Observations on the Use of Different Modes of Cisatracurium Administration in Hyperthermic Intraperitoneal Chemotherapy

Objective: To investigate the residual effects of cis-atracurium with different administrations in patients with hyperthermic intraperitoneal chemotherapy. Methods: 60 patients undergoing hyperthermic intraperitoneal chemotherapy were randomly divided into two groups with 30 cases in each group. All patients were induced with sufentanil 0.4ug/kg, propofol 2.0mg/kg and cis atracurium 0.2mg/kg. During the operation, sevo�urane and remifentanil were used to maintain anesthesia. BIS value was 45-55. The control group intermittently received cis-atracurium injection with 0.1mg/kg/h. The experimental group received continuous injection of cis-atracurium at a rate of 1.5ug/kg/min. Cis-atracurium was discontinued 30min before the end of the operation, sevo�urane inhalation was stopped 20min before the end of the surgery and remifentanil was discontinued 10min before the end. At the end of the operation, no muscle relaxant antagonism were applied. General information of patients was recorded. Mean arterial pressure (MAP), heart rate (HR), tidal volume (VT), respiratory rate (F), and blood oxygen saturation (SpO2) were recorded before anesthesia (T1) , at the time of tracheal catheter extraction (T2).Besides, the total amount of cis-atracurium, the time of recovery of spontaneous tidal volume to 6ml/kg (t1), the time of continuous lifting of the head for 5 s (t2), and the time from the withdrawal of muscle relaxant to the removal of the tracheal catheter (t3) were recorded. Blood gas analysis was also performed to record PaO2 and PaCO2 before anesthesia, when leaving the operating room and SICU. Moreover, relevant adverse reactions were recorded. Results:


Background
Good muscle relaxation is an important part of general anesthesia.This can ensure a smooth tracheal intubation and provide good conditions for surgical operation, maintaining smooth anesthesia and an uneventful operation.Therefore, muscle relaxation mainly relies on neuromuscular blocking drugs to achieve these [1] .At present, there are various types of muscle relaxants available, including depolarizing and non-depolarizing muscle relaxants.Non-depolarizing myorelaxants include rocuronium bromide, vecuronium bromide, atracurium, and cisatracurium.Among them, cisatracurium, without the histamine-releasing effect of atracurium, is mainly hydrolyzed by esterases, degraded by Hofmann elimination, and is not affected by liver or kidney function or age [2] .Thus, it is more commonly used in clinical practice.In addition, hyperthermic intraperitoneal chemotherapy (HIPEC) is the primary treatment modality for patients with peritoneal carcinoma [3] .Most patients with peritoneal cancer have advanced tumors and in ltrated abdominal tumor implantation.Thus, the surgery is di cult and prolonged.In addition, HIPEC results in redistribution of body uids and changes in the internal environment and body temperature.Thus, theoretically, it affects the metabolism of muscle relaxants (myorelaxants).Therefore, our study aims to investigate the effects of two relative common modes of cisatracurium administration in HIPEC.

General information
Sixty patients with peritoneal cancer who underwent HIPEC from June 2018 to June 2019 were selected and randomly divided into two groups of 30 patients each.One group was the control group, with intermittent intravenous administration of cisatracurium, and the other group was the experimental group, with continuous administration of cisatracurium.Inclusion criteria were as follows: ASA classi cation I-III, age 18-65 years, and signed informed consent form and agreement to be included in this study.Exclusion criteria were as follows: 1) presence of signi cant preoperative cardiopulmonary, hepatic, and renal insu ciency (including cardiac NYHA class II or higher, respiratory failure, Child-Pugh liver function class B or higher, and chronic renal insu ciency or ongoing dialysis); 2) presence of neuromuscular disorders; 3) presence of allergy to muscarinic drugs; and 4) recent use of drugs that affect neuromuscular conduction (including anticonvulsants, digitalis, diuretics, aminoglycoside antibiotics, and corticosteroids).The study was approved by the Ethics Committee of Beijing Shijitan Hospital, and all patients signed an informed consent form before the study.

Methods
All patients were routinely fasted from food and water before the surgery.After admission to the operating room, intravenous access was initiated, uids were instituted, and ECG, invasive arterial pressure, oxygen saturation, and electroencephalographic bifrequency index (BIS) were monitored.Anesthesia was induced sequentially with sufentanil 0.4 ug/kg, propofol 2.0 mg/kg, and cisatracurium 0.2 mg/kg (for four-time 95% effective dose [ED], cisatracurium's ED 95% was 0.05 mg/kg).After induction of anesthesia, the patient underwent tracheal intubation and was mechanically ventilated, and EtCO2 was maintained intraoperatively between 35 and 45 mmHg.Intravenous-inhalation combined anesthesia was chosen for the maintenance of anesthesia.Intraoperatively, sevo urane inhalation anesthesia was administered with the concentration of volatilization pot output at 1.8-3% and the concentration of 1.8 L/min inhaled oxygen at 50%.Remifentanil was injected continuously at a rate of 0.1-0.2ug/kg/min.A BIS value of 45-55 was maintained.Cisatracurium was added at a rate of 0.1 mg/kg/h intermittently in the control group according to the commonly used clinical dose.Cisatracurium was pumped continuously at a rate of 1.5 ug/kg/min in the experimental group.Cisatracurium was discontinued 30 min before the end of surgery.
Sevo urane inhalation was discontinued 20 min before the end of surgery.Remifentanil was discontinued 10 min before the end of surgery.Sufentanil was added at 0.1 ug/kg.The maintenance dose of anesthetics was adjusted at any time during surgery according to the progress of surgery, changes in depth of anesthesia, and changes in hemodynamic indices.
At the end of the procedure, no muscarinic antagonist was administered.The patient was observed for recovery of muscle relaxation.After the patient regained consciousness and reached the tracheal extubation indication, the patient was extubated after the secretions were su ciently aspirated in the oral cavity and trachea.Indications for extubation were as follows [25,26]: the patient was conscious and could respond to the call; cough and swallowing re exes and muscle strength were restored, and the patient could keep the head raised for 5 s; spontaneous breathing was restored, tidal volume reached 6 mL/kg, and regular respiratory rhythm was 12-20 cycles/min; and oxygen saturation (SpO2) is > 97% 5 min after discontinuation of oxygen.The patients were sent to the postoperative ICU recovery unit (SICU) for continued observation after the vital signs stablized.1.3.3Total dosage of cisatracurium, time to return to 6 mL/kg of tidal volume for spontaneous breathing (t1), time to the ability to hold the head up for 5 s (t2), and time from the discontinuation of the inotropes to the removal of the tracheal tube (t3) were recorded.Arterial blood gases without oxygen were analyzed using a Gem Premier 3000 blood gas analyzer (IL, USA), and arterial partial pressure of oxygen (PaO2) and partial pressure of carbon dioxide (PaCO2) were measured before anesthesia, at the time of exit from the operating room, and at the time of transfer from SICU for the assessment of respiratory function.1.3.4For the recording of adverse reactions, patients were observed for adverse events such as skin rash, laryngospasm, bronchospasm, presence of cardiac arrhythmias, and intraoperative hypotension after intravenous cisatracurium injection.Postoperative follow-up was performed to assess whether the patient had intraoperative knowledge.
1.4 Statistical methods SPSS 19.0 software was used for analysis.Normally distributed data were recorded as mean ± standard deviation, and independent samples t-test was used to compare the normally distributed data of the two groups, while chi-square test was used to compare the count data.P values <0.05 indicated statistical signi cance.

General information
The differences between the two groups in terms of age, gender, ASA classi cation, body mass index, duration of surgery, infusion volume, and urine volume were not statistically signi cant (P > 0.05) and were comparable.Statistical analysis revealed that time to return 6 mL/kg of tidal volume for spontaneous breathing (t1), time to be able to hold the head up for 5 s (t2), and time from the discontinuation of inotropic drugs to the removal of the tracheal tube (t3) were signi cantly shorter in the experimental group than in the control group, with statistically signi cant differences (P < 0.05).In contrast, there was no signi cant difference in PaO2 and PaCO2 between the two groups before anesthesia, at the time of exit from the operating room, or at the time of exit from the SICU (P > 0.05).

Comparison of patient adverse events
There were no intraoperative adverse events in either group.

Discussion
Sedation, analgesia, and myorelaxation constitute the three elements of general anesthesia.Among them, a good muscle relaxation effect is an important guarantee for a successful operation.Moreover, cisatracurium is a relatively more commonly used non-depolarizing myorelaxant in clinical practice.
Compared with other non-depolarizing myorelaxants, such as rocuronium and vecuronium, cisatracurium is stable, is mainly degraded by Hofmann elimination, has no signi cant accumulation effect, and is less affected by liver and kidney function and age [2,4] .Thus, it theoretically has some advantages for application in prolonged surgery.However, HIPEC has its special characteristics as follows: 1) it is complicated, has a long operation time, and requires prolonged anesthesia to maintain drug administration, which prolongs the half-life of continuous drug infusion; 2) the procedure has extensive trauma exposure and signi cant intraoperative uid loss, while HIPEC leads to intestinal dilation, uid redistribution, and accumulation in the third interstitial space, which affects the apparent distribution of drugs; 3) with HIPEC, the patient's body temperature, metabolic rate, and acidic metabolites all increase, which affect the metabolism of the drug [5][6][7] .Thus, exploring the muscle relaxation effects of different modes of administration of muscle relaxants in this type of surgery and their muscle relaxation residual effects is of great clinical signi cance to guide the application of muscle relaxants in HIPEC.
The study compared the effects of two different modes of cisatracurium administration on the muscle relaxation effect: intermittent administration and continuous pumping.In the traditional intermittent dosing method, a larger dose is usually administered followed by an additional dose based on clinical experience, theoretical half-life of the drug, intraoperative changes in the patient's airway pressure, presence or absence of body movements, and subjective perception of the surgeon.This mode of administration causes an intermittent and abrupt increase in cisatracurium blood concentration and rapid binding to muscarinic receptors to saturation [8] ; on the other hand, muscarinic clearance per unit time is accelerated.This mode of administration may thus result in large uctuations in blood concentration, unstable myorelaxation, and di culty in estimation of myorelaxation recovery time [9] .The other mode of administration is continuous pumping, which can maintain a relatively constant blood concentration, easily control the myorelaxation effect and recovery time, and reduce the occurrence of myorelaxation residuals [10] .In this study, the intraoperative cisatracurium dosage was signi cantly less in the continuous pumping patients than in the intermittent dosing group, and time to recovery of muscle strength, time to return to normal respiration, and time to extubation of the tracheal tube were all signi cantly shorter in the continuous pumping group than in the intermittent dosing group, with statistically signi cant differences.It is suggested that in the intermittent dosing group, whose infusion half-life was prolonged and more di cult to estimate, patients still had a degree of residual muscle relaxation and prolonged extubation time after surgery.In contrast, in the continuous infusion group, the blood drug concentration was relatively stable and there was no signi cant drug accumulation.
The head-up 5-s test was chosen in the study as the main index to determine the delayed effect of muscle relaxation.Previous reports have mostly used a four-string response ratio (TOFR = T4/T1) > 0.7 as a criterion for neuromuscular recovery [11][12].Although TOFR = 0.7 was chosen as an indicator for the termination of muscle relaxation effects in clinical practice, some studies found that even when TOFR = 0.7, some patients still had paralysis of the pharyngeal and upper respiratory muscles, weakness in st clenching, and inability to bite against the upper and lower incisors, which increased the risk of postoperative pulmonary complications [13][14] .In contrast, raising the head for 5 s not only suggests that the patient's respiratory function has largely recovered, but also shows that the patient's airway protection function has recovered, which in turn reduces the risk of aspiration and airway obstruction [15][16] .In the present study, we found that the time from the end of the procedure to head elevation lasting 5 s was signi cantly shorter in patients in the continuous infusion cisatracurium group, in contrast to some previous studies, which reported that the duration of muscle relaxation effect was signi cantly longer after continuous infusion of cisatracurium than after intermittently administration.This may be related to the concentration and rate of continuous infusion, the patient's underlying condition, and the type of surgical approach.
In addition, the study also investigated the presence or absence of the histamine-releasing effects of cisatracurium.The comparison revealed no signi cant changes in the mean arterial pressure or heart rate in patients before and after surgery, while none of the patients in either group experienced adverse events such as rash, ushing, laryngospasm, or bronchospasm during general anesthesia.It was con rmed that prolonged application of cisatracurium, without signi cant histamine-releasing effects, was safe and effective with continuous infusion.
In conclusion, the duration of muscle relaxation effect is signi cantly longer after intermittent administration than after continuous infusion of cisatracurium.Thus, continuous infusion is more suitable for prolonged surgery.In addition, there are some shortcomings in this study.The most notable one was the absence of myorelaxation monitor-related indicators, which will be subsequently combined with TOF values to comprehensively assess the pharmacodynamic changes in terms of subjective clinical indicators and objective indicators of myorelaxation monitoring.

Declarations
Ethics approval and consent to participate

1. 3
Observational indicators 1.3.1 General information of the patients, including gender, age, body mass index, ASA classi cation, and duration of anesthesia (min) and operation (min) were recorded.Intraoperative uid rehydration and urine volume were recorded.1.3.2Patients' vital signs (mean arterial pressure [MAP], heart rate [HR]) and respiratory indices (tidal volume [VT], respiratory rate [F], and SpO2) were recorded before anesthesia (T1) and at the time of tracheal tube removal (T2).

Table 1
Comparison of basic information between the two groups of patients a : statistically signi cant difference compared to the control group (p < 0.05)2.2Comparison of muscle relaxation and residual effects between the two groups

Table 2
Comparison of muscle relaxation outcomes between the two groups t1: time to recovery of spontaneous respiratory tidal volume to 6 mL/kg; t2: time to the ability to sustain head elevation for 5 s; t3: time from inotropic drug discontinuation to patient's tracheal extubation.a:statistically signi cant difference compared to control group (P < 0.05).2.3Comparison of patients' hemodynamic indicescomparison of the hemodynamic parameters between the two groups showed that there was no statistically signi cant difference in the mean arterial pressure, heart rate, tidal volume, respiratory rate, or oxygen saturation at T1 and T2 time points (P > 0.05).

Table 5
Comparison of intraoperative adverse events between the two groups of patients