Association of Serum Magnesium and Blood Pressure in Patients with Hypertensive Crises: A 2 Retrospective Cohort Study

49 50 Background: The role of magnesium in blood pressure has been studied among hypertensive patients, 51 however, no study has explored the role of magnesium in hypertensive crises. The primary objective of 52 this study is to evaluate the relationship between serum magnesium and blood pressure in patients with 53 hypertensive crises. 54 55 Methods: This study is a single-center, retrospective, chart review, cohort study of patients with 56 hypertensive crises. Patients were included in the study cohort if they were eighteen years of age or 57 older with an international classification disease ninth revision (ICD-9) code of 401.9 (hypertensive 58 crises: emergency or urgency) and a documented magnesium level on their electronic medical record. 59 The primary outcome of the study was to assess the correlation between serum magnesium on blood 60 pressure (systolic blood pressure and diastolic blood pressure) in patients with hypertensive crises. The 61 secondary outcomes were to assess the association between serum calcium, corrected calcium, and 62 serum potassium on blood pressure in patients with hypertensive crises and to determine the effects of 63 covariates in modulating the relationship between serum magnesium and blood pressure. Results: Two hundred and ninety-three included in the study. The primary outcome result showed that serum magnesium was positively correlated with systolic blood pressure (r=0.143, p=0.014), but not diastolic blood pressure. Serum calcium was also found to be positively correlated with systolic blood pressure, but not diastolic blood pressure. After adjusting for covariates in the solution for fixed effects analysis, serum magnesium, serum calcium, corrected calcium, and use of home proton pump inhibitors were correlated with systolic blood pressure at crises; while age, serum calcium, and corrected calcium were significantly correlated with diastolic blood pressure at crises. Conclusion: This study found a significant positive association between magnesium and systolic blood 74 pressure, but not diastolic blood pressure among patients with hypertensive crises. This positive 75 association of serum magnesium with systolic blood pressure was maintained after adjusting for 76 covariates. This study findings suggests a potential role of magnesium in blood pressure among patients 77 with hypertensive crises. Future studies should evaluate the role of serum magnesium modifying 78 therapies in controlling blood pressure in patients with hypertensive crises. This study found a significant positive association between magnesium and systolic blood pressure, but not diastolic blood pressure among patients with hypertensive crises. This positive association of serum magnesium with systolic blood pressure was maintained after adjusting for covariates. This study suggests a potential role of magnesium in blood pressure among patients with hypertensive crises. Large sample experimental studies are needed to evaluate the role of serum magnesium therapies in controlling blood pressure in patients with hypertensive crises. Future studies should also evaluate the role of serum calcium modifying therapies in blood pressure control in patients hypertensive crises.


Introduction 97
Magnesium is the second most abundant intracellular cation after potassium and the fourth most 98 abundant cation in the body (1-3). In adult humans, total body magnesium store is approximately 24 99 grams with 99% existing intracellularly [bone (53%), muscle (27%), and soft tissue (19%)] and 1% existing 100 in the extracellular space (serum and erythrocytes) (1,2). Normal total serum concentration is in the 101 7 inhibitor (17,18). Magnesium is also an essential cofactor for delta-6-desaturase enzyme which converts 145 linoleic acid to gamma linolenic acid, a precursor to prostaglandin E (17,18). Additionally, a strong 146 interaction has been found between magnesium and other electrolytes (potassium, calcium, and 147 sodium) in blood pressure reduction; with reduction of intracellular sodium and calcium, and increases 148 in intracellular magnesium and potassium shown to improve blood pressure (17,18). 149 150 Several observational clinical studies and a meta-analysis have evaluated the relationship between 151 serum magnesium and blood pressure in patients with and without hypertension (12,14,25,15,16,19-152 24); however, no published study to our knowledge has evaluated serum magnesium and blood 153 pressure relationship among patients with hypertensive crises. The available published studies 154 performed tests of association (correlation, odds ratio, risk ratios, and hazard ratios) between 155 magnesium and either blood pressure or hypertension (12,14,25,15,16,(19)(20)(21)(22)(23)(24). Among the ten studies 156 that performed a test of association between serum magnesium and either blood pressure or 157 hypertension, six studies found a significant negative association (14-16,20,21,24), three studies found 158 no significant relationship (12,19,23), and one study found a significant positive correlation between 159 serum magnesium and blood pressure in women only (25). The meta-analysis by Han  blood pressure has been studied extensively. Nine out of the ten studies (clinical trials, Cochrane Review 167 and meta-analyses) reviewed showed mostly positive association/effect of magnesium supplementation 8 in lowering SBP, DBP, or both (22,26-33); and only one study found no significant effect of magnesium 169 supplementation on blood pressure (34). This prevailing positive effect of magnesium supplementation 170 in lowering blood pressure proved compelling and served as the foundational rationale for our study 171 evaluating whether serum magnesium is a factor that contributes to the dysregulated high blood 172 pressure seen in patients with hypertensive crises. We hypothesized that low serum magnesium will be 173 significantly associated with blood pressure (SBP and DBP) in patients with hypertensive crises. 174

175
The primary objective of this study is to evaluate the correlation between serum magnesium and blood 176 pressure (SBP and DBP) in hypertensive crises. Secondary objectives were to evaluate the association 177 between serum calcium, corrected calcium, and serum potassium on blood pressure in patients with 178 hypertensive crises, and to determine the effects of covariates [age, sex, race, body mass index (BMI), 179 history of diabetes mellitus, use of proton pump inhibitors at home, use of blood pressure medications 180 at home or hospital, use of oral magnesium at home, use of intravenous magnesium at hospital, serum 181 calcium at crises, corrected calcium at crises, and serum potassium at crises] in modulating the 182 relationship between serum magnesium and blood pressure. inotropes or vasopressors (including epinephrine, norepinephrine, dopamine, phenylephrine, 232 vasopressin, dobutamine, or milrinone) during the hospital encounter were excluded from the study. 233 234 All patient data was obtained from ILH's electronic medical record. The following demographic data was 235 collected: age, sex, race, body mass index (BMI), and history of diabetes mellitus. Outcome variables 236 collected included serum magnesium (mg/dL), serum calcium (mg/dL), serum potassium (mEq/L), SBP 237 (mmHg), and DBP (mmHg). All outcome variables were collected at a time closest to the first 238 documented hypertensive crises' blood pressure during the hospital encounter and is denoted as "at 239 crises". Additionally, maximum and minimum values of SBP and DBP were recorded within 24-hours of 240 the first recorded hypertensive crises' blood pressure. Corrected calcium (mg/dL) was calculated using 241 the formula: corrected calcium = patient's measured serum calcium in mg/dL + (0.8 * (4 gm/dL -242 patient's measured albumin in gm/dL)). The corrected calcium was only calculated for patients whose 243 serum albumin was less than 4 gm/dL. Additional predictor variables collected include: home and 244 hospital use of blood pressure medications [inclusive of all blood pressure medication classes (for 245 example: calcium channel blockers) grouped in the electronic health record], at home use of proton 246 pump inhibitors, home use of oral magnesium, hospital use of intravenous magnesium, and albumin 247 levels (gm/dL). 248 249

Outcomes 250
The primary outcome of the study was to assess the correlation between serum magnesium on blood 251 pressure (SBP and DBP) in patients with hypertensive crises. The secondary outcomes of this study were 252 to evaluate the association between serum calcium, corrected calcium, and serum potassium on blood 253 pressure in patients with hypertensive crises, and to determine the effects of covariates (age, sex, race, 254 BMI, history of diabetes mellitus, use of proton pump inhibitors at home, use of blood pressure 255 medications at home or hospital, use of oral magnesium at home, use of intravenous magnesium at 256 hospital, serum calcium at crises, corrected calcium at crises, and serum potassium at crises) in 257 modulating the relationship between serum magnesium and blood pressure. An additional exploratory 258 outcome was to perform correlation analyses of serum magnesium, serum calcium, corrected calcium, 259 and serum potassium on the two independent variables: SBP and DBP measured at different time

Statistical Analyses 265
We performed a power analysis based on findings of our primary outcome variables (serum magnesium, 266 SBP, and DBP) from prior studies.(16,26,28) Based on these studies, we estimate that the R 2 (coefficient 267 of determination) for the linear regression between serum magnesium and either SBP or DBP will range 268 between of 0.06 -0.56. Our power analysis revealed that the target sample size for this study will range 269 between 140 -180 subjects, to give us a power of 0.80 at a significance level of 5%.     Covariates in the Mixed Model -Age, sex, race, history of diabetes, BMI, use of proton pump inhibitors at home, use of blood pressure medications at home or hospital, use of oral magnesium at home, use of intravenous magnesium at hospital, serum magnesium at crises, serum calcium at crises, corrected calcium at crises, and serum potassium at crises.
Alpha of < 0.05 defined as significant for best predictor variables.  Eight-hundred and thirty-seven patients who had a serum magnesium level and an ICD-9 code of 401.9 368 or a diagnosis of hypertensive crises, hypertensive urgency, and hypertensive emergency were identified 369 from ILH's electronic medical record (Figure 1). 544 patients were excluded after applying the study 370 exclusion criteria and 293 patients were included in the statistical analysis (Figure 1)