, Department of Anesthesia, Manipal Hospital, Bangalore, India. Received from the Department of Anesthesia, Manipal Hospital, Bangalore, India. Submitted for publication October 21, Accepted for pub lication July 12, Support was provided solely from institutional and/or departmental sources. This work was presented at the South Asian Association for Regional Cooperation Anaesthesia Meeting 2011, on August 28, 2011, in Bangalore, India, and has been presented as a poster in the World Congress of Anesthesiology 2012 held on March 25 31, 2012, in Buenos Aires, Argentina. Address correspondence to Dr. Murthy: Department of Anaesthesia, Manipal Hospital, No. 98, Old Airport Road, Bangalore , Karnataka, India. drhsmurthy@gmail.com. This article may be accessed for personal use at no charge through the Journal web site, Copyright 2012, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2012; 117: What We Already Know about This Topic Residual neuromuscular blockade is known to be associated with respiratory complications in the postoperative period after muscle relaxant usage What This Article Tells Us That Is New Residual neuromuscular blockade after the use of vecuronium, atracurium, or rocuronium results in reductions in forced vital capacity and peak expiratory flow in the immediate postoperative period, indicating impaired respiratory muscle function and present, irrespective of neuromuscular blocking agents. Postoperative PFT values for the -absent and -present groups were 62% and 49% of baseline forced vital capacity and 47% and 38% of baseline peak expiratory flow of the baseline, respectively. Postoperative forced vital capacity and peak expiratory flow values of -present patients were lower by 13% and 9% in absolute terms (P < 0.008) and 21% and 19% in relative terms, respectively, compared with -absent patients. Conclusion: results in reductions in forced vital capacity and peak expiratory flow in the immediate postoperative period indicating impaired respiratory muscle function. POSTOPERATIVE respiratory impairment may be due to various causes, which include patient factors like obesity and surgical factors like site of incision, tight dressings, gastric dilatation, postoperative pain, and effects of residual anesthetics. 1,2 All these factors can result in critical respiratory events like upper airway obstruction, pulmonary aspiration, atelectasis, and pneumonic consolidation. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal s Web site ( Anesthesiology, V 117 No December 2012

2 PERIOPERATIVE MEDICINE Despite using reversal agents at the end of surgery and clinically apparent return of neuromuscular function, residual neuromuscular blockade () is known to occur in the postanesthesia care unit (PACU). 3 5 may be a major cause of respiratory weakness in the immediate postoperative period, resulting in a restrictive respiratory pattern. Several recent volunteer and clinical studies have shown that is associated with respiratory complications. 6 9 However, despite a growing body of evidence establishing the clinical importance of, there are no data quantifying the impact of on pulmonary function in the immediate (first hour) postoperative period. We hypothesized that causes reduction in pulmonary function in the immediate postoperative period. The reduction in postoperative pulmonary function parameters was compared between patients with and without among different neuromuscular blocking (NMB) agents. Materials and Methods Study Design and Participation One hundred and fifty patients of either sex, American Society of Anesthesiologists grades 1 and 2, aged yr, coming for elective surgeries lasting for less than 3 h, requiring intraoperative neuromuscular blockade were recruited for a single-center open-label prospective randomized cohort study. Written informed consent was taken from patients. Data were collected for a 2-yr period (July 2008 June 2010) at Manipal Hospital (a corporate tertiary care center with postgraduate training program), Bangalore, Karnataka, India. The study was approved by the institutional review board (Hospital Ethics Committee for Human Research, Manipal Hospital, Bangalore, Karnataka, India), which supervised the data collection and safety issues. Exclusion criteria were patients with cardiorespiratory abnormalities (New York Heart Association heart failure grades 3 and 4, bronchial asthma, chronic obstructive pulmonary disease, and restrictive lung disease), renal insufficiency (serum creatinine more than 1.6 mg/dl), liver dysfunction (liver enzymes serum glutamic oxaloacetic transaminase/ serum glutamic pyruvic transaminase values elevated by more than 50% of normal), underlying neuromuscular disease, the use of drugs known to interfere with neuromuscular transmission, intraoperative hypothermia (core temperature less than 35 C), history of smoking, thoracic and upper abdominal surgeries, unwillingness to perform pulmonary function test (PFT), and severe obesity (body mass index greater than 35). Preoperative PFT Measurements During preanesthesia evaluation, all the patients were familiarized using a spirometer. Baseline PFT was performed, with patients in erect sitting posture and a nose clip attached, using Microplus TM gold standard pocket spirometer, Micromedical (Care Fusion, Rochester, Kent, United Kingdom). They were made to inhale maximally to total lung capacity and exhale maximally through the mouthpiece with lips closed around the mouthpiece. Three consecutive readings were recorded, and the best set of values was noted. Forced vital capacity (FVC), peak expiratory flow (PEF), respiratory rate, and oxygen saturation were recorded. Patients were informed about the train-of-four (TOF) measurements that would be performed postoperatively, the possible discomfort or pain associated with it, and the PFT that would be performed once more during the postoperative period. All patients were premedicated with intramuscular glycopyrrolate 0.2 mg half an hour before surgery. Intraoperative Management A computer-generated simple 1:1:1 randomization table (created using Microsoft Excel 2003 software, Redmond, WA) was used to allocate the muscle relaxant (vecuronium, atracurium, or rocuronium) to be used intraoperatively. This was revealed to the anesthesiologist just before entering the operating room. Standard intraoperative monitoring included electrocardiography, capnography, noninvasive blood pressure, pulse oximetry, and nasopharyngeal temperature. Neuromuscular monitoring was not performed during the intraoperative period. Anesthesia was induced with 1.5 mg/kg propofol, 2 μg/kg fentanyl, and 1.5 mg/kg lidocaine. For muscle relaxation, patients received either vecuronium ( mg/kg), atracurium (0.5 mg/kg), or rocuronium ( mg/kg). Anesthesia was maintained with % isoflurane in 50% oxygen and nitrous oxide mixture to maintain mean blood pressure within 20% of the baseline values. Analgesia was maintained by fentanyl (1 μg kg 1 h 1 boluses). The maintenance of muscle relaxation, either by top-up doses or infusions, was left to the discretion of the consultant anesthesiologist managing the patient. For the maintenance of muscle relaxation, patients received one of the three relaxants: vecuronium, 0.02 mg/kg top-up doses every min or 0.05 mg kg 1 h 1 continuous infusion; atracurium, 0.1 mg/ kg top-up doses every 20 min or 0.3 mg kg 1 h 1 continuous infusion; or rocuronium, 0.15 mg/kg top-up doses every 30 min or 0.3 mg kg 1 h 1 continuous infusion. Ventilation was controlled to maintain end-tidal carbon dioxide between 30 and 35 mmhg. Normothermia was maintained using forced air warming with Level1 TM (Smith Medical Inc., Rockland, MA). All the patients received neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg at the end of the surgery for reversal of neuromuscular blockade. Patients were extubated on the basis of clinical judgment of the anesthesiologist managing the case. Total dose of NMB agents used, time of administration of NMB agent at induction, time of administration of the last dose of NMB agent/stoppage of infusion, time of administration of reversal agent, and time of extubation were noted. TOF and PFT Measurements in PACU On arrival at the PACU, all patients received 5 l/min O 2 via mask and were monitored with electrocardiography, pulse oximeter, and noninvasive blood pressure. Neuromuscular monitor (TOF watch ; Organon Ltd., Dublin, Ireland) was Anesthesiology 2012; 117: Kumar et al.

3 Residual Neuromuscular Block and Pulmonary Function applied to all the patients. The acceleration transducer was attached to the volar aspect of the interphalyngeal joint of the thumb to sense the contraction of adductor pollicis muscle. The two surface electrodes were placed over the ulnar aspect of the wrist, the stimulating electrode over the ulnar nerve at the crease of the wrist, and the other electrode 4 cm proximal to it. The arm and fingers were immobilized using a splint, and free movement of the thumb was ensured. After an uncalibrated TOF stimulation (four pulses of 0.2-ms duration for 2 s at a frequency of 2 Hz; current intensity, 50 ma), which was repeated four to five times at an interval of 12 s between stimulations, the highest of the two consecutive reproducible TOF ratio was noted. TOF measurements were repeated every 5 min until a TOF ratio of 0.9 or more was reached. Patients were also checked every 5 min to see whether they were awake, alert, and willing to perform PFT. Once they were ready, three consecutive PFT readings were recorded in propped up position (back reclined at 45 with knee flexion of ), and the best set of values was noted. During the postoperative period, SpO 2 % and respiratory rate were noted. Patients were monitored by an observer for adverse respiratory events like hypoxia (SpO 2 less than 90%), shallow rapid breathing (respiratory rate higher than 30 breaths per minute), upper airway obstruction requiring nasopharyngeal or oropharyngeal airway, stridor, laryngospasm, inability to swallow, or pulmonary aspiration. Time of first TOF reading (baseline), time of attaining a TOF ratio of 0.9 or more, and time of performing postoperative PFT were noted. The TOF ratio at PFT was also noted. If the patient had already attained a TOF ratio of 0.9 or more before performing PFT, then the TOF measurement was not repeated and the last measured TOF ratio was taken as the TOF at PFT. In patients who still had not attained a TOF ratio of 0.9 at the time of performing PFT, the TOF measurement was repeated until a TOF ratio of 0.9 or more was attained. The TOF ratio less than 0.9 was used to define residual paralysis. Patients were divided into two groups, present (TOF less than 0.9) and absent (TOF 0.9), based on the TOF ratio at PFT. On the basis of the timings noted, various time intervals were calculated. The time intervals included the duration of neuromuscular blockade (time from administration of NMB agent at induction to administration of reversal agent), the reversal to attaining a TOF ratio of 0.9 or more, the reversal to postoperative PFT, and a TOF ratio of 0.9 or more to postoperative PFT. Plan of Analysis The various study variables including demographic data, time intervals, and PFT parameters were compared among the three groups of patients receiving vecuronium, atracurium, and rocuronium. Next, the study variables between patients with and without both within and across the vecuronium, atracurium, and rocuronium groups were compared. Finally, all the patients were pooled and classified based on the presence or absence of, irrespective of the muscle relaxant used as -present and absent groups and compared (fig. 1). For comparison of PFT parameters, four sets of values of both FVC and PEF were compared. First, preoperative Fig. 1. The plan of analysis used in the study. The patients were randomized into three primary groups based on the neuromuscular blocking agent received, as vecuronium, atracurium, and rocuronium groups and were compared. Each primary group was subdivided based on presence or absence of, and the subgroups were compared within and across the primary groups. Further, identical subgroups from all three primary groups were pooled and regrouped as -present and -absent groups and were compared. = residual neuromuscular blockade. Anesthesiology 2012; 117: Kumar et al.

4 PERIOPERATIVE MEDICINE values were compared. Predicted values for FVC and PEF were derived from the nomogram provided by Microplus TM gold standard pocket spirometer, Micro medical, using age, sex, and height of individual patients. Preoperative values as percentage of predicted FVC or PEF were calculated (% predicted = [preoperative value/predicted value] 100) and compared. Next, postoperative values were compared. Finally, postoperative values as percentage of preoperative values were calculated (postoperative value as % of preoperative value = postoperative value/preoperative value 100) and compared. The primary outcome we planned to study was to compare postoperative FVC and PEF reductions in patients with following the use of three different intermediate-acting NMB agents. A reduction of 15% or more in FVC or PEF in patients with compared with patients without was deemed to be clinically significant, as many clinically used pulmonary risk assessment scales use 15% difference in PFT parameters to grade the severity of pulmonary insufficiency. 10,11 Sample Size As data for PFT parameters in the immediate postoperative period were not available in the literature, sample size could not be estimated based on FVC or PEF. Instead, sample size estimation was performed based on the expected incidence of postoperatively. A previous meta-analysis showed a mean incidence of as 0.54 (95% CI, ) in nonmonitored (intraoperative TOF monitoring) patients who received intermediate-acting muscle relaxants. 12 Group size was determined by using the sample size estimation for proportions method, with an expected proportion of 0.54 and a two-tailed width of the CI of assuming a 95% confidence level. On the basis of this, we estimated that 28 patients were required to be studied in each group. We studied 50 patients in each group (a total of 150 patients) to compensate for the patients who would be lost because of recovery from before they could perform PFT. We assumed that 40 50% of patients, who would have been classified as having on arrival to PACU, would continue to have if PFT is performed within 30 min postoperatively. From our initial clinical experience of performing PFTs postoperatively, we knew that majority of the patients could perform PFT within 30 min. Statistical Methods Normally distributed continuous data are presented as mean ± SD. Continuous data, which are not distributed normally, are presented as median (interquartile range). P value less than 0.05 was considered statistically significant. Statistical analysis was performed using the Statistical Package for the Social Sciences (Version 15.0; IBM corporation, Armonk, NY). For comparing different NMB agents with regard to demographic data, PFT parameters, and other study variables, ANOVA or chi-square test were used. Student t test for independent samples was used to compare demographic data, PFT parameters, and other study variables between -present and -absent patients. Paired samples Student t test was used to compare preoperative and postoperative PFT parameters. P value less than0.013 was considered significant for multiple comparisons (PFT parameters) after applying Bonferroni correction. Results All 150 patients were able to perform PFT in the immediate postoperative period (within 1 h) and were included in the analysis. Fifty patients each received vecuronium, atracurium, and rocuronium for muscle relaxation. An analysis of TOF ratio on arrival to PACU (TOF at baseline) showed that 57% patients (n = 86) had (TOF less than 0.9), which persisted in 39 patients (26%) at the time of performing PFT. Comparison of Vecuronium, Atracurium, and Rocuronium Groups The three groups were well matched with respect to age, sex, weight, height, body mass index, and type of surgery. Various time intervals like the duration of neuromuscular blockade, the reversal to attaining a TOF ratio of 0.9 or more, the reversal to postoperative PFT measurement, and the time of attaining a TOF ratio of 0.9 or more to postoperative PFT measurement were similar among the groups. During the intraoperative period, less number of patients in rocuronium group (30 [60%]) received NMB agent either as top-ups or infusion compared with vecuronium (37 [74%]) and atracurium (45 [90%]) for the maintenance of muscle relaxation (P < 0.002). The mean ± SD values of TOF ratio on arrival to PACU (TOF at baseline) were 0.79 ± 0.17, 0.81 ± 0.16, and 0.85 ± 0.18 in the vecuronium, atracurium, and rocuronium groups, respectively (P < 0.001). At the time of performing PFT, the mean ± SD values of TOF ratio were 0.87 ± 0.14, 0.89 ± 0.12, and 0.90 ± 0.14 in the vecuronium, atracurium, and rocuronium groups, respectively (P < 0.001). An analysis of TOF at baseline showed that the incidence of was lower in rocuronium group (23 patients, 46%) compared with vecuronium group (33 patients, 66%) and atracurium group (30 patients, 60%) (P = 0.047). At the time PFT was performed, persisted in 16 patients (32%) in the vecuronium group, 11 patients (22%) in the atracurium group, and 12 patients (24%) in the rocuronium group, and there was no statistically significant difference in the incidence of among the three groups (table 1). The preoperative baseline PFTs were similar among the three groups. Baseline PEF values were 430 ± 104, 407 ± 110, and 414 ± 114 l/min and baseline FVC values were 2.66 ± 0.70, 2.69 ± 0.72, and 2.68 ± 0.74 l in the vecuronium, atracurium, and rocuronium groups, respectively. There was a statistically significant reduction in postoperative PEF (187 ± 99, 182 ± 93, and 192 ± 100 l/min) and FVC (1.46 ± 0.63, 1.61 ± 0.78, and 1.65 ± 0.82 l) in the vecuronium, atracurium, and rocuronium groups, respectively, compared with their respective preoperative values (P < 0.001). Anesthesiology 2012; 117: Kumar et al.

5 Residual Neuromuscular Block and Pulmonary Function Table 1. Comparison of Study Variables among Patients Receiving Vecuronium, Atracurium, and Rocuronium Vecuronium (n = 50) Atracurium (n = 50) Rocuronium (n = 50) P Value Age, yr 36 ± ± ± Sex (male female ratio) 22:28 25:25 24: Height, cm 64 ± 8 63 ± 9 65 ± Weight, kg 164 ± ± ± BMI, kg/m ± ± ± Baseline TOF ratio 0.79 ± ± ± 0.18 <0.001 TOF ratio at PFT 0.87 ± ± ± 0.14 <0.001 at baseline 33 (66%) 30 (60%) 23 (46%) at PFT 16 (32%) 11 (22%) 12 (24%) Type of surgery Lower abdominal 10 (20%) 9 (18%) 12 (24%) Laparoscopic 17 (34%) 16 (32%) 10 (20%) Others 23 (46%) 25 (50%) 28 (56%) NMBD maintenance <0.002 Top-up or infusion 37 (74%) 45 (90%) 30 (60%) Nil 13 (26%) 5 (10%) 20 (40%) Time intervals, min Duration of NMB 111 ± ± ± Reversal to attaining TOF (9 to 19) 12 (7 to 18) 9 (6 to 15) Reversal to postoperative PFT 14 (10 to 20) 15 (10 to 25) 10 (5 to 20) TOF 0.9 to postoperative PFT 0 ( 5 to 5) 0 (0 to 10) 0 (0 to 5) Data are presented as mean ± SD, median (interquartile range), or number of patients (%). Baseline TOF = mean TOF recorded on arrival to postanesthesia care unit; TOF at PFT = mean TOF recorded when PFT was performed. Lower abdominal surgeries (31 patients) included abdominal hysterectomy (21 patients), ovarian tumors (5 patients), laparotomy (4 patients), and myomectomy (2 patients). Laparoscopic surgeries (43 patients) included cholecystectomy (31 patients), appendicectomy (8 patients), and ovarian cyst excision (4 patients). Other surgeries (76 patients) included inner ear surgeries (23 patients), minor orthopedic procedures (38 patients), inguinal hernia repair (6 patients), liposuction (6 patients), and varicose vein surgery (3 patients). BMI = body mass index; NMB = neuromuscular blockade; NMBD = neuromuscular blocking drug; PFT = pulmonary function test; = residual neuromuscular blockade; TOF = train of four. The reduction in PEF and FVC from preoperative to postoperative measurements was similar when compared across vecuronium, atracurium, and rocuronium groups (table 2). Subgroup Analysis For further analysis, based on the TOF ratio at PFT, patients from each group (vecuronium, atracurium, and rocuronium) were subdivided into absent and present. The demographic data and other study variables were similar both within and across the subgroups except time intervals (reversal to attaining a TOF ratio of 0.9 or more, reversal to postoperative PFT, and a TOF ratio of 0.9 or more to postoperative PFT) within each group between -absent and -present patients (see table, Supplemental Digital Content 1, lww.com/aln/a885, comparing study variables among vecuronium, atracurium, and rocuronium groups). There was a statistically significant reduction in postoperative PEF and FVC compared with their respective preoperative values in both -absent and -present patients in all three groups (P < 0.001). The reduction in postoperative PFT parameters in -absent and -present patients were similar within each NMB group, except the postoperative FVC values expressed as percentage of preoperative values in vecuronium group (P < 0.001). The reductions in PFT parameters were similar in -absent patients across the three NMB groups. The differences in the reductions in PFT parameters in -present patients across the three NMB groups were not statistically significant (table 3; fig. 2). Comparison of -absent and -present Patients: A Secondary Analysis All 150 patients were pooled and regrouped as absent and present, based on the TOF ratio at PFT irrespective of the NMB agent used. At the time of PFT, 39 patients (26%) had TOF less than 0.9 ( present), and 111 patients (74%) had recovered to a TOF ratio of 0.9 or more ( absent). The mean ± SD values of TOF at the time of performing PFT for groups absent and present were 0.95 ± 0.04 and 0.71 ± 0.14, respectively (P < 0.001). All the patients except four in the absent group performed PFT within first 30 min of arrival to PACU. There was no difference between the groups in age, sex, weight, height, body mass index, type of surgery, and the type of relaxant used. The use of muscle relaxants for Anesthesiology 2012; 117: Kumar et al.

6 PERIOPERATIVE MEDICINE Table 2. Comparison of PFT Parameters among Patients Receiving Vecuronium, Atracurium, and Rocuronium Vecuronium (n = 50) Atracurium (n = 50) Rocuronium (n = 50) P Value PEF, l/min Preoperative 430 ± ± ± % Predicted 94 ± ± ± Postoperative 187 ± 99* 182 ± 93* 192 ± 100* % Preoperative 43 ± ± ± FVC, l Preoperative 2.66 ± ± ± % Predicted 71 ± ± ± Postoperative 1.46 ± 0.63* 1.61 ± 0.78* 1.65 ± 0.82* % Preoperative 55 ± ± ± Data are presented as mean ± SD. After applying Bonferroni s correction, P <0.013 (0.05/4) was considered as significant for comparison of PFT parameters among the groups. Predicted values for PFTs were derived from the nomogram provided by Microplus TM gold standard pocket spirometer, Micro medical (Care Fusion, Rochester, Kent, United Kingdom) using age, sex, and height of individual patients. *P < compared with respective preoperative values. FVC = forced vital capacity; PEF = peak expiratory flow; PFT = pulmonary function test; Preoperative = PFT values measured preoperatively; % predicted = preoperative value as the percentage of predicted: (Preoperative/Predicted) 100; Postoperative = PFT values measured postoperatively; % preoperative = postoperative value as % of preoperative value: (Postoperative/Preoperative) 100. maintenance intraoperatively, as top-ups and infusions, did not differ between the groups (table 4). Among the time intervals noted, there was no difference between the groups in the duration of neuromuscular blockade. After reversal, patients in the -absent group attained a TOF ratio of 0.9 or more earlier when compared with patients in the -present group (9 [6 13] min compared with 20 [15 28] min, P < 0.001). Patients in the -absent group performed postoperative PFTs at 15 (10 25) min after reversal when compared Table 3. Comparison of PFT Parameters between -present (TOF less than 0.9 at PFT) and -absent Patients within the Groups and -present (TOF less than 0.9 at PFT) Patients across Vecuronium, Atracurium, and Rocuronium Groups Vecuronium Atracurium Rocuronium Absent Present Absent Present Absent Present (n = 34) (n = 16) (n = 39) (n = 11) (n = 38) (n = 12) P Value PEF, l/min Preoperative 422 ± ± ± ± ± ± % Predicted 92 ± ± ± ± ± ± Postoperative 199 ± ± ± ± ± ± % Preoperative 46 ± ± ± ± ± ± FVC, l Preoperative 2.63 ± ± ± ± ± ± % Predicted 69 ± ± ± ± ± ± Postoperative 1.61 ± ± 0.48* 1.68 ± ± ± ± % Preoperative 62 ± ± ± ± ± ± Data are presented as mean ± SD. After applying Bonferroni s correction, P < (0.05/4) was considered as significant for comparison of PFT parameters among the groups. Predicted values for PFTs was derived from the nomogram provided by Microplus TM gold standard pocket spirometer, Micro medical (Care Fusion, Rochester, Kent, United Kingdom), using age, sex, and height of individual patients. *P = compared with absent. P < compared with absent. P value for comparison of -present patients among vecuronium, atracurium, and rocuronium. FVC = forced vital capacity; PEF = peak expiratory flow; PFT = pulmonary function test; = residual neuromuscular blockade; TOF = train of four; Preoperative = PFT values measured preoperatively; % predicted = preoperative value as % of predicted: (Preoperative/ Predicted) 100; Postoperative = PFT values measured postoperatively; % preoperative = postoperative value as % of preoperative value: (Postoperative/Preoperative) 100. Anesthesiology 2012; 117: Kumar et al.

7 Residual Neuromuscular Block and Pulmonary Function 47 ± 18% and 38 ± 17% (P = 0.008); FVC, 62 ± 21% and 49 ± 18% (P = 0.001), in the -absent and present groups, respectively (fig. 3). Postoperative FVC and PEF values expressed as a percentage of baseline were lower in the -present patients (by 13% and 9% in absolute terms, and 21% and 19% in relative terms, respectively) compared with -absent patients, and these reductions were statistically significant (after Bonferroni correction). None of the patients in both groups had hypoxia, upper airway obstruction, laryngospasm, or aspiration. Fig. 2. Postoperative reductions in (A) PEF and (B) FVC values as the percentage of preoperative values in patients with (-present) and without (-absent) among patients receiving vecuronium, atracurium, and rocuronium. Within the groups, only the FVC reduction in -present patients receiving vecuronium was significantly lower compared with -absent patients. *P < compared with the corresponding -absent patients. Across the groups, the postoperative PEF and FVC reductions among -absent patients receiving the three NMB agents were similar, and the difference in postoperative PEF and FVC reductions among -present patients receiving the three NMB agents was not statistically significant. PEF = peak expiratory flow; FVC = forced vital capacity; = residual neuromuscular blockade. with -present patients who could do it at 10 (5 15) min after reversal (P less than 0.001). The patients in the -absent group attained a TOF ratio of 0.9 or more at 2 (0 10) min before they could perform postoperative PFT, compared with patients in the -present group who attained a TOF ratio of 0.9 or more at 10 (5 10) min after performing postoperative PFT (P < 0.001) (table 4). The preoperative baseline PFTs were as follows: PEF, 415 ± 111 and 413 ± 102 l/min; FVC, 2.67 ± 0.70 and 2.69 ± 0.78 l in the -absent and the -present groups, respectively. The postoperative PFT values were as follows: PEF, 196 ± 101 and 157 ± 79 l/min; FVC, 1.66 ± 0.76 and 1.32 ± 0.65 l in the -absent and the -present groups, respectively, which were lower than the preoperative (baseline) values (P < 0.001) (table 5). The absolute values of postoperative PEF (P = 0.030) and FVC (P = 0.014) were lower in the -present group compared with the -absent group but were not statistically significant (after Bonferroni correction). The postoperative PFT values as a percentage of baseline were as follows: PEF, Discussion Incidence of In our study, patients received three commonly used intermediate-acting NMB agents. In the absence of intraoperative TOF monitoring, the overall incidence of on arrival to the PACU was 57% (n = 86). In a meta-analysis, Naguib et al. 12 found a mean incidence of of (95% CI, ) in patients who received intermediate-acting NMB agents without intraoperative TOF monitoring. The use of intraoperative neuromuscular monitoring is known to reduce the incidence of in the PACU. 13 Despite intraoperative TOF monitoring, some of the studies have reported a high incidence of (30 50%), 7,14 whereas others have reported a lower incidence (3.5 29%). 8,15 When individual NMB agents were considered, the incidence of on arrival to PACU was lower in patients who received rocuronium (46%) compared with those receiving vecuronium (66%) and atracurium (60%) (P < 0.047). The lower incidence of found with rocuronium is unlikely to be due to any pharmacological variation or advantage but rather may be because of the way it is used in clinical practice. In our study, the maintenance of muscle relaxation was left to the discretion of the consultant anesthesiologist managing the case. Lesser number of patients received rocuronium as top-ups or infusion for the maintenance of muscle relaxation (60%) compared with atracurium (90%) and vecuronium (74%) (P < 0.002). In an earlier study, Maybauer et al. 16 reported a similar incidence of, which was lower in patients receiving rocuronium (44%) compared with those receiving cisatracurium (57%) (P < 0.05). They attributed this to clinicians compensating for longer duration of action of rocuronium by stopping the infusion earlier. Effect of Residual Paralysis on PFTs Our study deals with physiological changes (PFT changes) occurring due to unintended complications () after a planned intervention (use of NMB agent). We quantified the changes in FVC and PEF as it would reflect the restrictive type of pulmonary functional defect caused by. 8 We found a statistically significant reduction in the postoperative PFT parameters in comparison with the baseline in the immediate postoperative period, more so in the presence of. These findings when translated to clinical situations could cause potentially serious respiratory complications. Anesthesiology 2012; 117: Kumar et al.

8 PERIOPERATIVE MEDICINE Table 4. Comparison of Study Variables between Absent and Present (TOF less than 0.9 at PFT) Absent (n = 111) Present (n = 39) P Value Age, yr 37 ± ± Sex (male female ratio) 54:57 (49%:51%) 16:23 (41%:59%) Height, cm 163 ± ± Weight, kg 65 ± ± BMI, kg/m ± ± Baseline TOF ratio 0.88 ± ± 0.17 <0.001 TOF ratio at PFT 0.95 ± ± 0.14 <0.001 Type of surgery Lower abdominal 24 (21%) 7 (18%) Laparoscopic 34 (31%) 9 (23%) Others 53 (48%) 23 (59%) Muscle relaxant used Vecuronium 34 (31%) 16 (40%) Atracurium 39 (35%) 11 (28%) Rocuronium 38 (34%) 12 (33%) NMBD maintenance Top-up or infusion 83 (75%) 28 (72%) Nil 28 (25%) 11 (28%) Time intervals, min Duration of NMB 116 ± ± Reversal to attaining TOF (6 to 13) 20 (15 to 28) <0.001 Reversal to postoperative PFT 15 (10 to 25) 10 (5 to 15) <0.001 TOF 0.9 to postoperative PFT 2 (0 to 10) 10 ( 10 to 5) <0.001 Data are presented as mean ± SD, median (interquartile range), or number of patients (%). Baseline TOF = mean TOF recorded on arrival to postanesthesia care unit; TOF at PFT= mean TOF recorded when PFT was performed. Lower abdominal surgeries (31 patients) included abdominal hysterectomy (21 patients), ovarian tumors (5 patients), laparotomy (4 patients), and myomectomy (2 patients). Laparoscopic surgeries (43 patients) included cholecystectomy (31 patients), appendicectomy (8 patients), and ovarian cyst excision (4 patients). Other surgeries (76 patients) included inner ear surgeries (23 patients), minor orthopedic procedures (38 patients), inguinal hernia repair (6 patients), liposuction (6 patients), and varicose vein surgery (3 patients). BMI = body mass index; NMB = neuromuscular blockade; NMBD = neuromuscular blocking drug; PFT = pulmonary function test; = residual neuromuscular blockade; TOF = train of four. A difference in the reduction of FVC or PEF of 15% or more was deemed to be considered significant in our study. Except for postoperative FVC reduction that occurred in -present patients of vecuronium group, other groups did not show such a difference in either FVC or PEF reductions. Also, the differences in FVC and PEF reductions in patients with across the three NMB agents (the primary outcome studied) were not statistically significant. This may be because the number of -present patients in each group (vecuronium, 16; atracurium, 11; and rocuronium, 12) may be too less to detect any such difference. In other words, our study may be underpowered to detect differences in pulmonary function reductions caused by occurring with different NMB agents. Also, the study was performed in a clinical-practice based setup where the maintenance of muscle relaxation was left to the discretion of the anesthesiologist managing the patient. Each group of patients would have received different effective doses of NMB agents for the maintenance of muscle relaxation although all of them received standardized bolus doses at induction of anesthesia. Further, we regrouped the patients and classified them as present and absent based on the presence or absence of at PFT irrespective of the NMB agent used. We assumed that produced by the three intermediate-acting muscle relaxants studied was similar with respect to pulmonary effects. In both the groups, PFT parameters were reduced to 40 60% of their respective preoperative values. Postoperative FVC and PEF values of -present patients were lower by 13% and 9% in absolute terms and 21% and 19% in relative terms, respectively, compared with -absent patients (table 5). Because the two groups differed only by the presence or absence of, the greater reductions in postoperative PFT parameters seen in patients with could be attributed to residual paralysis. Eikermann et al. 17 in their study on volunteers found statistically significant reduction in PFTs at a TOF ratio of 0.5 compared with baseline (TOF, 1.0). They found that at a TOF ratio of 0.5, FVC and PEF were 89% and 87% of baseline. In our study, postoperative FVC and PEF values in patients with were 79 and 81%, respectively, of that Anesthesiology 2012; 117: Kumar et al.

9 Residual Neuromuscular Block and Pulmonary Function Table 5. Comparison of PFT Parameters between Absent and Present (TOF less than 0.9 at PFT) Absent (n = 111) Present (n = 39) P Value PEF, l/min Preoperative 415 ± ± % of predicted 91 ± ± Postoperative 196 ± 101* 157 ± 79* % Preoperative 47 ± ± FVC, l Preoperative 2.67 ± ± % Predicted 72 ± ± Postoperative 1.66 ± 0.76* 1.32 ± 0.65* % Preoperative 62 ± ± Data are presented as mean ± SD. After applying Bonferroni s correction, P < (0.05/4) was considered as significant for comparison of PFT parameters among the groups. Predicted values for PFTs was derived from the nomogram provided by Microplus TM gold standard pocket spirometer, Micro medical (Care Fusion, Rochester, Kent, United Kingdom), using age, sex, and height of individual patients. *P < compared with respective preoperative values. FVC = forced vital capacity; PEF = peak expiratory flow; PFT = pulmonary function test; = residual neuromuscular blockade; TOF = train of four; Preoperative = PFT values measured preoperatively; % Predicted = preoperative value as % of predicted: (Preoperative / Predicted) 100; Postoperative = PFT values measured postoperatively; % Preoperative = postoperative value as % of preoperative value: (Postoperative / Preoperative) 100. of the recovered patients. This is comparable with the reductions in PFT values seen in the study by Eikermann et al. 17 if the PFT values of recovered patients in our study are equated to the baseline values of their study. In a study by Ali et al. 18 on nonanesthetized volunteers, vital capacity and PEF were % and % of the baseline values at a TOF ratio of In another study on volunteers, Eikermann et al. 8 observed that at a TOF ratio of 0.5, FVC decreased to 78 ± 14% of baseline whereas at a TOF ratio of 0.83, FVC recovered to acceptable levels (94 ± 6% of baseline). Eikermann et al. 8 stated that FVC is a sensitive indicator of respiratory muscle function. As respiratory muscle weakness results in ineffective cough and inability to clear secretions from airways, FVC recovery is considered important for Fig. 3. Postoperative reductions in PEF and FVC values as the percentage of preoperative values in patients with (present) and without (-absent). The postoperative PEF and FVC reductions were greater in -present patients than -absent patients. *P = 0.008, $ P = PEF = peak expiratory flow; FVC = forced vital capacity; = residual neuromuscular blockade. preventing pulmonary complications. These volunteer studies show statistically significant reductions in PFT values in the presence of. Our study demonstrates the same in the immediate postoperative period after general anesthesia in which intermediate-acting NMB agents were used in a clinical situation. PFT is a voluntary act and cannot be performed without the active participation and willingness of the patient. We had aimed to perform PFT within 30 min after the first assessment of TOF on arrival to PACU, and all patients except four in the -absent group were able to do so. There was a statistically significant difference in the interval between reversal to performance of PFT postoperatively between the -present group and the -absent group (P < 0.001) (table 4). A difference of 5 min may not be sufficient to explain the greater reductions in postoperative PFTs seen in patients who developed, as pulmonary function is known to be depressed for prolonged periods after general anesthesia Many authors have found postoperative PFT reductions from 4 h (forced expiratory volume in the first second by 65% and FVC by 60%) 19 to as late as 72 h (forced expiratory volume in the first second by 53 77% and FVC by 51 79%) 20,21 after general anesthesia. However, our study may be the first one to compare PFT changes within the first hour of postoperative period. Limitations Intraoperative neuromuscular monitoring is known to reduce the incidence of postoperative, 13 which was not performed in our study. Using acceleromyography, Baillard et al. 22 found discordance between two TOF ratios measured in isolation at 30-s interval in 24% of awake Anesthesiology 2012; 117: Kumar et al.

10 PERIOPERATIVE MEDICINE postoperative patients. In an attempt to overcome this, we repeated the TOF measurements and noted the higher of the two consecutive reproducible values. Despite our effort, the values may not be accurate. In addition, a previous study has shown that corresponding values of TOF ratio was higher when measured by acceleromyography compared with mechanomyography, which is the gold standard in neuromuscular monitoring. 23 Because acceleromyography was used in our study, we could be underestimating the incidence of. Other than FVC and PEF, maximal inspiratory pressure and maximal expiratory pressure are the other two parameters used to quantify postoperative muscle weakness. 11 In our study, maximal inspiratory pressure and maximal expiratory pressure were not monitored. Serial postoperative PFT measurements performed at various time intervals, such as 4 h, 1 day, and 3 days postoperatively, would have helped us to know the course of recovery of PFT values to the preoperative levels. In our study, the preoperative FVC values were low. They were 72 74% of the predicted values. This may be because the nomogram used for calculating predicted FVC values did not have correction for race. This still would not have affected our results because each patient acted as his or her own control as we compared postoperative values with their respective preoperative values. The reduction in postoperative pulmonary function in patients with was found during a secondary analysis of data. Finally, the assumption we made about the effect of caused by different NMB agents on pulmonary function being similar needs to be tested by an adequately powered study using standardized equipotent doses of muscle relaxants for maintenance of muscle relaxation. Summary and Conclusion In our routine clinical practice setup, we studied 150 patients using three different intermediate-acting NMB agents and found 57% had on arrival to PACU, which persisted in 26% of patients until the time of performing PFT. The comparison of reductions in PFT parameters caused by among different NMB agents did not show statistically significant difference. When we regrouped the patients, we found that in patients with, although clinically not apparent, there was a 21% reduction in FVC and a 19% reduction in PEF in the immediate postoperative period compared with patients who had completely recovered from neuromuscular blockade. In conclusion, results in statistically significant reductions in FVC and PEF in the immediate postoperative period. References 1. Hedenstierna G: Respiratory physiology, Miller s Anesthesia, 7th edition. Edited by Miller RD, Eriksson LI, Fliesher LA, Wiener-Kronish JP, Young WL. Philadelphia, Churchill Livingstone, 2010, pp Siafakas NM, Mitrouska I, Bouros D, Georgopoulos D: Surgery and the respiratory muscles. Thorax 1999; 54: Baurain MJ, Hoton F, D Hollander AA, Cantraine FR: Is recovery of neuromuscular transmission complete after the use of neostigmine to antagonize block produced by rocuronium, vecuronium, atracurium and pancuronium? Br J Anaesth 1996; 77: Shabana K, Divatia JV, Sareen R: Comparison of residual neuromuscular blockade between two intermediate acting nondepolarizing neuromuscular blocking agents- rocuronium and vecuronium. Indian J Anaesth 2006; 50: Kim KS, Lew SH, Cho HY, Cheong MA: Residual paralysis induced by either vecuronium or rocuronium after reversal with pyridostigmine. Anesth Analg 2002; 95: Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS, Nisman M: Intraoperative acceleromyographic monitoring reduces the risk of residual neuromuscular blockade and adverse respiratory events in the postanesthesia care unit. ANESTHESIOLOGY 2008; 109: Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS: Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg 2008; 107: Eikermann M, Groeben H, Hüsing J, Peters J: Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. ANESTHESIOLOGY 2003; 98: Eikermann M, Vogt FM, Herbstreit F, Vahid-Dastgerdi M, Zenge MO, Ochterbeck C, de Greiff A, Peters J: The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade. Am J Respir Crit Care Med 2007; 175: Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J: Interpretative strategies for lung function tests. Eur Respir J 2005; 26: Sharma GD: Pulmonary function testing in neuromuscular disorders. Pediatrics 2009; 123 Suppl 4:S Naguib M, Kopman AF, Ensor JE: Neuromuscular monitoring and postoperative residual curarisation: A meta-analysis. Br J Anaesth 2007; 98: Murphy GS, Szokol JW, Avram MJ, Greenberg SB, Marymont JH, Vender JS, Gray J, Landry E, Gupta DK: Intraoperative acceleromyography monitoring reduces symptoms of muscle weakness and improves quality of recovery in the early postoperative period. ANESTHESIOLOGY 2011; 115: Kopman AF, Zank LM, Ng J, Neuman GG: Antagonism of cisatracurium and rocuronium block at a tactile train-of-four count of 2: Should quantitative assessment of neuromuscular function be mandatory? Anesth Analg 2004; 98: Baillard C, Gehan G, Reboul-Marty J, Larmignat P, Samama CM, Cupa M: Residual curarization in the recovery room after vecuronium. Br J Anaesth 2000; 84: Maybauer DM, Geldner G, Blobner M, Pühringer F, Hofmockel R, Rex C, Wulf HF, Eberhart L, Arndt C, Eikermann M: Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium. Anaesthesia 2007; 62: Eikermann M, Groeben H, Bünten B, Peters J: Fade of pulmonary function during residual neuromuscular blockade. Chest 2005; 127: Ali HH, Wilson RS, Savarese JJ, Kitz RJ: The effect of tubocurarine on indirectly elicited train-of-four muscle response and respiratory measurements in humans. Br J Anaesth 1975; 47: Mahul P, Burgard G, Costes F, Guillot B, Massardier N, el Khouri Z, Cuilleret J, Geyssant A, Auboyer C: [Postoperative Anesthesiology 2012; 117: Kumar et al.

11 Residual Neuromuscular Block and Pulmonary Function respiratory function and cholecystectomy by laparoscopic approach]. Ann Fr Anesth Reanim 1993; 12: Mimica Z, Biocić M, Bacić A, Banović I, Tocilj J, Radonić V, Ilić N, Petricević A: Laparoscopic and laparotomic cholecystectomy: A randomized trial comparing postoperative respiratory function. Respiration 2000; 67: Karayiannakis AJ, Makri GG, Mantzioka A, Karousos D, Karatzas G: Postoperative pulmonary function after laparoscopic and open cholecystectomy. Br J Anaesth 1996; 77: Baillard C, Bourdiau S, Le Toumelin P, Ait Kaci F, Riou B, Cupa M, Samama CM: Assessing residual neuromuscular blockade using acceleromyography can be deceptive in postoperative awake patients. Anesth Analg 2004; 98: Claudius C, Skovgaard LT, Viby-Mogensen J: Is the performance of acceleromyography improved with preload and normalization? A comparison with mechanomyography. ANESTHESIOLOGY 2009; 110: ANESTHESIOLOGY REFLECTIONS FROM THE PIERRE VIARS MUSEUM Paul Bert: From Physiology to Barometric Pressure Paul Bert ( ) was a French physiologist and a politician (he founded with Jules Ferry the public, nondenominational, and obligatory school). In 1878, he published a book on his barometric pressure research. He demonstrated that bubbles, which kill animals during decompression accidents, contain nitrogen and carbon di oxide. He also studied the toxicity of high pressure oxygen on the central nervous system the so-called Paul Bert effect. This book (1,161 pages) was a classical reference book for divers, submariners, and aeronauts. The Paul Bert Prize was created by both the National Space Agency (NASA) and the American Society of Physiology to reward research in space physiology. Jean-Bernard Cazalaà, M.D., President of Club d Histoire de l Anesthésie et de la Réanimation (French Association for the History of Anesthesiology and Critical Care), France ( and Musée Viars, CHU Pitié-Salpêtrière, Paris, France. Anesthesiology 2012; 117: Kumar et al.