Retrospective analysis of the association between intraoperative magnesium sulfate infusion and postoperative acute kidney injury after major laparoscopic abdominal surgery

Magnesium sulfate can be used as a co-adjuvant drug during the perioperative period and has multiple benefits. Recent evidence suggested that perioperative magnesium sulfate infusion may lower the risk of postoperative acute kidney injury (AKI). We investigated the association between intraoperative magnesium sulfate infusion and incidence of AKI after major laparoscopic abdominal surgery. We retrospectively analyzed the medical records of adult patients 20 years or older who underwent elective major laparoscopic abdominal surgery (>2 hours) between 2010 and 2016. We investigated the association between intraoperative magnesium sulfate infusion and the incidence of postoperative AKI until postoperative day (POD) 3 using a multivariable logistic regression analysis. We included 3,828 patients in this analysis; 357 patients (9.3%) received an intraoperative magnesium sulfate infusion and 186 patients (4.9%) developed postoperative AKI by POD 3. A multivariable logistic regression analysis showed that magnesium infusion was associated with a significant decrease (63%) in postoperative AKI (odds ratio, 0.37; 95% confidence interval, 0.14–0.94; P = 0.037). Our study suggested that intraoperative magnesium sulfate infusion is associated with a reduced risk of postoperative AKI until POD 3 for patients who underwent laparoscopic major abdominal surgery. Well-designed, prospective studies should be conducted to further substantiate these findings.

study reported that premedication of intravenous magnesium lowered cisplatin-induced nephrotoxicity in cancer patients 19 . However, the renoprotective effects of magnesium sulfate remain controversial, and there is insufficient evidence to support its efficacy. In particular, the association between magnesium sulfate infusion during the perioperative period and postoperative AKI remains largely unknown.
Therefore, this study investigated the association between magnesium sulfate infusion during surgery and postoperative AKI for patients who underwent laparoscopic major abdominal surgery.

Discussion
This study suggested that intraoperative magnesium sulfate infusion is associated with a lower incidence of AKI on POD 0-3 after a major laparoscopic abdominal surgery. Our findings are meaningful because this study only included laparoscopic surgical procedures, which are increasingly becoming more popular because of their ability to facilitate recovery 20 ; other potential risk factors (e.g., antibiotics, radiocontrast, anemia) that may be associated with AKI until POD 3 were also included in the analysis.
The significant association between magnesium sulfate infusion and a lower risk of postoperative AKI may be attributable to several factors. First, the renoprotective effects of magnesium against hypoxic renal tissue injury, which has been suggested based on in vitro and animal studies, have had a role in the lower risk 16,17 . Previous studies showed that magnesium sulfate was associated with protection against oxidative damage from acute renal ischemia 16,17 . Based on this assumption, magnesium was reported to be associated with renoprotective effects against cisplatin-induced AKI 19,21 , contrast-induced AKI 22 , and diabetic nephropathic kidney injury 18 . In our study, patients were exposed to several agents that could induce nephrotoxicity on POD 0-3, including non-steroidal anti-inflammatory drugs, radiocontrast, antibiotics or antiviral drugs, and hypotension or anemia. The nephrotoxicity of these clinical events is associated with oxidative renal injury, and the infusion of magnesium sulfate may protect the renal system following the induction of nephrotoxicity on POD 0-3.
According to an animal study, magnesium is known to have anti-inflammatory effects 23 . A recent in vivo study showed that magnesium sulfate attenuated the inflammatory response of the placenta perfused with lipopolysaccharide 24 . Because inflammation is related to the pathophysiology of AKI 25 , the potential anti-inflammatory effects of magnesium sulfate might have been associated with postoperative AKI in this study. Although recent studies reported potential renoprotective effects of magnesium sulfate 18,26 , this is still a controversial issue, and further prospective clinical trials should be performed 14 .
Interestingly, this study found other potential risk factors for postoperative AKI, such as intraoperative vasopressor infusion, antibiotics or antiviral drug use, radiocontrast use, hydroxyethyl starch use, and exposure of anemia. Antibiotics or antiviral drug use, radiocontrast, anemia, and hydroxyethyl starch might have a role in nephrotoxicity itself, as reported in previous studies 27  www.nature.com/scientificreports www.nature.com/scientificreports/ starch could be used for patients who are critically ill during the perioperative period because of sepsis or shock. With perioperative shock or sepsis, postoperative AKI might occur frequently 28,29 . Therefore, these factors associated with postoperative AKI should be further interpreted.
This study has a clinical impact because it can be a useful reference for future prospective, randomized trials in the perioperative setting. Scientifically, sample size estimation is necessary to show the statistical significance of the results, if any, to avoid the recruitment of an excessively large sample cohort 30 . For example, with an objective of a 50% reduction in the incidence of postoperative AKI with a 0.05 chance of type 1 error and 80% power, using an incidence of 5.1% (observed in the total patients in this study), 848 patients in the magnesium group and the non-magnesium group are needed. To our knowledge, there was no background study that evaluated the effects of intraoperative magnesium sulfate infusion on the occurrence of postoperative AKI in the perioperative setting. Therefore, our results can contribute to the design of future prospective trial.
This study had a few limitations. First, there was a possibility of selection bias due to the retrospective nature of our study design. Second, the results may not be generalizable because this study was conducted at a single center. Third, we only used serum creatinine as the criterion for AKI diagnosis because we could not accurately measure the hourly urine output of the patients. Therefore, a considerable number of patients without serum creatinine data on POD 0-3 were excluded from this study. Finally, because we intended to relatively analyze the homogenous surgical population, many patients were excluded from this analysis, which limited its generalizability to other surgical populations. Nevertheless, this analysis is meaningful because it is the first human study performed in the perioperative setting that suggested the potential renoprotective effects of magnesium sulfate against postoperative AKI.
In conclusion, this study suggested that intraoperative magnesium sulfate infusion is associated with the reduced potential risk of postoperative AKI until POD 3 for patients who underwent laparoscopic major abdominal surgery. In the future, well-designed prospective studies should be conducted to further substantiate these findings.

Methods
This study was a retrospective cohort study that was approved by the Institutional Review Board (IRB) of Seoul National University Bundang Hospital (SNUBH) (approval number: B-1803/459-105; approval date: 2018.03.12). The informed consent requirement was waived by the IRB due to the retrospective nature of this study, and this work adhered to the applicable STROBE guidelines.

Patients.
The medical records of patients 20 years or older who underwent elective laparoscopic major abdominal surgery at SNUBH between January 1, 2010 and December 31, 2016 were analyzed. Major laparoscopic abdominal surgery was defined as a surgical procedure involving laparoscopy-guided resection of an intraperitoneal organ that lasted more than 2 hours. We included only laparoscopic procedures for two reasons. First, the performance of laparoscopic procedures has been continuously increasing, resulting in these procedures becoming the most common surgical technique 31 . Second, the reduction of surgical trauma and carbon dioxide pneumoperitoneum during laparoscopic surgery is known to attenuate immune-mediated inflammatory responses, which could affect the occurrence of AKI 32,33 .
Even when the surgery involved resection of the intraperitoneal organ that lasted for more than 2 hours, we excluded the following patients: patients who underwent emergency surgery; patients who underwent single-port laparoscopy due to the possibility of fewer inflammatory responses during surgery compared to multi-port laparoscopy; patients discharged by postoperative day (POD) 3; end-stage renal disease (ESRD) patients who underwent renal replacement therapy (RRT) during the preoperative period; patients who underwent nephrectomy www.nature.com/scientificreports www.nature.com/scientificreports/ or nephroureterectomy, which are surgical procedures that may affect renal functions; patients who underwent simple appendectomy or cholecystectomy; patients with incomplete medical records, including serum creatinine data; and patients who underwent intraoperative open conversion.
Laparoscopic major abdominal surgery at SNUBH. At SNUBH, experienced surgical teams proficiently resected major intraperitoneal organs (liver 34 , stomach 35 , colorectal surgery 36 ) during the study period. Anesthetic management generally involved balanced anesthesia using desflurane and remifentanil or total intravenous anesthesia using propofol and remifentanil. Table 1) at SNUBH for laparoscopic surgery with the intention of improvement of surgical space conditions and less postoperative pain 37 . In the operating room, magnesium sulfate was infused beginning from the induction of anesthesia until the end of surgery. When administering magnesium sulfate, a mixture of 50 mg kg −1 of magnesium sulfate in 100 mL isotonic saline was infused over 15 minutes during the induction of anesthesia, and the infusion rate was adjusted throughout the surgery using the reference rate of 15 mg kg −1 h −1 based on the patient's vital signs. If there was a complication due to magnesium sulfate infusion during surgery, such as hypotension, then adequate hydration or the use of a vasopressor was performed by the anesthesiologist. During the study period, there was no reported severe complication of magnesium sulfate infusion. We defined the magnesium sulfate group as the patients who received magnesium sulfate during surgery; the other patients were defined as the non-magnesium group.  www.nature.com/scientificreports www.nature.com/scientificreports/ Diagnosis of postoperative AKI on POD 0-3 (dependent variable). Postoperative AKI was diagnosed per the criteria and grading suggested by the Kidney Disease: Improving Global Outcomes (KDIGO) 38 . However, considering the varying periods of urinary catheter use across laparoscopic surgical procedures, only serum creatinine (not urine output) was used for a more accurate diagnosis of AKI. At SNUBH, serum creatinine (mg dL −1 ) is measured within 1 month of scheduled surgery for all patients who are scheduled to undergo an elective surgery. This measurement was defined as preoperative serum creatinine (that is, baseline serum creatinine).

Magnesium sulfate infusion during surgery (exposure group). Magnesium sulfate infusion for anesthesia was used mainly by S. H. Do (defined as anesthesiologist A in
AKI stage 1 was defined as a serum creatinine level exceeding 0.3 mg/dL or an increase in serum creatinine by 1.5-to 1.9-times that of the preoperative level. AKI stage 2 was defined as an increase in serum creatinine by 2.0to 2.9-times that of the preoperative level. AKI stage 3 was defined as serum creatinine level exceeding 4.0 mg/dL, an increase in serum creatinine by more than three-times that of the preoperative level, or a new round of RRT within 48 hours. These assessments and the diagnosis of postoperative AKI were performed from POD 0 to 3.

Covariates.
Patients' demographic, clinical, and surgery-related information were collected for analysis.
Preoperative kidney function was assessed based on the estimated glomerular filtration rate (eGFR) (mL min −1 1.73 m −2 ), which was calculated using the Modification of Diet in Renal Disease calculation 39 : 186 × (preoperative serum creatinine) −1.154 × (age) −0.203 × (0.742 if female). The performance of surgery by a staff anesthesiologist (anesthesiologist A and others) was also included as a covariate. In addition, we collected the following data, which may represent potential risk factors for postoperative AKI on POD 0-3: antibiotics or antiviral drug use (vancomycin, cephalosporin, aminoglycoside, rifampin, acyclovir, and sulfonamide); radiocontrast use; histamine 2 receptor antagonist or proton pump inhibitor use; development of intraoperative hypotension (mean blood pressure <60 mmHg over 1 minute); hydroxyethyl starch use; non-steroidal anti-inflammatory drug use; vasopressor use; and development of anemia (hemoglobin <10 g dL −1 ). Study endpoint. The purpose of this study was to examine whether the incidence of AKI was reduced during the 3 days after major laparoscopic abdominal surgery when magnesium sulfate was used for anesthetic management compared to when magnesium sulfate infusion was not used.

Statistical analysis.
Patients' baseline characteristics are presented as the number and percentage or mean and SD. Student's t-test and Chi-squared test were used for continuous and categorical variables, respectively, to compare the magnesium and non-magnesium groups. We first performed the univariable logistic regression   www.nature.com/scientificreports www.nature.com/scientificreports/ analysis to identify factors that may be associated with postoperative AKI. Next, after confirming that the covariates that satisfy P < 0.1 during the univariable logistic regression analysis had no problems with multicollinearity (variance inflation factors between variables <2.0), a final multivariable logistic regression analysis was performed with these covariates. The goodness of fit for each final multivariable logistic model was tested using the Hosmer and Lemeshow tests. Because AKI is related to preoperative kidney dysfunction 40 , we tested the interaction of intraoperative magnesium infusion with preoperative eGFR resulting in the occurrence of AKI to determine the necessity for a subgroup analysis. After confirming that there was no significant interaction between intraoperative magnesium infusion and preoperative eGFR resulting in the occurrence of AKI, we did not perform a subgroup analysis.
To detect a 3% difference in the incidence of postoperative AKI between the magnesium group and non-magnesium group with a 0.05 chance of a type 1 error and 80% power, a total of 3,839 patients (magnesium group, 349; non-magnesium group, 3,490) were needed. All statistical analyses were performed using IBM SPSS 24.0 software (IBM Corp., Armonk, NY); statistical significance was set at P < 0.05.

Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.