In this retrospective study, a total of 8175 patients were analyzed, and the proportions of patients with hypo-, normo-, and hypermagnesemia were 22.87%, 66.84%, and 10.29%, respectively. Of note, hypermagnesemia was significantly associated with both 28-day and 90-day mortality of septic patients when adjusted for cofounders. Unexpectedly, septic patients with subsequent hyper- and even still hypomagnesemia who received MgSO4 supplementation were found to have a significantly increased risk of 28-day and 90-day mortality.
Mg, the so-called “the forgotten electrolyte”, is an essential element of life support[17, 18]. Magnesium disorders are commonly reported in critically ill patients and a great number of patients are characterized by hypomagnesemia, with a range of 22% and 60%. Our study confirmed that the morbidity of hypomagnesemia is as high as 22.87%, which was consistent with a previous report. Interestingly, the incidence of hypermagnesemia was almost one-half that of hypomagnesemia in septic patients. Perhaps due to the low incidence of hypermagnesemia in the past, we ignored this type of electrolyte disorder. There is no magnesium regulatory system other than urinary excretion, and Mg levels rise as kidney function declines. Unfortunately, more than 50% of the causes of acute kidney injury (AKI) are sepsis , and AKI may result in hypermagnesemia in septic patients. Due to the development and popularity of CRRT, hypermagnesemia was less frequent than hypomagnesemia.
Notably, both hypomagnesemia and hypermagnesemia are associated with disease severity and various clinical symptoms, including cardiac arrhythmias, neurotoxicity, diminished deep tendon reflexes, muscle weakness and even cardiac arrest. Several studies revealed that hypomagnesemia was associated with increased mortality and poor prognosis in critically ill patients with a higher prevalence of severe sepsis and septic shock[11, 15]. For example, a prospective observational study showed that patients who developed hypomagnesemia had significantly longer ICU stays and higher mortality. Limaye et al demonstrated that patients with hypomagnesemia needed longer mechanical ventilation support and had higher mortality than those with normal Mg levels. Similarly, two studies[22, 23] on a relatively large number of patients also concluded that hypomagnesemia was associated with higher mortality. Studies have shown that hypomagnesemia increases the mortality of patients, and a small number of studies have also found that hypermagnesemia can increase the mortality of patients. In a cross-sectional study by Haider et al, the authors analyzed baseline Mg concentrations of over 5000 patients and showed that hypermagnesemia was a strong independent risk factor for mortality in a multivariate Cox regression model. Our study evaluated the time-weighted Mg value because this would reflect the total Mg exposure during their ICU stay, which we believe would be more representative to reveal the association between Mg and mortality. Unexpectedly, hypermagnesemia was significantly associated with increased 28-day and 90-day mortality. In addition, to explore the nonlinear relationship between Mg and our primary endpoints, we used restricted cubic splines based on a time-dependent model, and the results of the spline model were the same as those of the Cox model. For further confirmation of our results, we developed sensitivity analyses from different views and obtained similar results.
Therefore, combined with our study, hypomagnesemia was not associated with mortality while hypermagnesemia was harmful to septic patients. The reasons may be as follows. At the acute phase of sepsis, the acquired causes of hypomagnesemia can be attributed to decreased oral intake or gastrointestinal absorption, or redistribution triggered by severe illness, or liquid dilution during fluid resuscitation[25, 26]. We may speculate that low levels of serum Mg could be relatively transient and be adjusted or even reversed with the onset of AKI or subsequent supplementation with magnesium sulfate. Previous studies[3, 11, 27] mainly focused on baseline Mg concentrations at admission, which would not reflect the whole level of Mg, thus ignoring some potential risk factors during the development of sepsis that could influence the mortality rate. Hypermagnesemia might cause severely lowered blood pressure, bradycardia, respiratory paralysis, coma, and cardiac arrest, which might aggressively deteriorate sepsis development. The excretion of Mg is controlled primarily by the kidney, which is one of the most vulnerable organs during the development of sepsis. Hypermagnesemia may be associated with acute kidney injury and thus cause poor prognosis in septic patients. Since the impact of hypermagnesemia in septic patients has been studied less than hypomagnesemia, the specific mechanism of hypermagnesemia on body function remains unclear.
Since the treatment of hypomagnesemia remains unclear, we further explored the effects of Mg supplements (magnesium sulfate, MgSO4) on the relationship between serum Mg levels and mortality. Considering the different timings of Mg supplementation in different patients, we assessed Mg levels in a time-fixed and time-varying manner. A time-fixed manner regarded baseline Mg levels before receiving magnesium sulfate and a time-varying manner was presented as the Mg levels after magnesium sulfate supplementation. Interestingly, in our present study, Mg levels of the pre-MgSO4 supplement were not associated with mortality when adjusted for confounders, however, after the administration of the MgSO4 supplement, the subsequent hyper- and hypomagnesemia were associated with increased 28-day and 90-day mortality. The further spline model showed similar results. This result indicated that supplementation with magnesium sulfate might be positively associated with the mortality of septic patients. Although there is an ongoing argument that mild hypermagnesemia may be beneficial to patients because of the anti-inflammatory, antioxidant, and anti-apoptotic effects of Mg[32, 33], we still emphasize that clinical physicians should be cautious about Mg oversupplementation in septic patients. Since kidneys are vulnerable during sepsis, and patients with kidney function impairment are at risk for severe hypermagnesemia if large doses of Mg are given, supplementation could cause poor manifestations. In addition, we could not analyze the bolus speed and doses of MgSO4 supplementation or the timing of subsequent Mg concentration monitoring, and we can only speculate that the speed and doses may affect the relationship between Mg levels and mortality. Of note, serum Mg levels do not correlate well with total body stores, as the majority are intracellular, and serum concentrations may be transiently elevated for a few hours after administration of an IV dose. Therefore, we suggest that Mg levels should be measured daily or more frequently and be controlled more strictly in septic patients receiving magnesium sulfate therapy.
There are some limitations of this study. First, we could only evaluate serum Mg levels during the whole ICU stay due to the lack of total reported Mg and ionized Mg levels. Some studies revealed that ionized Mg might be a more physiologically relevant marker than total Mg levels[10, 34, 35]. Studies on total Mg and ionized Mg in septic patients should be performed to further disclose the relationship between Mg levels and mortality rates. Second, we did not take into consideration the association between Mg abnormalities and acute kidney injury. Third, we did not analyze the degree of hypo- or hypermagnesemia, or the relevant poor outcomes, since patients with different degrees of hypo- or hypermagnesemia may exhibit different symptoms and thus have various prognoses. Fourth, this study was observational and could not demonstrate the causal-relationship between Mg levels and outcome. Fifth, although we adjusted for potential confounding factors, there might also be residual confounding factors. Sixth, as we can see in spline analysis, the confidence intervals were wide at higher magnesium due to its sparse sample size. Thus, the results with extreme levels of potassium should be interpreted with caution.