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Comparison of neostigmine and sugammadex for hemodynamic parameters in cardiac patients undergoing noncardiac surgery
Journal of Clinical Anesthesia (2015) 28, xxx–xxx
Original contribution
Comparison of neostigmine and sugammadex for hemodynamic parameters in cardiac patients undergoing noncardiac surgery☆ Deniz Kizilay MD ⁎, Didem Dal MD (Professor), Kemal T. Saracoglu MD (Assistant Professor), Zeynep Eti MD (Professor), Fevzi Y. Gogus MD (Professor) Department of Anesthesiology, Marmara University Medical School, Istanbul, Turkey Received 29 September 2014; accepted 6 August 2015
Keywords: Sugammadex; Neostigmine; Atropine; Cardiac patient; Gamma-cyclodextrin; Rocuronium
Abstract Study Objective: The aim of this study is to compare the hemodynamic effects of neostigmine-atropine combination and sugammadex in patients with cardiac problems undergoing noncardiac surgery. Design: Prospective randomized study. Setting: In the operating room. Patients: Ninety patients with a class 2 or 3 cardiovascular disease according to the New York Heart Association classification and aged between 18 and 75 years undergoing noncardiac surgery were randomized. Interventions: Group N (n = 45) received 0.03 mg/kg IV neostigmine when T2 appeared as measured with a nerve muscle stimulator. When heart rate was 5 beats/min (± 10 beats/min) lower than the heart rate before administration of the medication, 0.5 mg IV atropine sulfate was given. Group S (n = 45) received 3 mg/kg IV sugammadex when T2 appeared as measured with a nerve muscle stimulator. Measurements: Heart rate, mean systolic and diastolic blood pressures, and electrocardiographic alterations including the QTc (QT Fredericia and QT Bazett) were recorded. Main Results: There were no significant differences between and within the groups in terms of QTc values. Sugammadex group had a significant decrease on heart rate 1 minute after the medication when compared to the measurement before the medication (P b .05). Heart rate and systolic blood pressure increased in neostigmine group 3 minutes after the medication and during postoperative measurements (P b .05). Sugammadex group had lower systolic, diastolic, and mean blood pressures and heart rate when compared to neostigmine group (P b .05). Conclusions: We suggest that sugammadex might be preferred as it provides more hemodynamic stability compared to neostigmine-atropine combination to reverse rocuronium-induced neuromuscular blockage in cardiac patients undergoing noncardiac surgery. © 2015 Elsevier Inc. All rights reserved.
☆
The authors state no conflict of interest. ⁎ Corresponding author at: Department of Anesthesiology, Marmara University Medical Faculty, Fevzi Cakmak Mah. Mimar Sinan Cad. No:41 Ust Kaynarca Pendik. Istanbul, Turkey. E-mail address: [email protected] (D. Kizilay). ☆ The authors state no conflict of interest. http://dx.doi.org/10.1016/j.jclinane.2015.08.002 0952-8180/© 2015 Elsevier Inc. All rights reserved.
2
1. Introduction Although neuromuscular block may recover spontaneously, using pharmacological agents are still necessary to prevent possible residual paralysis and related side effects [1]. Cholinesterase inhibitors can be used to recover nondepolarizing neuromuscular block. However, administration of neostigmine might be problematic due to its side effects including anaphylaxis, convulsions, nausea, vomiting, fecal incontinence, atropine-resistant bradycardia in high doses, A-V block, cardiac arrhythmia including nodal rhythm, nonspecific electrocardiographic (ECG) alterations, hypotension, and fetal bradycardia crossing the placenta. Because of these reasons, anticholinergic agents such as atropine are commonly used [2]. However, patients with coronary artery disease may not tolerate decreased oxygen delivery and increased oxygen demand in myocardium due to tachycardia. Sugammadex is a modified, water-soluble γ-cyclodextrin including a lipophilic core [3]. It is selective to steroidal neuromuscular blocking agents. Its effects on blood pressure, heart rate, respiration, and thermoregulation were not found clinically significant in previous studies [4-6]. Moreover, alone or in combination with rocuronium or vecuronium, sugammadex does not cause QT prolongation [7]. Studies comparing the hemodynamic effects of sugammadex and conventional cholinesterase inhibitor/anticholinergic combination in cardiac patients are limited. In the current study, we aimed to compare the hemodynamic effects of sugammadex and neostigmineatropine combination in cardiac patients undergoing noncardiac surgery.
2. Methods Our research protocol was approved by Ethics Committee of Marmara University Medical School (03/03/2011, protocol: 09.2011.0034), and informed consents were obtained from patients. We included 90 patients with grade 2 or 3 cardiovascular disease according to New York Heart Association's classification undergoing noncardiac surgery. All patients were between 18 and 75 years old. Patients free of any clinical infection, chronic alcohol use or substance abuse history, and contraindications to atropine, neostigmine, or sugammadex were enrolled to the study. Patients who did not give written consent or those who had respiratory or cardiac arrest, cerebral bleeding, ischemia, infarct, or a hypersensitivity reaction to any of the study medications were excluded. In this prospective, randomized study patients were randomly assigned to the groups in a 1:1 ratio. As a premedication, all patients received intramuscular 3 mg midazolam and 0.5 mg atropine 45 minutes before the operation. In the operation room, 5 mg/kg IV thiopental
D. Kizilay et al. sodium was used for anesthesia induction, and 0.8 mg/kg IV rocuronium bromide was used for muscle relaxation. Before intubation patients were monitored with a muscle nerve stimulator. Patients were intubated with proper endotracheal tube, and anesthesia was maintained with 1 Minimum Alveolar concentration sevoflurane, 70% N2O, and 30% O2. All patients were monitored with ECG; systolic, diastolic, and mean arterial pressure monitor; and pulse oximeter. Measurements were recorded every 5 minutes. Patients in the first group (group S) received IV 3 mg/kg sugammadex at the end of surgery when T2 level in train of four reappeared. Patients in the second group (group N) received IV 0.03 mg/kg neostigmine at the end of surgery when T2 level reappeared, which was monitored with a nerve muscle stimulator. In both groups, before and 1, 3, and 5 minutes after neostigmine administration, we recorded heart rate, systolic and diastolic blood pressures, and mean arterial pressure. Cardiac electrophysiological changes were recorded with a 12-lead ECG starting before the operation until 5 minutes after the medication. In addition, when heart rate was 5 beats/min (± 10 beats/min) lower than the heart rate before administration of the medication, 0.5 mg IV atropine sulfate was given. Patients were transferred to the postanesthesia care unit, and a 12-lead ECG was performed 10 minutes after the transfer. An experienced cardiologist evaluated the recorded ECGs. In addition, heart rate and blood pressure were recorded at postoperative 1 and 10 minutes. We examined patients to detect any deterioration during postoperative period.
2.1. Statistical analysis We used SPSS for Windows 10.0. Demographic variables were compared with an independent-samples Student t test. Comparisons of American Society of Anesthesiologists (ASA) and New York Heart Association classifications and comorbid disease were done with a χ2 test. Within-group comparisons were done with analysis of variance, and between-groups comparisons were done with unpaired t test. Pearson correlation test was used for correlations. We used a P value threshold of .05 for statistical significance.
3. Results There was not any significant difference between groups in terms of age, sex, and weight (P N .05) (Table 1). Duration of surgery and anesthesia were significantly longer, and total dose of rocuronium was significantly higher in group S when compared to group N (P b .05) (Table 1). There was no significant difference between groups for neither ASA nor New York Heart Association classification (P N .05). There was no significant difference in terms of comorbid disorders except for coronary artery disease.
Neostigmine vs sugammadex in cardiac patients Table 1
3
Demographic features of groups (mean ± SD)
Age (y) Weight (kg) Duration of surgery (min) Duration of anesthesia (min) Total dose of rocuronium (mg) Sex M/W
Group N, n = 45
Group S, n = 45
P
58.62 ± 12.12 77.95 ± 13.93 69.55 ± 37.12 89.55 ± 39.06 47.44 ± 17.27 22/23 (24.4%/25.6%)
63.37 ± 11.57 78.80 ± 15.06 103.11 ± 52.33 126.77 ± 61.20 59.77 ± 22.23 19/26 (21.1%/28.9%)
.060 .783 .001 ⁎ .001 ⁎ .004 ⁎ .672
⁎ P b .05 refers to the statistical difference.
There was no difference in terms of heart rate 1 minute before and after the medication in Group N (P N .05). There were significant increases in heart rate at the other time points when compared to the measurement before the medication and 1 minute after the medication, and similarly, heart rate was significantly higher in other time points when compared to the measurement 1 minute after the medication (P b .05). However, there was a significant decrease in heart rate between the measurements at postoperative minute 1 and 10 (P b .05). In group S, there was a significant decrease in heart rate between the measurements before and 1 minute after the medication (P b .05). We detected significant increases between the measurements before the medication and 1 minute after the medication and 3 minutes after the medication (Fig. 1). Moreover, we found a significant increase in heart rate between the measurements at 5 minutes after the medication and at postoperative measurements (P b .05). Heart rate was significantly lower in group S than in group N before the medication and 1, 3, and 5 minutes after the medication (P b .05) (Fig. 1). Systolic blood pressure did not differ in group N between the measurements before and 1 minute after the medication (P N .05). However, it was significantly higher at other time points when compared to the measurement at 1 minute after the medication (P b .05). There was a significant decrease between the measurements 1 minute after the medication and 10 minutes after the (P b .05) (Fig. 2). There was not any
significant difference in systolic blood pressure measurements in group S before the medication and 1 minute and 3 minutes after the medication (P N .05). However, systolic blood pressure was significantly higher between time points (P b .05). Systolic blood pressure was significantly lower in group S than in group N at 1, 3, and 5 minutes after the medication and 1 and 10 minutes after surgery (P b .05) (Fig. 2). There was a significant increase on diastolic blood pressure before medication and 1 and 3 minutes after the medication in group N (P b .05). There was a significant increase in diastolic blood pressure between the measurements before the medication and 1, 3, and 5 minutes after the medication and at postoperative measurements (P b .05). Group S had significantly lower diastolic blood pressure measures than group N before the medication, 3 and 5 minutes after the medication, and 1 minute after the operation (P b .05, Fig. 3). There was a significant increase in mean arterial blood pressure in group N 5 minutes after medication and 1 and 10 minutes after surgery (P b .05). There was no significant difference between other time points (P N .05). There was a significant increase in mean arterial blood pressure in group S 5 minutes after the medication and 1 and 10 minutes after the operation (P b .05). There was no significant difference between other time points (P N .05). Mean arterial blood pressure was significantly lower in group S than in group N at all time points (P b .05; Fig. 4).
BM: before the medication; AM 1 min: after the medication 1 min; AM 3 min: after the medication 3 min; AM 5 min: after the medication 5 min; P 1 min: postoperative 1 min; P 10 min: postoperative 10 min
Fig. 1
Comparison of heart rate between groups, #P b .05.
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D. Kizilay et al.
BM: before the medication; AM 1 min: after the medication 1 min; AM 3 min: after the medication 3 min; AM 5 min: after the medication 5 min; P 1 min: postoperative 1 min; P 10 min: postoperative 10 min
Fig. 2
Comparison of systolic blood pressure measures between groups, #P b .05.
There was no significant difference between any time points that QTcF or QTcB was measured in groups (P N .05; Tables 2 and 3). There was a mild positive correlation between heart rate before medication and QTcF in group N (P = .017; r = 0.353). Again in group N, systolic blood pressure at postoperative 10 minutes was negatively correlated with QTcB (P = .01; r = − 0.378). In both groups, we did not find any correlations between heart rate, blood pressure measures, QTcB, and QTcF in any other time points. We did not detect any erythematous skin problems or disguise in patients.
4. Discussion In this study, the hemodynamic effects of sugammadex and neostigmine were compared in cardiac patients undergoing noncardiac surgery. As the increase on hemodynamic parameters was more prominent in patients administering neostigmine, we found that sugammadex yields a stable cardiac function. Qt interval is an ECG measure of ventricular depolarization and subsequent repolarization. Prolongation of Qt is
responsible for perioperative sudden cardiac arrest [8-10]. Qt prolongation can be seen in organic heart diseases; congestive heart failure; left ventricular dysfunction; coronary artery disease; sinus bradycardia; bundle-branch block; metabolic disturbances such as hypokalemia, hypomagnesemia, and hypocalcemia; women and people older than 65 years. These factors, thus, may increase the risk of “torsades de pointes” [11,12]. Neostigmine is commonly used to reverse neuromuscular block. However, in higher doses, neostigmine may cause atropine-resistant bradycardia, cardiac arrhythmia including nonspecific ECG alterations, nodal rhythm, A-V block, and hypotension. Anticholinergic agents such as atropine are used together with neostigmine to minimalize bradycardia, hypersalivation, and bronchospasm that are related to neostigmine [13]. Although it is not common, atropine may cause nodal rhythm and atrial arrhythmias. Moreover, it might be troublesome for cardiac patients as it may cause tachycardia which results in decreased oxygen delivery to the heart. Ventricular fibrillation was reported with the concomitant use of anticholinesterase and anticholinergic agents in a patient with mitral prolapses [14]. In a patient with alcoholic cirrhosis, ST-elevation related to coronary vasospasm was
BM: before the medication; AM 1 min: after the medication 1 min; AM 3 min: after the medication 3 min; AM 5 min: after the medication 5 min; P 1 min: postoperative 1 min; P 10 min: postoperative 10 min
Fig. 3
Comparison of diastolic blood pressure measures between groups, #P b .05.
Neostigmine vs sugammadex in cardiac patients
5
BM: before the medication; AM 1 min: after the medication 1 min; AM 3 min: after the medication 3 min; AM 5 min: after the medication 5 min, P 1 min: postoperative 1 min; P 10 min: postoperative 10 min
Fig. 4
Comparison of mean arterial pressure measures between groups, #P b .05.
reported with use of neostigmine-atropine combination [15]. In this case, it was thought that vasospasm occurred due to the coronary artery spasm as a response to acetylcholine. In the study of Saarnivaara and Simola [16], 84 ASA I to II patients were included. First group received 0.04 mg/kg neostigmine and 0.008 mg/kg glycopyrrolate; second group received 0.04 mg/kg neostigmine and 0.02 mg/kg atropine; third group received 0.2 mg edrophonium and 0.3 mg atropine; fourth group received 0.5 mg edrophonium and 0.07 mg/kg atropine. In all groups, heart rate increased 1 minute before the medication and after the extubation, and blood pressure increased after extubation. QTc interval was prolonged 1 and 2 minutes after medication and extubation. Cardiac arrhythmia was reported in 3 patients. In our study, we administered 0.03 mg/kg neostigmine– 0.5 mg atropine toward the end of anesthesia to patients in group N. Similar to Saarnivaara and Simola [16], we found an increase in hemodynamic parameters. However, QTcB and QTcF were not prolonged. Prolongation of the QTc in the study of Saarnivaara and Simola [16] might be due to the heart rate that was equal or higher than 90. In our study, on the other hand, heart rate was always less than 90 between 1 and 5 minutes after medication. In the study of Lock et al [17], 58 ASA I to III patients were included. Group I received 0.04 mg/kg neostigmine and 0.02 mg/kg atropine when train of four was between 0.2 and 0.7, and group II received 0.02 mg/kg neostigmine and 0.01 mg/kg atropine when TOF was between 0.7 and 0.9. In both groups, an increase in the heart rate was detected. However,
Table 2
Qt or QTc interval did not differ. Authors concluded that concomitant use of neostigmine and atropine can be used safely, although they are known to be proarrhythmic. Khuenl-Brady et al [18] found that patients using neostigmine had higher heart rate and blood pressure than patients using sugammadex in a study of ASA I to III patients older than 18 years. Sacan et al [19] evaluated the effect of neostigmine-glycopyrrolate, edrophonium-atropine, and sugammadex on the neuromuscular blockage that was created with rocuronium. They detected higher heart rate in patients receiving neostigmine than in other groups of patients. Lemmens et al [20] performed a study in ASA I to IV patients older than 18 years comparing the effect of sugammadex and neostigmine to reverse the vecuroniuminduced deep neuromuscular block under sevoflurane anesthesia. They found that 2 and 10 minutes after the medication, heart rate was higher in neostigmine group than in sugammadex group. In our study, similar to the last study, heart rate, systolic and diastolic blood pressures, and mean arterial pressure were higher after the medication in neostigmine-atropine group. However, these increases did not cause any clinical problems. It was reported that sugammadex might reverse neostigmine-resistant curarization [21]. In healthy subjects, sugammadex did not have any effects on blood pressure, heart rate, respiration, and thermoregulation [3,6]. Gijsenbergh et al [13] explored the pharmacokinetics, safety, and efficacy of sugammadex in 29 healthy men and detected the QTc prolongation in 8 participants. However, 3 of them had that after sugammadex, whereas 5 of them had it after placebo.
QTcF measures (ms, mean ± SD) Group N, n = 45
Group S, n = 45
P
Before the medication (ms) 389.53 ± 39.10 399.33 ± 41.74 .254 After the medication (ms) 389.86 ± 39.35 399.44 ± 41.58 .256 Postoperative 10 389.66 ± 39.39 399.48 ± 41.47 .253 minutes (ms)
Table 3
QTcB measures (ms, mean ± SD) Group N, n = 45
Group S, n = 45
P
Before the medication (ms) 412.28 ± 35.96 413.75 ± 34.42 .844 After the medication (ms) 412.17 ± 36.36 414.11 ± 34.48 .796 Postoperative 10 min (ms) 412.26 ± 36.37 414.04 ± 34.17 .812
6 In our study, we applied 3 mg/kg sugammadex toward the end of the anesthesia. There was no significant difference in terms of the QTc interval. In another study that tested the effect of sugammadex in a pediatric population, there was no QTc prolongation [22]. Molina et al [23] reported a case with a very high dose of sugammadex accidentally (40 mg/kg) to reverse the deep neuromuscular block by rocuronium. In this patient, there were no clinical alterations on blood pressure, heart rate, or ECG parameters. It was pointed out in a review that sugammadex does not alter blood pressure and heart rate in animals under general anesthesia [24]. Although Qt prolongation is not detected, it is important to consider possible ECG alterations when proarrhythmic agents such as neostigmine and atropine are used. In our study, we monitored cardiac electrophysiological alterations using a Holter ECG beginning from surgery until couple hours after the operation. Thus, we could not detect Qt interval prolongation that starts in late postoperative period. We believe that the reasons of the increases on heart rate, systolic and diastolic blood pressures, and mean arterial pressure are multiple. Pain might be one of the most important reasons affecting these parameters. However, we did not evaluate pain in our study. This is one of the limitations of this study. In accordance with previous studies, we did not detect any differences in terms of QTc interval. We found an increase on systolic, diastolic, and mean blood pressures after the medication in group S. However, this increase was somewhat lower in group N statistically. We believe that the decrease on heart rate (mean, 2 beats/min) 1 and 3 minutes after the medication in group S was not clinically significant. We did not detect any clinical complication or adverse effect.
5. Conclusions
D. Kizilay et al.
[4]
[5]
[6]
[7]
[8]
[9] [10] [11] [12] [13]
[14]
[15]
[16]
[17] [18]
In the current study, we aimed to compare the hemodynamic effects of neostigmine and sugammadex in cardiac patients who underwent noncardiac surgery. We did not find any difference on Qt interval between 2 groups. Although there were significant increases on hemodynamic parameters in both groups, this increase was more prominent in patients receiving neostigmine. Therefore, we suggest that sugammadex might be a safety option to reverse neuromuscular blockage in cardiac patients undergoing noncardiac surgery.
[19]
[20]
[21]
References [1] Jones RK, Cadwell JE, Brull SJ, Soto RG. Reversal of profound rocuronium-induced blockade with sugammadex: a randomized comparison with neostigmine. Anesthesiology 2008;109:816-24. [2] Welliver M, Mc Donough J, Kalynych N, Redfern R. Discovery, development and clinical application of sugammadex sodium, a selective relaxant binding agent. Drug Des Devel Ther 2008;2:49-59. [3] Bom A, Bradley M, Cameron K, et al. A novel concept of reversing neuromuscular block: chemical encapsulation of rocuronium bromide
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by a cylodextrin-based synthetic host. Angew Chem Int Ed Engl 2002; 41:266-70. Dahl V, Pendeville PE, Hollmann MW, Heier T, Abels EA, Blobner M. Safety and efficacy of sugammadex for the reversal of rocuroniuminduced neuromuscular blockade in cardiac patients undergoing non cardiac surgery. Eur J Anaesthesiol 2009;26:874-84. Epemolu O, Bom A, Hope F, Mason R. Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of novel reversal agent Org 25969. Anesthesiology 2003;99:634-7. Brull SJ, Naguib M. Elective reversal of muscle relaxation in general anaesthesia: focus on sugammadex. Drug Des Devel Ther 2009;3: 119-29. De Kam PJ, Van Kuijik J, Prohn M, Thomsen T, Peeters P. Effects of sugammadex doses up to 32 mg/kg alone or in combination with rocuronium or vecuronium on QTc prolongation: a thorough QTc study. Clin Drug Investig 2010;30:599-601. Owczuk R, Wujtewicz MA, Zienciuk-Krajka A, Lasińska-Kowara M, Piankowski A, Wujtewicz M. The influence of anesthesia on cardiac repolarization. Minerva Anestesiol 2012;78:483-95. Bocker PD, Whyte SD, Ladusans EJ. Long Qt syndrome and anesthesia. Br J Anaesth 2003;90:349-66. Curry TB, Gaver R, White RD. Acquired long Qt syndrome and elective anesthesia in children. Paediatr Anaesth 2006;16:471-8. Camm J. Clinical trial design to evaluate the effects of drugs on cardiac repolarization: current state of the art. Heart Rhythm 2005;2:23-9. Zareba W. Drug induced Qt prolongation. Cardiol J 2007;14:523-33. Gijsenbergh F, Ramael S, Houwig N, Van Iersel T. First human exposure of org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology 2005;103:695-703. Zeidan A, Baraka A. Ventricular fibrillation related to reversal of neuromuscular blockade in a patient with long Qt syndrome. Anaesthesia 2005;60:724-5. Kido K, Mizuta K, Mizuta F, Yasuda M, Igari T, Takahashi M. Coronary vasospasm during the reversal of neuromuscular block using neostigmine. Acta Anaesthesiol Scand 2005;49:1395. Saarnivaara L, Simola M. Effects of four anticholinesterase-anticholinergic combinations and tracheal extubation on QTc interval of the ECG, heart rate and arterial pressure. Acta Anaesthesiol Scand 1998;42: 460-3. Lock G, Fialho G, Lima DC, Almeida MC. Electrocardiographic changes after neostigmine-atropine mixture. J Anesth Clin Res 2012;3:1-4. Khuenl-Brady K, Watmill M, Vanacker B, Lora-Tamayo J, Rietbergen H, Alvarez-Gomez J. Sugammadex provides faster reversal of vecuronium-induced neuromuscular blockade compared with neostigmine: a multicenter, randomized, controlled trial. Anesth Analg 2010;110:64-73. Sacan O, White P, Tufanogulları B, Klein K. Sugammadex reversal of rocuronium-induced neuromuscular blockade: a comparison with neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg 2006;104:569-74. Lemmens HJ, El-Orbany MI, Berry J, Morte JB Jr, Martin G. Reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine. BMC Anesthesiol 2010;10:15. Zhang MQ. Drug specific cyclodextrins: the future of rapid neuromuscular block reversal. Drugs Future 2003;28:347-54. Plaud B, Meretoja O, Hofmockel R, et al. Reversal of rocuroniuminduced neuromuscular blockade with sugammadex in pediatric and adult surgical patients. Anesthesiology 2009;110:284-94. Molina AL, De Boer HD, Klimek M, Heeringa M, Klein J. Reversal of rocuronium-induced (1.2 mg/kg) profound neuromuscular block by accidental high dose of sugammadex (40 mg/kg). Br J Anaesth 2007; 98:624-7. Hemmerling TM, Zaouter C, Geldner G, Nauheimer D. Sugammadexa short review and clinical recommendations for the cardiac anesthesiologist. Ann Card Anaesth 2010;13:206-16.
Original contribution
Comparison of neostigmine and sugammadex for hemodynamic parameters in cardiac patients undergoing noncardiac surgery☆ Deniz Kizilay MD ⁎, Didem Dal MD (Professor), Kemal T. Saracoglu MD (Assistant Professor), Zeynep Eti MD (Professor), Fevzi Y. Gogus MD (Professor) Department of Anesthesiology, Marmara University Medical School, Istanbul, Turkey Received 29 September 2014; accepted 6 August 2015
Keywords: Sugammadex; Neostigmine; Atropine; Cardiac patient; Gamma-cyclodextrin; Rocuronium
Abstract Study Objective: The aim of this study is to compare the hemodynamic effects of neostigmine-atropine combination and sugammadex in patients with cardiac problems undergoing noncardiac surgery. Design: Prospective randomized study. Setting: In the operating room. Patients: Ninety patients with a class 2 or 3 cardiovascular disease according to the New York Heart Association classification and aged between 18 and 75 years undergoing noncardiac surgery were randomized. Interventions: Group N (n = 45) received 0.03 mg/kg IV neostigmine when T2 appeared as measured with a nerve muscle stimulator. When heart rate was 5 beats/min (± 10 beats/min) lower than the heart rate before administration of the medication, 0.5 mg IV atropine sulfate was given. Group S (n = 45) received 3 mg/kg IV sugammadex when T2 appeared as measured with a nerve muscle stimulator. Measurements: Heart rate, mean systolic and diastolic blood pressures, and electrocardiographic alterations including the QTc (QT Fredericia and QT Bazett) were recorded. Main Results: There were no significant differences between and within the groups in terms of QTc values. Sugammadex group had a significant decrease on heart rate 1 minute after the medication when compared to the measurement before the medication (P b .05). Heart rate and systolic blood pressure increased in neostigmine group 3 minutes after the medication and during postoperative measurements (P b .05). Sugammadex group had lower systolic, diastolic, and mean blood pressures and heart rate when compared to neostigmine group (P b .05). Conclusions: We suggest that sugammadex might be preferred as it provides more hemodynamic stability compared to neostigmine-atropine combination to reverse rocuronium-induced neuromuscular blockage in cardiac patients undergoing noncardiac surgery. © 2015 Elsevier Inc. All rights reserved.
☆
The authors state no conflict of interest. ⁎ Corresponding author at: Department of Anesthesiology, Marmara University Medical Faculty, Fevzi Cakmak Mah. Mimar Sinan Cad. No:41 Ust Kaynarca Pendik. Istanbul, Turkey. E-mail address: [email protected] (D. Kizilay). ☆ The authors state no conflict of interest. http://dx.doi.org/10.1016/j.jclinane.2015.08.002 0952-8180/© 2015 Elsevier Inc. All rights reserved.
2
1. Introduction Although neuromuscular block may recover spontaneously, using pharmacological agents are still necessary to prevent possible residual paralysis and related side effects [1]. Cholinesterase inhibitors can be used to recover nondepolarizing neuromuscular block. However, administration of neostigmine might be problematic due to its side effects including anaphylaxis, convulsions, nausea, vomiting, fecal incontinence, atropine-resistant bradycardia in high doses, A-V block, cardiac arrhythmia including nodal rhythm, nonspecific electrocardiographic (ECG) alterations, hypotension, and fetal bradycardia crossing the placenta. Because of these reasons, anticholinergic agents such as atropine are commonly used [2]. However, patients with coronary artery disease may not tolerate decreased oxygen delivery and increased oxygen demand in myocardium due to tachycardia. Sugammadex is a modified, water-soluble γ-cyclodextrin including a lipophilic core [3]. It is selective to steroidal neuromuscular blocking agents. Its effects on blood pressure, heart rate, respiration, and thermoregulation were not found clinically significant in previous studies [4-6]. Moreover, alone or in combination with rocuronium or vecuronium, sugammadex does not cause QT prolongation [7]. Studies comparing the hemodynamic effects of sugammadex and conventional cholinesterase inhibitor/anticholinergic combination in cardiac patients are limited. In the current study, we aimed to compare the hemodynamic effects of sugammadex and neostigmineatropine combination in cardiac patients undergoing noncardiac surgery.
2. Methods Our research protocol was approved by Ethics Committee of Marmara University Medical School (03/03/2011, protocol: 09.2011.0034), and informed consents were obtained from patients. We included 90 patients with grade 2 or 3 cardiovascular disease according to New York Heart Association's classification undergoing noncardiac surgery. All patients were between 18 and 75 years old. Patients free of any clinical infection, chronic alcohol use or substance abuse history, and contraindications to atropine, neostigmine, or sugammadex were enrolled to the study. Patients who did not give written consent or those who had respiratory or cardiac arrest, cerebral bleeding, ischemia, infarct, or a hypersensitivity reaction to any of the study medications were excluded. In this prospective, randomized study patients were randomly assigned to the groups in a 1:1 ratio. As a premedication, all patients received intramuscular 3 mg midazolam and 0.5 mg atropine 45 minutes before the operation. In the operation room, 5 mg/kg IV thiopental
D. Kizilay et al. sodium was used for anesthesia induction, and 0.8 mg/kg IV rocuronium bromide was used for muscle relaxation. Before intubation patients were monitored with a muscle nerve stimulator. Patients were intubated with proper endotracheal tube, and anesthesia was maintained with 1 Minimum Alveolar concentration sevoflurane, 70% N2O, and 30% O2. All patients were monitored with ECG; systolic, diastolic, and mean arterial pressure monitor; and pulse oximeter. Measurements were recorded every 5 minutes. Patients in the first group (group S) received IV 3 mg/kg sugammadex at the end of surgery when T2 level in train of four reappeared. Patients in the second group (group N) received IV 0.03 mg/kg neostigmine at the end of surgery when T2 level reappeared, which was monitored with a nerve muscle stimulator. In both groups, before and 1, 3, and 5 minutes after neostigmine administration, we recorded heart rate, systolic and diastolic blood pressures, and mean arterial pressure. Cardiac electrophysiological changes were recorded with a 12-lead ECG starting before the operation until 5 minutes after the medication. In addition, when heart rate was 5 beats/min (± 10 beats/min) lower than the heart rate before administration of the medication, 0.5 mg IV atropine sulfate was given. Patients were transferred to the postanesthesia care unit, and a 12-lead ECG was performed 10 minutes after the transfer. An experienced cardiologist evaluated the recorded ECGs. In addition, heart rate and blood pressure were recorded at postoperative 1 and 10 minutes. We examined patients to detect any deterioration during postoperative period.
2.1. Statistical analysis We used SPSS for Windows 10.0. Demographic variables were compared with an independent-samples Student t test. Comparisons of American Society of Anesthesiologists (ASA) and New York Heart Association classifications and comorbid disease were done with a χ2 test. Within-group comparisons were done with analysis of variance, and between-groups comparisons were done with unpaired t test. Pearson correlation test was used for correlations. We used a P value threshold of .05 for statistical significance.
3. Results There was not any significant difference between groups in terms of age, sex, and weight (P N .05) (Table 1). Duration of surgery and anesthesia were significantly longer, and total dose of rocuronium was significantly higher in group S when compared to group N (P b .05) (Table 1). There was no significant difference between groups for neither ASA nor New York Heart Association classification (P N .05). There was no significant difference in terms of comorbid disorders except for coronary artery disease.
Neostigmine vs sugammadex in cardiac patients Table 1
3
Demographic features of groups (mean ± SD)
Age (y) Weight (kg) Duration of surgery (min) Duration of anesthesia (min) Total dose of rocuronium (mg) Sex M/W
Group N, n = 45
Group S, n = 45
P
58.62 ± 12.12 77.95 ± 13.93 69.55 ± 37.12 89.55 ± 39.06 47.44 ± 17.27 22/23 (24.4%/25.6%)
63.37 ± 11.57 78.80 ± 15.06 103.11 ± 52.33 126.77 ± 61.20 59.77 ± 22.23 19/26 (21.1%/28.9%)
.060 .783 .001 ⁎ .001 ⁎ .004 ⁎ .672
⁎ P b .05 refers to the statistical difference.
There was no difference in terms of heart rate 1 minute before and after the medication in Group N (P N .05). There were significant increases in heart rate at the other time points when compared to the measurement before the medication and 1 minute after the medication, and similarly, heart rate was significantly higher in other time points when compared to the measurement 1 minute after the medication (P b .05). However, there was a significant decrease in heart rate between the measurements at postoperative minute 1 and 10 (P b .05). In group S, there was a significant decrease in heart rate between the measurements before and 1 minute after the medication (P b .05). We detected significant increases between the measurements before the medication and 1 minute after the medication and 3 minutes after the medication (Fig. 1). Moreover, we found a significant increase in heart rate between the measurements at 5 minutes after the medication and at postoperative measurements (P b .05). Heart rate was significantly lower in group S than in group N before the medication and 1, 3, and 5 minutes after the medication (P b .05) (Fig. 1). Systolic blood pressure did not differ in group N between the measurements before and 1 minute after the medication (P N .05). However, it was significantly higher at other time points when compared to the measurement at 1 minute after the medication (P b .05). There was a significant decrease between the measurements 1 minute after the medication and 10 minutes after the (P b .05) (Fig. 2). There was not any
significant difference in systolic blood pressure measurements in group S before the medication and 1 minute and 3 minutes after the medication (P N .05). However, systolic blood pressure was significantly higher between time points (P b .05). Systolic blood pressure was significantly lower in group S than in group N at 1, 3, and 5 minutes after the medication and 1 and 10 minutes after surgery (P b .05) (Fig. 2). There was a significant increase on diastolic blood pressure before medication and 1 and 3 minutes after the medication in group N (P b .05). There was a significant increase in diastolic blood pressure between the measurements before the medication and 1, 3, and 5 minutes after the medication and at postoperative measurements (P b .05). Group S had significantly lower diastolic blood pressure measures than group N before the medication, 3 and 5 minutes after the medication, and 1 minute after the operation (P b .05, Fig. 3). There was a significant increase in mean arterial blood pressure in group N 5 minutes after medication and 1 and 10 minutes after surgery (P b .05). There was no significant difference between other time points (P N .05). There was a significant increase in mean arterial blood pressure in group S 5 minutes after the medication and 1 and 10 minutes after the operation (P b .05). There was no significant difference between other time points (P N .05). Mean arterial blood pressure was significantly lower in group S than in group N at all time points (P b .05; Fig. 4).
BM: before the medication; AM 1 min: after the medication 1 min; AM 3 min: after the medication 3 min; AM 5 min: after the medication 5 min; P 1 min: postoperative 1 min; P 10 min: postoperative 10 min
Fig. 1
Comparison of heart rate between groups, #P b .05.
4
D. Kizilay et al.
BM: before the medication; AM 1 min: after the medication 1 min; AM 3 min: after the medication 3 min; AM 5 min: after the medication 5 min; P 1 min: postoperative 1 min; P 10 min: postoperative 10 min
Fig. 2
Comparison of systolic blood pressure measures between groups, #P b .05.
There was no significant difference between any time points that QTcF or QTcB was measured in groups (P N .05; Tables 2 and 3). There was a mild positive correlation between heart rate before medication and QTcF in group N (P = .017; r = 0.353). Again in group N, systolic blood pressure at postoperative 10 minutes was negatively correlated with QTcB (P = .01; r = − 0.378). In both groups, we did not find any correlations between heart rate, blood pressure measures, QTcB, and QTcF in any other time points. We did not detect any erythematous skin problems or disguise in patients.
4. Discussion In this study, the hemodynamic effects of sugammadex and neostigmine were compared in cardiac patients undergoing noncardiac surgery. As the increase on hemodynamic parameters was more prominent in patients administering neostigmine, we found that sugammadex yields a stable cardiac function. Qt interval is an ECG measure of ventricular depolarization and subsequent repolarization. Prolongation of Qt is
responsible for perioperative sudden cardiac arrest [8-10]. Qt prolongation can be seen in organic heart diseases; congestive heart failure; left ventricular dysfunction; coronary artery disease; sinus bradycardia; bundle-branch block; metabolic disturbances such as hypokalemia, hypomagnesemia, and hypocalcemia; women and people older than 65 years. These factors, thus, may increase the risk of “torsades de pointes” [11,12]. Neostigmine is commonly used to reverse neuromuscular block. However, in higher doses, neostigmine may cause atropine-resistant bradycardia, cardiac arrhythmia including nonspecific ECG alterations, nodal rhythm, A-V block, and hypotension. Anticholinergic agents such as atropine are used together with neostigmine to minimalize bradycardia, hypersalivation, and bronchospasm that are related to neostigmine [13]. Although it is not common, atropine may cause nodal rhythm and atrial arrhythmias. Moreover, it might be troublesome for cardiac patients as it may cause tachycardia which results in decreased oxygen delivery to the heart. Ventricular fibrillation was reported with the concomitant use of anticholinesterase and anticholinergic agents in a patient with mitral prolapses [14]. In a patient with alcoholic cirrhosis, ST-elevation related to coronary vasospasm was
BM: before the medication; AM 1 min: after the medication 1 min; AM 3 min: after the medication 3 min; AM 5 min: after the medication 5 min; P 1 min: postoperative 1 min; P 10 min: postoperative 10 min
Fig. 3
Comparison of diastolic blood pressure measures between groups, #P b .05.
Neostigmine vs sugammadex in cardiac patients
5
BM: before the medication; AM 1 min: after the medication 1 min; AM 3 min: after the medication 3 min; AM 5 min: after the medication 5 min, P 1 min: postoperative 1 min; P 10 min: postoperative 10 min
Fig. 4
Comparison of mean arterial pressure measures between groups, #P b .05.
reported with use of neostigmine-atropine combination [15]. In this case, it was thought that vasospasm occurred due to the coronary artery spasm as a response to acetylcholine. In the study of Saarnivaara and Simola [16], 84 ASA I to II patients were included. First group received 0.04 mg/kg neostigmine and 0.008 mg/kg glycopyrrolate; second group received 0.04 mg/kg neostigmine and 0.02 mg/kg atropine; third group received 0.2 mg edrophonium and 0.3 mg atropine; fourth group received 0.5 mg edrophonium and 0.07 mg/kg atropine. In all groups, heart rate increased 1 minute before the medication and after the extubation, and blood pressure increased after extubation. QTc interval was prolonged 1 and 2 minutes after medication and extubation. Cardiac arrhythmia was reported in 3 patients. In our study, we administered 0.03 mg/kg neostigmine– 0.5 mg atropine toward the end of anesthesia to patients in group N. Similar to Saarnivaara and Simola [16], we found an increase in hemodynamic parameters. However, QTcB and QTcF were not prolonged. Prolongation of the QTc in the study of Saarnivaara and Simola [16] might be due to the heart rate that was equal or higher than 90. In our study, on the other hand, heart rate was always less than 90 between 1 and 5 minutes after medication. In the study of Lock et al [17], 58 ASA I to III patients were included. Group I received 0.04 mg/kg neostigmine and 0.02 mg/kg atropine when train of four was between 0.2 and 0.7, and group II received 0.02 mg/kg neostigmine and 0.01 mg/kg atropine when TOF was between 0.7 and 0.9. In both groups, an increase in the heart rate was detected. However,
Table 2
Qt or QTc interval did not differ. Authors concluded that concomitant use of neostigmine and atropine can be used safely, although they are known to be proarrhythmic. Khuenl-Brady et al [18] found that patients using neostigmine had higher heart rate and blood pressure than patients using sugammadex in a study of ASA I to III patients older than 18 years. Sacan et al [19] evaluated the effect of neostigmine-glycopyrrolate, edrophonium-atropine, and sugammadex on the neuromuscular blockage that was created with rocuronium. They detected higher heart rate in patients receiving neostigmine than in other groups of patients. Lemmens et al [20] performed a study in ASA I to IV patients older than 18 years comparing the effect of sugammadex and neostigmine to reverse the vecuroniuminduced deep neuromuscular block under sevoflurane anesthesia. They found that 2 and 10 minutes after the medication, heart rate was higher in neostigmine group than in sugammadex group. In our study, similar to the last study, heart rate, systolic and diastolic blood pressures, and mean arterial pressure were higher after the medication in neostigmine-atropine group. However, these increases did not cause any clinical problems. It was reported that sugammadex might reverse neostigmine-resistant curarization [21]. In healthy subjects, sugammadex did not have any effects on blood pressure, heart rate, respiration, and thermoregulation [3,6]. Gijsenbergh et al [13] explored the pharmacokinetics, safety, and efficacy of sugammadex in 29 healthy men and detected the QTc prolongation in 8 participants. However, 3 of them had that after sugammadex, whereas 5 of them had it after placebo.
QTcF measures (ms, mean ± SD) Group N, n = 45
Group S, n = 45
P
Before the medication (ms) 389.53 ± 39.10 399.33 ± 41.74 .254 After the medication (ms) 389.86 ± 39.35 399.44 ± 41.58 .256 Postoperative 10 389.66 ± 39.39 399.48 ± 41.47 .253 minutes (ms)
Table 3
QTcB measures (ms, mean ± SD) Group N, n = 45
Group S, n = 45
P
Before the medication (ms) 412.28 ± 35.96 413.75 ± 34.42 .844 After the medication (ms) 412.17 ± 36.36 414.11 ± 34.48 .796 Postoperative 10 min (ms) 412.26 ± 36.37 414.04 ± 34.17 .812
6 In our study, we applied 3 mg/kg sugammadex toward the end of the anesthesia. There was no significant difference in terms of the QTc interval. In another study that tested the effect of sugammadex in a pediatric population, there was no QTc prolongation [22]. Molina et al [23] reported a case with a very high dose of sugammadex accidentally (40 mg/kg) to reverse the deep neuromuscular block by rocuronium. In this patient, there were no clinical alterations on blood pressure, heart rate, or ECG parameters. It was pointed out in a review that sugammadex does not alter blood pressure and heart rate in animals under general anesthesia [24]. Although Qt prolongation is not detected, it is important to consider possible ECG alterations when proarrhythmic agents such as neostigmine and atropine are used. In our study, we monitored cardiac electrophysiological alterations using a Holter ECG beginning from surgery until couple hours after the operation. Thus, we could not detect Qt interval prolongation that starts in late postoperative period. We believe that the reasons of the increases on heart rate, systolic and diastolic blood pressures, and mean arterial pressure are multiple. Pain might be one of the most important reasons affecting these parameters. However, we did not evaluate pain in our study. This is one of the limitations of this study. In accordance with previous studies, we did not detect any differences in terms of QTc interval. We found an increase on systolic, diastolic, and mean blood pressures after the medication in group S. However, this increase was somewhat lower in group N statistically. We believe that the decrease on heart rate (mean, 2 beats/min) 1 and 3 minutes after the medication in group S was not clinically significant. We did not detect any clinical complication or adverse effect.
5. Conclusions
D. Kizilay et al.
[4]
[5]
[6]
[7]
[8]
[9] [10] [11] [12] [13]
[14]
[15]
[16]
[17] [18]
In the current study, we aimed to compare the hemodynamic effects of neostigmine and sugammadex in cardiac patients who underwent noncardiac surgery. We did not find any difference on Qt interval between 2 groups. Although there were significant increases on hemodynamic parameters in both groups, this increase was more prominent in patients receiving neostigmine. Therefore, we suggest that sugammadex might be a safety option to reverse neuromuscular blockage in cardiac patients undergoing noncardiac surgery.
[19]
[20]
[21]
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