This study demonstrate that high doses of magnesium reduce microalbuminuria in traumatic critically ill patients at 36 hour post infusion. Although no significant difference observed among trends, there was a positive trend toward better outcomes in treatment groups in total antioxidant power, lipid peroxidation and TNF-α between treatment and placebo groups.
Microvascular changes induced by nitric oxide (NO) and other proinflammatory factors and their interaction with leukocytes amplify inflammatory response in SIRS patients. Endothelial cells could be injured through inflammatory response and cause an increase in capillary permeability particularly in glomerular vessels which induces kidneys to undergo transient proteinuria. The deleterious scale of these changes can be measured by increased levels of microalbuminuria. The population enrolled in this study was homogenous and consisted of neurotraumatic critically ill only. The purpose of this study is to evaluate the efficacy and rational of magnesium infusion on neurotraumatic patients. In traumatic condition, an energy depletion dilemma emerges in cellular level. The consequence of this depletion is reduction in activity of transmembrane calcium ion transport channels which leads to distorted ion balance and permeability changes. Membrane permeability changes cause calcium influx in cells, which results in many deleterious reactions such as alternation of adenosine triphosphate (ATP) production in mitochondria, overproduction of reactive oxygen species (ROS), NO generation and release of proinflammatory factors[1, 2]. Magnesium could serve as antagonist of calcium to inhibit these harmful effects in traumatic patients.
In previous animal studies it was demonstrated that hypomagnesaemia can cause systemic inflammatory syndrome. Magnesium deficiency opens N-methyl-D-aspartate (NMDA) calcium channels and activates nuclear factor-kappa B (NF-kB) as primary mechanism of inflammation. However, in this study after magnesium infusion, the levels of TNF-α, total antioxidant power and lipid peroxidation did not demonstrate any significant change at various periods of analysis. Therefore, administration of magnesium salt did not display any anti-inflammatory activities in critically ill patients with normal levels of this ion. Effect of body magnesium levels (plasma, erythrocyte and urine) and its association with microalbuminuria has been previously studied on type 1 diabetic patients. A negative relation between erythrocyte magnesium level and microalbuminuria was observed suggesting hypomagnesaemia as a risk factor for proteinuria in diabetic patients. In another study, it was suggested that hypomagnesaemia is an independent risk factor for microalbuminuria in type two diabetic patients. In the present study there has been a lag about 48–72 hour between hospital and ICU admission that might be the time that most critical changes in level of TNF-α and oxidative marker occurred and thus less significant changes were observed subsequently. As we mentioned in previous study with cytokines determination of cutoff point for cytokine measurement in ethnic populations remained unclear and problematic. Our previous study verified that N-acetylcysteine performs as a free radical scavenger and an anti-inflammatory agent and improves microalbuminuria in acute respiratory distress syndrome patients. It has been illustrated that severity of microalbuminuria has a direct relationship with mortality and morbidity rates[9, 16]. Although, no significant change in TNF-α and oxidative factors showed up in the study time window, the change in microalbumin suggests that inflammation has been reduced in the high dose treatment subjects. In order to omit the bias of hypomagnesaemia effect on proteinuria, patients with normal levels of serum magnesium were allowed to be enrolled in this clinical study. Magnesium total serum concentration is the most studied laboratory parameter and considered poorly related to cellular status of magnesium in the patient’s body. Magnesium loading test or ionized serum magnesium concentration is used for evaluation of magnesium sufficiency in the body. Magnesium loading test was not utilized for evaluation of magnesium status in this study because patients received a large dose of magnesium before enrollment in the study and the result would be compromised and unreliable. Therefore, ionized serum magnesium test was utilized in order to establish magnesium status. Ionized serum magnesium test has been applied to establish magnesium status instead of magnesium loading test due to limitation of previous magnesium intake. In this study, the serum albumin concentration was assessed prior to the evaluation of magnesium status. High levels of albumin may interfere with ionized serum magnesium test and may negatively impact the accurate evaluation for microalbuminuria.
Although, management of patients in ICU is somehow complicated and dependent of the status of each patient, it was decided to use an established protocol as a base amount for moderate dose of magnesium that was safe over the years in ICU. Two fold of that dose has been assumed as high dose of magnesium for this study. The positive effect of magnesium dosing in critically ill patients is under debate and the results are controversial. Determination of a specific dose was difficult because compensation for magnesium depletion was not the aim of this study. The normomagnesemic populations have never been studied before to the extent of our knowledge. Therefore, clinically significant results would be due to the theoretical role of magnesium. There were no significant difference among groups during time, but after 36 hours, the MACR in high dose magnesium group was significantly lower than control group (Figure1).
Mild bradycardia and hypotension were the only side effects observed in patients who received magnesium. Therefore we suggest that magnesium doses as high as the ones used in this study are relatively safe for infusion of critically ill patients. However magnesium therapy should be considered in special populations. Magnesium is generally cleared by kidneys and magnesium therapy in higher doses should be administered with more caution in patients with any risk of renal failure.
Administration of magnesium as a therapeutic agent is not a common approach, but it is routinely employed to correct the hypomagnesemic state. In this study magnesium sulfate infusion was administered as an anti-inflammatory therapeutic agent and some optimistic results were obtained. In order to obtain a more definitive conclusion, another more elaborated clinical trial is recommended.
There was a beneficial trend toward high magnesium load where we left the study (Figure1). The number of subjects and the duration of study were limited in this trial. The results could not be generalized to the population in this condition, but it is recommended to conduct more studies with longer duration and greater sample size. It is also recommended to infuse magnesium in longer duration and more divided intervals.