Effects of intraoperative Magnesium Sulfate Infusion on emergency agitation during General Anesthesia in patients undergoing Radical Mastectomy: a randomized controlled study

doi:10.21203/rs.3.rs-2830287/v1

Background

Emergency agitation is a common postoperative complication in patients under general anesthesia, which can lead to unpredictable damages such as shedding of drainage tube and bleeding from the wound. The purpose of the study is to investigate whether intraoperative infusion of Magnesium Sulfate reduces the incidence of emergency agitation (EA) in patients undergoing radical mastectomy, and to evaluate its safety and efficacy.

Methods

A total of 70 patients were randomly assigned to two groups: the Magnesium group (M group) and the control group (C group). After a routine intravenous anesthetic induction, patients in the M group received a 30mg/kg bolus of intravenous magnesium during the first hour and then a continuous infusion of 10mg/kg ×h until the end of the surgery, patients in the C group received 0.9% saline at the same volume and rate. The sedation-agitation scale (SAS) and the visual analogue scale were used to assess agitation and pain, respectively.

Results

Compared to the C group, the M group reduced the incidence of EA significantly (odds ratio 0.26, 95% confidence interval 0.09–0.71, P = 0.009). The postoperative pain scores of the two groups were comparable. Additionally, the M group required a lower dosage of remifentanil during surgery compared to the C group(300.4 ± 84 versus 559.3 ± 184µg, respectively, P<0.001).

Conclusions

the administration of intraoperative magnesium sulfate infusion is a safe and effective method for reducing the incidence of emergency agitation in patients undergoing radical mastectomy.

Trail registration:

The study was registered in Chictr.org with the identifier: ChiCTR2300070595 on 18/04/2023.

radical mastectomy

magnesium sulfate

emergency agitation

emergency agitation (EA) is a commonly observed adverse reaction in patients undergoing general anesthesia, which characterized by a sequence of sudden and complex actions, including excitement, agitation, hyperactivity of limbs and unconscious crying ^[1]. Although it typically within a short period after extubation (usually 5-10minutes, and less than 30minutes), it can pose potential risks to both patients and medical staff. Postoperative agitation not only leads to inadequate nursing resources but also prolongs hospital stay and increases hospital costs ^{[2, 3]}. Therefore, it is crucial to explore safe and effective approaches to reduce the incidence of EA in clinical practice. Clinical anesthesiologists have made great endeavors to decrease EA and have achieved significant success in this regard. Sedatives and analgesics are the most frequently used medications to administrate emergency agitation, such as opioids, dexmedetomidine, ketamine and magnesium sulfate ^{[4, 5]}. Magnesium sulfate is an NMDA receptor antagonist ^[6], which is increasingly being used as an adjuvant agent ^[7]. Studies have demonstrated that magnesium sulfate has been validly utilized to reduce the occurrence of EA in children ^[5], and it does not cause any side effects. Research has shown that magnesium sulfate is an effective treatment for reducing the occurrence of EA in children ^[5]. Radical mastectomy is a frequently used surgical method for treating breast cancer ^[8]. However, it is a high-risk factor associated with surgery for EA ^[9]. According to some reports, the overall incidence of emergency agitation in adults is ranges from 0.25–19% ^{[3, 10]}. It is still unclear whether intravenous infusion of magnesium sulfate can reduce the incidence of EA during the early recovery stage of radical mastectomy in patients under general anesthesia. Therefore, the purpose of the current study was to evaluate the effects of intravenous infusion of magnesium sulfate on EA in female patients undergoing radical mastectomy and provide evidence for improving recovery and prognosis.

Ethics and participants

This randomized controlled study was conducted at Affiliated Hospital of North Sichuan Medical College between January 2023 and February 2023, and was approved by the Ethics Committee of Affiliated Hospital of North Sichuan Medical College(2022ER494-1). All methods are in line with the relevant guidelines and regulations of the study. Written informed consent was obtained from all participants aged 18–65 years old who were scheduled for radical mastectomy and had an ASA physical status of I or II. The following were the exclusion criteria: cardiac ischemia, history of cardiac conduction block, history of neuromuscular disease, pregnancy, chronic treatment with calcium channel blockers, liver dysfunction, diabetic neuropathy or known to hypersensitive to magnesium compounds. Patients who declined to participant were also excluded. All participants were randomly assigned to either the magnesium sulphate group or the control group.

Randomization

Patients were randomly divided into the magnesium sulfate group (M group) and the control group (C group) by internet-based randomization software.

Anesthesia and intervention

Every subject had no premedication. On arrival at the operating room, ECG, pulse oximetry (S_PO₂), non-invasive blood pressure on the calf (NIBP, to facilitate surgery) and bispectral index (BIS) were monitored. MAP and HR were documented as baseline values approximately 10 minutes after the patients arrived. Anesthesia induction was performed with propofol 2mk/kg and fentanyl 3µg/kg, followed by cis-atracurium 0.15mg/kg to paralyze the muscles. Tracheal intubation was performed when the anesthesia reached an appropriate depth, and mechanical ventilation was conducted with respiratory parameters adjusted to a suitable range. In the magnesium group, patients received a 30mg/kg bolus of intravenous magnesium within one hour after induction and then a continuous infusion of 10mg/kg ×h until the end of the surgery, patients in the control group received 0.9% saline at the same volume and rate. Remifentanil was titrated to maintain the mean arterial pressure within 20% of baseline and heart rate no less than 50bmp, in the meanwhile, sevoflurane was titrated to maintain the BIS value at 40–60. Atropine or vasopressor was administrated if the two values observed below maintenance range. Remifentanil was terminated while stitching the wound, and every patient received intravenous fentanyl 1mg/kg. At the end of the surgery, all other medications were disconnected.

Data collection

Indicators, including emergency agitation, postoperative pain, as well as the means to manage them, were evaluated by a blinded investigator. EA was assessed using the Rikers Sedation Agitation scale ^{[11, 12]}, which includes the following categories: 1. Unresponsive; 2. Very sedated; 3. Sedated: Difficult to arouse; 4. Calm, cooperative: Calm, easily aroused, follows commands;5. Agitated: Anxious or mildly agitated, becomes calm when verb instructions are provided;6. Very agitation: cannot remain calm, despite frequent verbal remainders of limits; 7. Dangerous agitation. The scale has been widely applied and has been proved to be both valid and reliable ^[13]. Postoperative pain was evaluated using the Visual Analogue scale ^[14]. Tramadol was administrated intravenously at a dose of 25mg as a rescue analgesic when patients occurred agitation. Medication was only allowed after the evaluation of EA and pain scoring were completed to avoid any confusion regarding outcome measurements.

Observation outcomes

After surgery, patients were transferred to the Post-Anesthesia Care Unit (PACU). The primary observation outcome was the incidence of emergency agitation 0 min (T0) arrived at the PACU. The secondary outcomes included the incidence of EA at 5(T1), 10(T2), 15(T3), 30(T4) minutes after arrival, as well as the VAS scores at the same points in time. Additionally, the consumption of remifentanil, reaction time (from sevoflurane disconnection to recovery of consciousness), extubation time (from sevoflurane disconnection to extubation) were recorded. Any adverse effects related to the intravenous infusion of magnesium sulfate, such as arrythmia or neuromuscular paralysis and breathing difficulties, were also documented.

Statistical analysis

The sample size of the study was calculated from the incidence of EA at 0 min entering the PACU of the preliminary experiment based on 15 participants each group, consequently, subjects (32 per each) were required to attained a power of 80% and a type Ⅰ error of 0.05. To account for a potential 10% dropout rate, we enrolled 35 subjects each group.

Statistical analysis was performed by SPSS (ver.25.0, IBM Co., Armonk, NY, USA). For normally distributed data, means and standard deviation (mean ± SD) were used, and the difference was compared with the Student’ s t-test. For non-normally distributed data, median (interquartile distance) M (P₂₅, P₇₅) was used for results, and the difference was analyzed using the Mann-Whitney U test. Categorical data was expressed as percentages and analyzed using the Chi-square test or Fisher’s exact test. A P value less than 0.05 was considered statistically significant.

In this study, we enrolled 70 patients all together who were assessed for eligibility and randomly allocated to two groups: magnesium group (Group M, n = 35) and the control group (Group C, n = 35) (Fig. 1).

None of the patients were dropped out for various reasons. Demographics and perioperative measurements were compared between the two groups, and it was found that intraoperative remifentanil consumption was different significantly between them (300.4 ± 84 versus 559.3 ± 184µg in M group and C group, respectively, P<0.001)). The total dose of rescue analgesic of two groups was comparable (P<0.001) (Table 1).

Emergency agitation was defined as aimless motion, excessive movement or aggressive behaviors and uncertain sounds generated by the patients without any instruction or command. We assessed EA at various time points after admission to PACU and found that intraoperative infusion of magnesium sulfate significantly reduced the incidence of EA in comparison with the control group (odds ratio 0.26, 95% confidence interval 0.09–0.71, P = 0.009). At T3, EA was still present in four patients in the control group and one in the magnesium group, which indicated there was no significant different between them(P = 0.197), no patients in either group showed EA at T4 (Table 2). The Rikers SAS scoring was also performed, the control group received patently higher scores compared to the magnesium group (5(4,5) versus 4(3,5), P<0.001), and the severity of EA at other points of time were similar to that described above (Table 2). All patients were given certain analgesic before the end of the surgery, and postoperative pain was well controlled, resulting in relatively low overall scores. In terms of the VAS scores, there was a statistically significant difference between the two groups at each assessment point (Table 3). Reaction time and extubation time were not extended and no adverse effects associated with magnesium sulfate were observed.

In the current study, it was turned out to be that intraoperative infusion of magnesium sulfate was beneficial to reduce the incidence of emergency agitation during general anesthesia in patients undergoing radical mastectomy. Meanwhile, this intervention was found to diminish the consumption of remifentanil during the surgery and alleviate.

In 1961, the conception of EA was first proposed by Eckenhoff ^[15] et al. EA is described as an inappropriate behavior during the early recovery stage from general anesthesia, and is deemed to have many risk factors ^{[9, 16]}, as follows: (1) patient-related: children and young male appear commonly than others, history of mental disorder, alcoholic, opioid abusers ^[1]. (2) anesthesia-related: inhalational anesthetic is significantly greater than total intravenous anesthesia ^[17], preoperative acceptance benzodiazepine^【3】, postoperative pain ^[18].(3)surgery-related: Oral surgery, otolaryngological surgery, breast operation and abdominal operation are associated with a higher risk of EA in adult patients ^{[9, 19]}.

With the improvement of life and the advancements in medical technology, the average lifespan of humans has extended, diseases can be diagnosed and treated timely. It is reported that 1.5 million women worldwide are diagnosed with breast cancer each year ^[20]. The morbidity of breast cancer is second only to that of cervical cancer, but its mortality is considerable and requires early detection, early diagnosis and early treatment. Radical mastectomy, a common treatment for breast cancer patients, is typically performed under general anesthesia ^[8]. Furthermore, it is also an independent surgery-related risk factor for EA, which may be connected with postoperative pain and excessive anxiety caused by the change of appearance of breast ^[2].

Sevoflurane is an inhalational anesthetic that can contribute to a high incidence of EA when patients have a rapid recovery ^[21]. A study suggested that this phenomenon above may be attributable to the direct suppression effect of inhalational anesthetics on the central nerve system ^[22]. Another earlier study found that sevoflurane increased lactate concentration in the parietal cortex, which was correlated with basic cognition ^[23]. In the present study, there was no evident difference in the use of sevoflurane between the two groups.

Magnesium sulfate is a traditional agent widely applied in the treatment of gestational hypertension and eclampsia ^[7]. As an N-methyl-D-aspartate (NMDA) receptor antagonist, magnesium sulfate has been regarded as an adjuvant dedication that diminish the anesthetic requirements ^{[24, 25]}. Magnesium sulfate prevents noxious stimulus from causing central sensitization by binding to NMDA receptors or reducing excitatory transmitters in the peripheral nervous system. A previous study verified that magnesium sulfate reduced the total dose of remifentanil ^[26], which is consistent with the present study. Intraoperative consumption of remifentanil in the magnesium group was lower distinctly compared to the control group. According to the result, there is a significant difference of postoperative pain scoring between two groups, which coincides with the previous trail ^[6]. However, neither of two groups scored highly on the VAS, which may be due to the addition of fentanyl before the end of surgery.

The mechanism of magnesium sulfate mitigates the occurrence of EA remains unclear. While postoperative pain is viewed as a risk factor for EA, Weldon et al. ^[27] indicated that EA could not be relieved effectively after patients with EA during recovery from general anesthesia are treated with analgesic. Increasing lactic acid in the cortex is related to EA, however, an animal study has shown that magnesium sulfate could inhibit lactic acid concentration in the brain and improve brain hemodynamics ^{[28, 29]}. The infusion rate of magnesium sulfate used in the present study was based on a previous study ^[5], and no adverse effects were undetected. However, the incidence of EA in the control group in this study was different from that reported in previous studies ^{[3, 10]}, which may be relevant to differences in anesthesia methods, surgery duration and methods of evaluating emergency agitation.

Severe EA can lead to drainage tube shedding, wound bleeding and cardio-cerebral vascular accidents, which can increase the duration and expenses of hospitalization. Given these unbeneficial aspects, magnesium sulfate wound be a proper agent for reducing the occurrence of EA in patients undergoing radical mastectomy with general anesthesia.

However, limitations of the current study should be observed: Firstly, it was a single-center clinical study with a relatively small number of subjects, so larger sample sizes and multi-center studies are needed to provide further support for the conclusion. Secondly, postoperative pain scores were only recorded within 30minutes after the surgery, so it is unknown whether there is a significant difference between the two groups and whether analgesics are applied after 30 minutes. Lastly, Blood magnesium concentration was not monitored in each group before and after the surgery, and the dosage of magnesium sulfate was based on a previous study, so further investigations are needed to determine the optimal dose schedule of magnesium sulfate.

The intraoperative infusion of magnesium sulfate is a safe and effective method for reducing the incidence of emergency agitation in patients undergoing radical mastectomy, in the meanwhile, the administration of intraoperative magnesium sulfate infusion can decrease the remifentanil consumption and postoperative pain. Moreover, it does not appear to be connected with any increased postoperative side-effects.

The Author(s). 2023 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other thirdparty material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Acknowledgements

We would like to thank all the patients and related institutions for providing help to the study.

Authors contributions

YP and YHS were responsible for study design and organization. YHS and DCL performed the preliminary study, gathered and analyzed the data. YHS was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Funding

None

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Affiliated Hospital of North Sichuan Medical College(2022ER494-1). Written informed consent was obtained from each patient.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Table 1. demographic characteristics and perioperative measurements

variable	M group(n=35)	C group(n=35)	P value
Age; years	52(48, 57)	54(48, 59)	0.374
Height; cm	154.4±4.0	154.9±6.1	0.727
Weight; kg	58.5±6.1	57±7.2	0.332
Duration of anesthesia; min	166(152,187)	154(138,183)	0.224
Duration of surgery; min	128（117，145）	120（103，150）	0.347
Reaction time; min	10(9,12)	10(9,12)	0.967
Extubation time; min	12(10,13)	12(11,13)	0.528
PONV (n, %)	3(8.6)	5(14.3)	0.644
The consumption of remifentanil; μg	300.4±84	559.3±184	＜0.001^*
Dose of rescue analgesics	0(0,25)	25(25,25)	＜0.001^*
ET-Sevo (vol, %)	1.7（1.5，1.9）	1.7（1.6，1.9）	0.609

Categorical variables were represented as mean ± standard deviation, number of patients (%) or median(range). PONV, postoperative nausea and vomiting. ET-sevo, the mean end-tidal sevoflurane concentration. ^*P＜0.05.

Table 2. Postoperative emergency agitation at various points

	M group(n=35)	C group(n=35)	P value
Incidence of EA (n, %)
T0	9(25.7)	20 (56)	0.009^*
T1	6(16.7)	14(40)	0.039^*
T2	2(5.7)	9(25.7)	0.035^*
T3	1(2.8)	4(11.4)	0.197
T4	0	0	1
The SAS scoring
T0 95%CI	4(3,5) 3.6,4.2	5(4,5) 4.5,4.9	＜0.001^*
T1 95%CI	4(3,4) 3.7,4.1	4(4,5) 4.1,4.5	0.007^*
T2 95%CI	4(4,4) 3.8,4.1	4(4,5) 4.0,4.4	0.027^*
T3 95%CI	4(4,4) 3.8,4.1	4(4,4) 3.8,4.2	0.579
T4 95%CI	4(4,4) 3.8,4.0	4(4,4) 3.9,4.0	0.645

Categorical variables were represented as mean ± standard deviation, number of patients(%), median(range) and 95% confidence interval. EA, emergency agitation. SAS, sedation and agitation scale. CI, confidence interval.^*P＜0.05.

Table 3. Postoperative pain profile within 30min

Vas scores	M group(n=35)	Control group(n=35)	P value
T0	0(0,1)	2(0,3)	0.011^*
T1	0(0,1)	1(0,2)	0.013^*
T2	1(0,2)	2(0,3)	0.020^*
T3	1(0,2)	2(2,3)	＜0.001^*
T4	2(1,2)	2(2,3)	＜0.001^*

Categorical variables were represented as mean ± standard deviation, number of patients(%), median(range) and 95% confidence interval. VAS, visual analogue scale. ^*P＜0.05.

No competing interests reported.

Effects of intraoperative Magnesium Sulfate Infusion on emergency agitation during General Anesthesia in patients undergoing Radical Mastectomy: a randomized controlled study

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Materials and Methods

Ethics and participants

Randomization

Anesthesia and intervention

Data collection

Observation outcomes

Statistical analysis

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Journal Publication

Version 1