Introduction

Patients undergoing cardiac surgery are at a high risk of perioperative complications, including postoperative atrial fibrillation (POAF), one of the most common adverse events, with incidence rates ranging from 10 to 50%. [1–4] Since POAF can lead to significant morbidity and mortality [3–6], prevention is essential to improve outcomes. [7] The mechanistic basis of POAF remains an active area of research, with inflammatory processes, oxidative stress, changes in the autonomic nervous system, and changes of the membrane potential of cardiomyocytes recognized as important influencing factors. [8] One group of factors proposed as potential causes of POAF are electrolyte imbalances, such as hypomagnesemia, which might influence membrane potential. [9] The effect of perioperative magnesium administration has been studied in several randomized trials over the past few years. [10–12] However, such studies focused on total Magnesium levels (tMg) and did not investigate the levels of ionized magnesium (iMg), the physiologically active form. Thus, any effect these levels may have on the incidence of new-onset arrhythmias remains unclear. [13] In this study we investigate the association between serum magnesium levels at different time points and the occurrence of POAF following cardiac surgery, aiming to better describe the role of magnesium in the incidence of POAF, and to identify suitable time points for measurement and intervention.

Methods

Results

Two-hundred patients were enrolled in our study between August 2022 and February 2023 (Fig 1). The mean age of the participants was 67 years (SD 10.7 years), with 143 (70.8%) males. Approximately half of the patients underwent valve repair or replacement surgeries (57%), whereas the remaining patients underwent elective CABG. The baseline characteristics of the patients are summarized in Table 1.

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Table 1. Demographic data.

https://doi.org/10.1371/journal.pone.0345860.t001

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Fig 1. Participant flowchart.

https://doi.org/10.1371/journal.pone.0345860.g001

Overall, 55 patients (27.5%) developed POAF. Measurements of magnesium levels at the five pre-specified time points in all patients showed no statistically significant differences between patients who ultimately developed POAF and those who did not. However, there was a notable difference in the pre-specified subgroup of patients undergoing isolated CABG-surgery (baseline characteristics: S1 Table), where patients who developed new-onset POAF had higher mean plasma iMg concentrations at anesthesia induction, compared to those who did not develop POAF (mean iMg 0.71 mmol/L (SD 0.11) vs. 0.65 mmol/L (SD 0.07), P = 0.05). Concentrations of tMg at the same time point did not differ notably (mean tMg 0.86 mmol/L (SD 0.12) vs. 0.83 mmol/L (SD 0.07), P = 0.38). The outcomes of the whole cohort and subgroup analyses are summarized in Table 2.

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Table 2. Primary outcome.

https://doi.org/10.1371/journal.pone.0345860.t002

Discussion

No significant differences were observed in our study regarding iMg levels at any of the pre-specified time points or in the dynamics of magnesium levels between patients who developed POAF and those who did not, across a heterogeneous cohort of 200 patients undergoing open-chest cardiac surgery with cardiopulmonary bypass. We observed large interpersonal variations in plasma iMg levels throughout treatment course in our cohort. In patients who developed POAF, a trend toward higher mean postoperative iMg, but not tMg, levels was observed.

Exploratory subgroup analyses revealed that iMg levels could be indicative of an elevated risk for development of POAF in patients undergoing isolated CABG surgeries. In these patients, magnesium, as well as imbalances in magnesium levels can play a crucial role in the development of POAF [14,15]. In patients undergoing surgeries involving the electrophysiological structures of the heart, such as valve replacement, magnesium does not appear to play a key role. This could, in part, be due to the fact that structural changes affect the cardiac conductive system of the heart and may be the primary driver of POAF in this cohort, indicating a pathophysiologically different phenotype of POAF. The association between valve surgeries and disruption to the heart's conduction system has been well established [16], as has the fact that this association represents an individual risk factor for the development of POAF. These patients developed arrhythmias due to causes other than electrolyte imbalance. In our cohort, more than half of the patients underwent valve replacement or combined surgeries, which may hence have masked any notable effects across the entire cohort. Our data indicate that further investigation of the potential association between abnormal iMg levels and the onset of POAF is warranted, especially in patients undergoing CABG surgery. In these patients, there is a potential that measuring iMg levels offers added benefits over measuring tMg alone. However, the relatively small size of our cohort and the lack of statistical power to conclusively demonstrate this, precludes any definitive statement, and further research is needed. The role of serum magnesium levels has been discussed in the context of atrial fibrillation and other arrhythmias, both after cardiac surgery and in nonsurgical patients, mostly with regard to the administration of magnesium as a therapeutic agent. [9,17–20] In most studies to date, the target variable has been tMg concentration, and the findings are that hypomagnesemia is associated with new-onset POAF. Our data suggest that the pathophysiology might be more complicated, and more research is needed to validate the role of magnesium and its administration in enhancing perioperative safety for patients at risk of developing new-onset POAF. In addition, the risk factors for imbalance in iMg levels in patients undergoing cardiac surgery are not well defined, and require further investigation. Given that iMg is the electrophysiologically active form and can be measured at the point-of-care, a case could be made for it being at the center of physicians’ and researchers’ considerations regarding magnesium status and supplementation in patients at risk of POAF. [21,22]

Our study has several limitations that have to be considered when interpreting the results. First, this was a small exploratory study without prespecified power calculation and results should strictly be considered as hypothesis-generating. Further, patients with POAF and those without differed on some baseline variables (e.g., for baseline Euroscore and CKD-incidence). Also, no long-term follow-up of patients was done and we do not provide data on POAF incidence at hospital discharge. However, this study also has its strengths as iMg-levels and POAF in cardiac surgery patients have not yet been studied conclusively. Hence, this study provides preliminary data on iMg levels that can be anticipated at different time points in patients undergoing cardiac surgery, as well as data on dynamic changes, offering insight into time windows for potential interventions. These findings can be used in future studies to help demonstrate the effects of iMg levels on the occurrence of POAF and further patient-centered outcomes, depending on individual risk profiles. Therefore, future trials should adopt individualized intervention designs, aligned with the tenets of precision medicine to determine when, in whom, and how much magnesium should be administered and which iMg levels to target.

Supporting information