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Abstract

Introduction

Magnesium sulfate is a potential anesthetic adjunct in cancer surgery. However, no definite consensus exists on the use of magnesium sulfate in patients undergoing major cancer surgery.

Objective

This study aimed to examine the trends and factors associated with magnesium sulfate administration in patients who underwent major cancer surgery in South Korea.

Materials and Methods

In this retrospective and population-based cohort study, we used 5-year health data that were extracted from the National registration database in South Korea from January 1, 2016 to December 31, 2020. All adult patients who underwent major cancer surgery during 2016–2020 in South Korea were included.

Results

In total, 253,538 patients were included. Among these patients, 6.6% (16,708/253,538) were administered magnesium sulfate during major cancer surgery. In multivariable logistic regression modeling, older age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.02-1.02; P < .001), esophageal cancer surgery (vs lung cancer surgery [OR, 3.04; 95% CI, 2.80-3.30; P < .001]), increased Charlson comorbidity index score (OR, 1.03; 95% CI, 1.02-1.03; P < .001), mild-to-moderate disability (OR, 1.08; 95% CI, 1.03-1.14; P = .003), and severe disability (OR, 1.16; 95% CI, 1.05-1.27; P = .003) were associated with a higher incidence of perioperative magnesium sulfate administration for major cancer surgery. Video-assisted thoracoscopic surgery or laparoscopy (OR, .57; 95% CI, .55-.59; P < .001) and propofol-based total intravenous anesthesia (OR, .86; 95% CI, .82-.89; P < .001) were associated with a lower incidence of perioperative Mg sulfate administration for major cancer surgery.

Conclusions

In South Korea, 6.6% of the patients who underwent major cancer surgery were administered magnesium sulfate during surgery. Certain factors, such as old age, thoracic cancer surgery, open laparotomy or thoracotomy, greater comorbid status, and inhalation anesthesia, were potentially associated with magnesium sulfate administration in patients undergoing major cancer surgery.

Keywords

cancer cancer treatment epidemiology surgery trends

Introduction

Cancer is the second major cause of death, and the cancer burden on individuals, communities, and healthcare systems is increasing gradually worldwide.¹ Adequate supplementation of nutrients through diet is considered an important factor in determining the prognosis of patients with cancer.^2-4 Magnesium (Mg) intake via diet is low in Western countries, which is related to the incidence of cancer, since Mg plays a major role in several essential cellular processes, such as DNA replication and repair and cell proliferation.¹ Cancer progression and anticancer therapy frequently exhaust Mg, which disturbs Mg homeostasis in cancer cells.^1,5

Surgery is the main treatment option for the management of patients with cancer; however, surgery could result in postoperative hypomagnesemia as a complication.^6-9 Perioperative supplemental Mg in major cancer surgery can be beneficial for patients with cancer. Historically, Mg sulfate has performed various roles as an adjuvant anesthetic.¹⁰ Mg sulfate is useful for the treatment or prevention of underlying diseases, which can be perioperatively aggravated in patients who are severely ill. Mg ions are safe and effective in the prevention and treatment of cardiac arrhythmias, asthma, and acute respiratory failure.^11-15 Moreover, Mg sulfate plays an adjuvant role in perioperative analgesia and the enhancement of muscle relaxation.^16-25 Hypercoagulability during cancer surgery can be reduced using intraoperative Mg sulfate supplement.⁹ Despite this evidence of the benefits of Mg, no definite consensus exists on the use of Mg sulfate during major cancer surgery.

Therefore, this study aimed to examine the trends and factors associated with Mg sulfate administration in patients who underwent major cancer surgery in South Korea.

Materials and Methods

Study Design and Ethical Concerns

This study was a retrospective population-based cohort study, and the reporting of this study conforms to the STROBE guidelines.²⁶ The Institutional Review Board (IRB) of Seoul National University Bundang Hospital in Seongnamsi, Gyeonggido, South Korea, approved the study protocol (approval number: X-2105-686-904, approval date: 29 April 2021). Moreover, the ethical committee of the National Health Insurance Service (NHIS) (NHIS-2022-1-336) agreed to provide data following the approval of the study protocol. The requirement for informed consent was waived by the IRB since data were retrospectively analyzed in anonymous forms extracted from the NHIS database. Thus, all patient details were de-identified in this study.

Data Source and Study Population

We used the NHIS database in South Korea for data extraction. As a single and public health insurer in South Korea, the NHIS contains information regarding all disease diagnoses and prescriptions for procedures and drugs. The procedures, including cancer surgery and disease diagnoses, are registered using the International Classification of Diseases, 10th revision (ICD-10 codes). In addition, the demographic and socio-economic status-related information is also contained and managed in the NHIS database.

We enrolled patients (aged ≥18 years) who underwent major cancer surgery with curative intent following hospitalization from January 1, 2016, to December 31, 2020. Lung, gastric, colorectal, esophageal, small bowel, liver, pancreatic, and bile duct or gallbladder cancers were the major cancers included. In South Korea, patients with cancer had to be registered in the NHIS database to receive financial coverage for the examination and treatment expenses. These registrations of cancer diagnosis by ICD-10 codes enable patients to receive financial support (approximately 95%) for the total treatment cost of cancer.

Study Objectives

First, we examined the proportion of patients who were administered Mg sulfate during major cancer surgery from 2016 to 2020. Second, we examined the proportion of Mg sulfate administration for each cancer surgery over a 5-year period. Third, we investigated the factors associated with Mg sulfate use among patients who underwent major cancer surgery in South Korea from 2016 to 2020.

Collected Variables

Demographic information (age and sex) of the patients was collected. Details on the employment status, residence, and national household income level of the patients undergoing major cancer surgery were also collected to determine the socio-economic status of the patients. The government should possess information regarding the household income level of patients annually as the annual insurance premium is determined according to the household income. Thus, the individuals who had difficulty in paying the insurance premiums owing to poor economic status were included in the medical aid program group. Except for those in the medical aid program group, all the patients were divided into 4 groups using quartile ratios. The residence of patients was classified as urban or rural. For adjustment of the capacity of the hospitals in which each major cancer surgery had been performed, information on the type of hospitals and annual case volumes was used. Type of hospitals included tertiary general or general hospitals, and the annual case volume in each hospital was calculated using the following formula: total cases of major cancer surgeries during 2016–2020/5 years. Thus, the annual case volume of major cancer surgeries was classified into 4 groups according to the quartile ratio: Q1 group, <361 surgeries; Q2 group, 362–758 surgeries; Q3 group, 759–2718 surgeries; and Q4 group, >2718 surgeries. The surgical technique was categorized into 2: receipt of video-assisted thoracoscopic surgery (VATS) or laparoscopy. The Charlson Comorbidity Index (CCI) was used to reflect the comorbid status of patients undergoing major cancer surgery using ICD-10 codes (Table S1). The disability status was also used to reflect the comorbid status because all individuals with disabilities had to be registered in the NHIS database to obtain the benefits of the social welfare system in South Korea. Disabilities were determined by specialist doctors of each field according to the criteria of difficulty in daily life associated with the disability. The disabilities were classified into 6 groups according to the severity, and patients with disabilities were divided into 2 groups: those with severe disability (grades 1–3) and those with mild-to-moderate disability (grades 4–6).

Statistical Analyses

Continuous variables with normal distributions are shown as mean (standard deviation), and categorical variables are presented as numbers (percentages). Continuous variables with normal distributions between the Mg use and non-Mg use groups were compared using Student’s t test. The χ² or Fisher exact test was used to compare the categorical variables between the 2 groups. Multivariate logistic regression was used to evaluate the factors associated with Mg sulfate administration during major cancer surgery. The Statistical Package for the Social Sciences (SPSS) software (version 25.0, SPSS Inc., Chicago, IL, USA) was used for all analyses. In all the analyses, P values <.05 indicated statistical significance.

Results

Total Population

The clinico-pathological characteristics of the patients (n = 253,538) who underwent major cancer surgery in this study are listed in Table 1. The mean age of the patients was 65.9 years, and 36.6% of the patients were male. Gastric and lung cancer surgeries were the first (30.2%) and second (21.4%) most frequent surgeries, respectively. Moreover, 63.2% of the surgeries were performed using VATS or laparoscopic techniques. The patients stayed at the hospital for a mean of 13.4 days and spent a mean of 9670.7 USD for hospitalization. Furthermore, 6.1% (3032/50,101) of the patients were administered Mg sulfate in 2016 and 7.0% (3565/50,495) in 2020 (Figure 1). Mg sulfate administration was most frequent in esophageal cancer surgery (24.6%, 987/4016) (Figure 2).

Table 1.

Clinico-Pathological Characteristics of Patients (n = 253,538).

Variable	Mean (SD) or Number (%)
Age, year	65.9 (11.6)
Male sex	93,560 (36.9)
Having a job at surgery	155,926 (61.5)
Residence at surgery
Urban area	106,199 (41.9)
Rural area	140,182 (55.3)
Unknown	7157 (2.8)
Household income level
Medical aid program	12,806 (5.1)
Q1 (lowest)	43,598 (17.2)
Q2	42,954 (16.9)
Q3	56,358 (22.2)
Q4 (highest)	87,045 (34.3)
Unknown	10,777 (4.3)
Annual case volumes of major cancer surgery
Q1<361	62,812 (24.8)
Q2: 362–758	64,239 (25.3)
Q3: 759–2718	61,717 (24.3)
Q4>2718	64,770 (25.5)
Type of hospital
Tertiary general hospital	250,970 (99.0)
General hospital	2568 (1.0)
Type of cancer surgery
Lung cancer surgery	54,176 (21.4)
Gastric cancer surgery	76,590 (30.2)
Colorectal cancer surgery	47,392 (18.7)
Esophageal cancer surgery	4016 (1.6)
Small bowel cancer surgery	7417 (2.9)
Liver cancer surgery	26,546 (10.5)
Pancreatic cancer surgery	16,643 (6.6)
BD or GB cancer surgery	20,758 (8.2)
Propofol-based TIVA	58,323 (23.0)
LOS, day	13.4 (9.0)
Total cost for hospitalization in USD	9670.7 (5844.3)
VATS or laparoscopy	160,340 (63.2)
CCI, point	5.0 (2.7)
Disability at surgery
Mild to moderate	24,002 (9.5)
Severe	6367 (2.5)
Year of surgery
2016	50,101 (19.8)
2017	50,039 (19.7)
2018	50,464 (19.9)
2019	51,989 (20.5)
2020	50,945 (20.1)

SD, standard deviation; BD, bile duct; GB, gallbladder; TIVA, total intravenous anesthesia, LOS, length of hospital stays; USD, United States Dollar; VATS, video-assisted thoracoscopic surgery; CCI, Charlson comorbidity index.

Figure 1.

Proportion of magnesium sulfate administration in major cancer surgeries from 2016 to 2020.

Figure 2.

Proportion of magnesium sulfate administration in each type of major cancer surgery.

Comparison Between the Magnesium (Mg) and Non-Mg Groups

In total, 16.708 (6.6%) of the patients underwent major cancer surgery with perioperative Mg. There were more elderly female patients in the Mg group than in the non-Mg group (Table 2). The patients in the Mg group showed higher CCI score, lower rurality, and disabilities more frequently than those in the non-Mg group. Nearly all of the patients in the Mg group underwent surgeries in the tertiary general hospital compared to the patients in the non-Mg group (100% vs 98.9%). The patients in the Mg group mainly underwent surgery for 4 types of cancer: lung (27.5%), stomach (17.8%), colorectal (15.1%), and hepatic (13.1%) cancers. Propofol-based total intravenous anesthesia, VATS, or laparoscopic techniques were used less frequently in the Mg group than in the non-Mg group. Patients in the Mg group had longer hospital stay and higher total hospitalization costs than those in the non-Mg group.

Table 2.

Comparison of Clinico-pathological Characteristics Between Mg Group and Non-Mg Group.

Variable	Mg Group n = 16,708	Non-Mg Group n = 236,830	P-Value
Age, year	68.2 (11.3)	65.8 (11.6)	<.001
Male sex	5871 (35.1)	87,689 (37.0)	<.001
Having a job at surgery	9893 (59.2)	146,033 (61.7)	<.001
Residence at surgery			<.001
Urban area	7243 (43.4)	98,956 (41.8)
Rural area	8890 (53.2)	131,292 (55.4)
Unknown	575 (3.4)	6582 (2.8)
Household income level			<.001
Medical aid program	1010 (6.0)	11,796 (5.0)
Q1 (lowest)	2833 (17.0)	40,765 (17.2)
Q2	2770 (16.6)	40,184 (17.0)
Q3	3537 (21.2)	52,821 (22.3)
Q4 (highest)	5754 (34.4)	81,291 (34.3)
Unknown	804 (4.8)	9973 (4.2)
Annual case volumes of major cancer surgery			<.001
Q1<361	3888 (23.3)	58,924 (24.9)
Q2: 362–758	5374 (32.2)	58,865 (24.9)
Q3: 759–2718	5130 (30.7)	56,587 (23.9)
Q4>2718	2316 (13.9)	62,454 (26.4)
Type of hospital			<.001
Tertiary general hospital	16,704 (100.0)	234,266 (98.9)
General hospital	4 (.0)	2564 (1.1)
Type of cancer surgery			<.001
Lung cancer surgery	4598 (27.5)	49,578 (20.9)
Gastric cancer surgery	2966 (17.8)	73,624 (31.1)
Colorectal cancer surgery	2520 (15.1)	44,872 (18.9)
Esophageal cancer surgery	987 (5.9)	3029 (1.3)
Small bowel cancer surgery	771 (4.6)	6646 (2.8)
Liver cancer surgery	2184 (13.1)	24,362 (10.3)
Pancreatic cancer surgery	1675 (10.0)	14,968 (6.3)
BD or GB cancer surgery	1007 (6.0)	19,751 (8.3)
Propofol-based TIVA	3527 (21.1)	54,796 (23.1)	<.001
LOS, day	18.9 (13.3)	13.0 (8.4)	<.001
Total cost for hospitalization in USD	15,260.1 (12,433.2)	9276.4 (4827.1)	<.001
VATS or laparoscopy	8726 (52.2)	151,614 (64.0)	<.001
CCI, point	5.4 (2.9)	4.9 (2.7)	<.001
Disability at surgery			<.001
Mild to moderate	1881 (11.3)	22,121 (9.3)
Severe	504 (3.0)	5863 (2.5)
Year of surgery			<.001
2016	3032 (18.1)	47,069 (19.9)
2017	3379 (20.2)	46,660 (19.7)
2018	3111 (18.6)	47,353 (20.0)
2019	3621 (21.7)	48,368 (20.4)
2020	3565 (21.3)	47,380 (20.0)

BD, bile duct; GB, gallbladder; TIVA, total intravenous anesthesia, LOS, length of hospital stays; USD, United States Dollar; VATS, video-assisted thoracoscopic surgery; CCI, Charlson comorbidity index.

Associated Factors for Perioperative Mg Sulfate Administration

Table 3 shows the results of the multivariate logistic regression model for perioperative Mg sulfate administration in major cancer surgery. Older age (odds ratio [OR], 1.02; 95% confidence interval [CI], 1.02-1.02; P < .001), esophageal cancer surgery (vs lung cancer surgery [OR, 3.04; 95% CI, 2.80-3.30; P < .001]), increased CCI score (OR, 1.03; 95% CI, 1.02-1.03; P < .001), mild-to-moderate disability (OR, 1.08; 95% CI, 1.03-1.14; P = .003), and severe disability (OR, 1.16; 95% CI, 1.05-1.27; P = .003) were associated with a higher incidence of perioperative Mg sulfate administration for major cancer surgery. VATS or laparoscopy (OR, .57; 95% CI, .55-.59; P < .001) and propofol-based TIVA (OR, .86; 95% CI, .82-.89; P < .001) were associated with a lower incidence of perioperative Mg sulfate administration for major cancer surgery.

Table 3.

Multivariable Logistic Regression Model for Perioperative Magnesium Sulfate Infusion.

Variable	Or (95% CI)	P-Value
Age, year	1.02 (1.02, 1.02)	<.001
Male sex	1.00 (.97, 1.03)	.982
Having a job at surgery	.95 (.91, .98)	.002
Residence at surgery
Urban area	1
Rural area	.95 (.92, .99)	.006
Unknown	.99 (.84, 1.17)	.903
Household income level
Medical aid program	.98 (.90, 1.06)	.964
Q1 (lowest)	1
Q2	1.00 (.95, 1.06)	.964
Q3	.96 (.91, 1.01)	.151
Q4 (highest)	1.01 (.96, 1.06)	.717
Unknown	.99 (.86, 1.14)	.928
Annual case volumes of major cancer surgery
Q1<361	1
Q2: 362–758	1.33 (1.27, 1.39)	<.001
Q3: 759–2718	1.41 (1.35, 1.48)	<.001
Q4>2718	.50 (.47, .53)	<.001
Type of hospital
Tertiary general hospital	1
General hospital	.03 (.01, .08)	<.001
Type of cancer surgery
Lung cancer surgery	1
Gastric cancer surgery	.36 (.34, .38)	<.001
Colorectal cancer surgery	.46 (.44, .48)	<.001
Esophageal cancer surgery	3.04 (2.80, 3.30)	<.001
Small bowel cancer surgery	.80 (.73, .87)	<.001
Liver cancer surgery	.73 (.68, .77)	<.001
Pancreatic cancer surgery	.77 (.72, .82)	<.001
BD or GB cancer surgery	.42 (.39, .46)	<.001
Propofol-based TIVA	.86 (.82, .89)	<.001
VATS or laparoscopy	.57 (.55, .59)	<.001
CCI, point	1.03 (1.02, 1.03)	<.001
Disability at surgery
Mild to moderate	1.08 (1.03, 1.14)	.003
Severe	1.16 (1.05, 1.27)	.003
Year of surgery
2016	1
2017	1.10 (1.04, 1.16)	.001
2018	.98 (.93, 1.04)	.517
2019	1.11 (1.06, 1.17)	<.001
2020	1.09 (1.03, 1.15)	.001

OR, odds ratio; CI, confidence interval; BD, bile duct; GB, gallbladder; TIVA, total intravenous anesthesia; VATS, video-assisted thoracoscopic surgery; CCI, Charlson comorbidity index.

Discussion

In this population-based cohort study, 6.6% patients who underwent major cancer surgery were administered Mg sulfate during surgery. Factors, such as older age, higher CCI score, disabilities, open thoracotomy or laparotomy, and esophageal cancer surgery, were potentially associated with Mg sulfate administration in patients who underwent major cancer surgery.

Despite evidence of the benefits of Mg sulfate use for major cancer surgery or general anesthesia, Mg sulfate was used in only 6.6% of the major cancer surgeries. Certain barriers to the use of Mg sulfate under general anesthesia exist. In general, barriers to evidence-based practice include negative attitude, lack of education and training, and logistical difficulties concerning application.²⁷ Mg sulfate has been used more frequently in tertiary hospitals than in general hospitals following the adjustment of severity and age of patients, which could be related to the higher quality and quantity of systems and human resources in education, training, and research in tertiary general hospitals.²⁸

Mg sulfate is significantly cheap and beneficial in treating frequent hypomagnesemia related to surgery,⁸ is a frequently used medication²⁹ or is administered to treat cancer,¹ controls pain,^18,24 enhances the muscle relaxing effect of muscle relaxants,^30,31 and possibly has an anticancer effect.^1,5 It can be used more generally for anesthesia and surgery, especially in patients with a low CCI score. However, perioperative Mg supplementation was applied only to 6.6% of the major cancer surgeries for 5 years and was administered only to patients with higher CCI scores, older age, prolonged hospitalization, and higher total cost of hospitalization. This suggests that its use could be related to the therapeutic effects of Mg on arrhythmia or asthma in patients with more severe diseases. Mg ions are safe and effective in the prevention and treatment of cardiac arrhythmia such as atrial fibrillation.¹¹ Various electrophysiological actions of Mg ions affect the cardiac conduction system.¹² Mg therapy for cardiac arrhythmias has been effective in patients with hypomagnesemia. It can be effectively used for refractory ventricular tachycardia and ventricular fibrillation, decreasing the ventricular response in atrial fibrillation for Wolff–Parkinson–White syndrome, “torsades de pointes,” and digoxin poisoning.^11,32 Additionally, the mechanisms of action of Mg ions in acute asthma could be associated with cellular homeostasis, acetylcholine, histamine release, inhibition of bronchial smooth muscle contraction, and enhanced bronchodilation.³³ Mg ion administration has thus been accepted as a standard treatment for moderate-to-severe acute asthma in adult patients.^13-15

Increased Mg sulfate use is associated with open surgery compared to VATS or laparoscopic surgery. Open surgery is significantly more painful than minimally invasive surgeries, such as VATS or laparoscopic surgery.³⁴ Patients can experience additional pain relief from Mg during open surgery. The adjuvant role of Mg sulfate in perioperative analgesia is attracting the anesthesiologists’ attention.²⁰ Mg ions appear to be effective in controlling perioperative pain and autonomic, somatic, and endocrine reflexes to noxious stimuli.^18-20 A reduction in intraoperative and postoperative opioids is observed with intraoperative Mg IV infusion.^19,21-24 Mg ions block N-methyl-D-aspartate receptors and inhibit the influx of calcium ions into cells and lead to analgesia, despite no direct effect on analgesia. This could be associated with reduced central sensitization.²⁵ However, since Mg sulfate can help secure the surgical field by inducing a deep neuromuscular block,³⁵ it could be a useful option in laparoscopic cancer surgery. Thus, the use of Mg sulfate for laparoscopic cancer surgery could be increased in the future.

In lung cancer surgery, Mg sulfate plays a significant role in controlling arrhythmia, dilating the bronchus, and controlling postoperative pain.⁷ Atrial fibrillation, which occurs frequently after lung cancer surgery, is associated with increased morbidity and mortality.³⁶ Mg sulfate is an effective and safe drug of choice for preventing and treating arrhythmic complications without lung complications, such as bronchospasm by beta blockers or pulmonary fibrosis by amiodarone.³⁶ This may explain why Mg was most frequently used in lung cancer surgery in the present study.

This study has certain limitations. First, we were unable to determine why anesthesiologists used Mg sulfate.²⁷ Anesthesiologists who did not use Mg sulfate might not be convinced by the benefits of Mg sulfate, or they were not familiar with using Mg sulfate as an adjunct and had no knowledge of an adequate method of using supplemental Mg sulfate intraoperatively. Second, the cancer stage, patients’ severity based on vital signs or laboratory results, and perioperative management and results, such as pain relief or antiarrhythmic effects, were not obtained via the NHIS database. However, this is the first study to investigate the use of Mg sulfate in major cancer surgeries. This result can be used for educating and spreading awareness concerning the use of Mg sulfate for major cancer surgery in the future. Second, since we included all adult patients who were admitted to the hospital and underwent major cancer surgery with curative intent between January 1, 2016 and December 31, 2020, we were unable to perform sample size calculation or justify the sample size in this study.

Conclusion

In conclusion, in South Korea, 6.6% of the patients who underwent major cancer surgery were administered Mg sulfate during surgery. Certain factors, such as old age, thoracic cancer surgery, open laparotomy or thoracotomy, more comorbid status, and inhalation anesthesia, were potentially associated with Mg sulfate administration in patients who underwent major cancer surgery. Since no current guideline recommending the use of perioperative Mg sulfate in cancer surgery exists, our study is the first study to reveal the trends and factors associated with Mg sulfate administration for cancer surgery in a real-world clinical setting. Therefore, our study may provide rationale for future research in patients who may benefit from Mg sulfate administration for cancer surgery.

Supplemental Material

Supplemental Material - Trends in Perioperative Magnesium Sulfate Use in Patients Who Underwent Major Cancer Surgery: A Retrospective Population-Based Cohort Study in South Korea

Supplemental Material for Trends in Perioperative Magnesium Sulfate Use in Patients Who Underwent Major Cancer Surgery: A Retrospective Population-Based Cohort Study in South Korea by In-Ae Song, Tak-kyu Oh and Sang-Hwan Do in Cancer Control

Footnotes

Acknowledgments

None.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Tak-kyu Oh

Sang-Hwan Do

Supplemental Material

Supplemental material for this article is available online.

Appendix

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