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Importance of magnesium sulfate supplementation in the prevention of hypomagnesemia and hypocalcemia during chemoradiation in head and neck cancer.
Grašič Kuhar, C, Strojan, P, Zadnik, V, Zakotnik, B
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS). 2018;:327-331
Abstract
In advanced squamous cell carcinoma of the head and neck, concomitant radiotherapy with cisplatin and/or cetuximab is frequently combined with cisplatin-based induction chemotherapy, which can cause severe hypomagnesemia, hypocalcemia, and hypokalemia. The aim of our study was to analyze the effects of magnesium sulfate supplementation on the incidence of hypomagnesemia, hypokalemia, and hypocalcemia during four cycles of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy followed by concomitant radiotherapy (CRT) with cisplatin and cetuximab. Twenty-five patients included in a phase II prospective study received routine magnesium sulfate infusions before each cycle of cisplatin, and additional supplementation based on laboratory findings. During TPF, the incidence of grade 1/2 and grade 3/4 hypomagnesemia was 16% and 4%, respectively; and increased despite magnesium supplementation during CRT to 72% and 8%, respectively. During TPF, a grade 2 and grade 4 hypocalcemia occurred in 8% and 4%, respectively; and during CRT, it reached 36% (grade 1/2). Grade 1 hypokalemia only was observed during TPF (4%) and CRT (8%). The median amounts of supplemented magnesium sulfate during TPF and CRT were 20 mEq and 50 mEq, respectively. It appears that a low incidence of grade 3/4 hypomagnesemia and hypocalcemia in our patients resulted from intensive magnesium supplementation. Thorough measurements of magnesium and calcium during cisplatin-based chemoradiation protocols in patients with head and neck cancer are crucial in preventing the development of grade 3/4 hypomagnesemia and hypocalcemia.
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Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT.
Hochster, HS, Grothey, A, Hart, L, Rowland, K, Ansari, R, Alberts, S, Chowhan, N, Ramanathan, RK, Keaton, M, Hainsworth, JD, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2014;(6):1172-8
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Abstract
BACKGROUND Oxaliplatin is an integral component of colorectal cancer treatment, but its use is limited by neurotoxicity. The Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT) tested intermittent oxaliplatin (IO) administration and the use of concurrent calcium and magnesium salts (Ca/Mg), two modifications intended to reduce neurotoxicity and extend the duration of treatment. PATIENTS AND METHODS In this trial involving double randomization, 140 patients were randomized to receive modified FOLFOX7 plus bevacizumab with IO (eight-cycle blocks of oxaliplatin treatment) versus continuous oxaliplatin (CO); and Ca/Mg versus placebo (pre- and postoxaliplatin infusion). The primary end point was time-to-treatment failure (TTF). RESULTS One hundred thirty-nine patients were entered and treated up to the point of early study termination due to concerns by the data-monitoring committee (DMC) that Ca/Mg adversely affected tumor response. Tumor response was not a study end point. Given DMC concerns, an additional independent, blinded radiology review of all images showed no adverse effect of treatment schedule or Ca/Mg on response by Response Evaluation Criteria In Solid Tumors. The IO schedule was superior to CO [hazard ratio (HR) = 0.581, P = 0.0026] for both TTF and time-to-tumor progression (TTP) (HR = 0.533, P = 0.047). CONCLUSIONS An IO dosing schedule had a significant benefit on both TTF and TTP versus CO dosing in this trial despite the very attenuated sample. There was no effect of Ca/Mg on response.
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The effect of intravenous magnesium sulfate on serum levels of N-terminal pro-brain natriuretic peptide (NT pro-BNP) in elective CABG with cardiopulmonary bypass.
Dabbagh, A, Bastanifar, E, Foroughi, M, Rajaei, S, Keramatinia, AA
Journal of anesthesia. 2013;(5):693-8
Abstract
INTRODUCTION Nowadays, many patients undergo coronary artery bypass grafting (CABG) with a cardiopulmonary bypass (CPB); while a number of therapeutic agents have been used to suppress its related inflammatory process. Magnesium sulfate (MgSO4) solution has been used as an anti-inflammatory agent. Among the cardiac biomarkers, N-terminal pro brain natriuretic peptide (NT Pro-BNP) is one of the most widely recognized. We performed this study to assess the effect of MgSO4 solution on NT Pro-BNP levels in patients undergoing CABG with CPB. MATERIALS AND METHODS In a double-blind clinical trial, after IRB approval for ethical considerations, during a 12-month period, 88 adult patients aged 40-70 years qualified for the study after inclusion and exclusion criteria were considered. After random allocation of the patients between the two groups, anesthesia, surgical procedure, cardiopulmonary bypass (CPB) methods, and postoperative care were made as similar as possible; however, one group received a MgSO4 infusion (15 mg/kg/h) and the other group saline (placebo). Pre- and post-operative levels of NT Pro-BNP were assessed using an electrochemical luminescence immunoassay in an Elecsys 2010 (Roche, Indianapolis, IN, USA). The results were compared using a Student's t-test. A P value less than 5% was considered significant. RESULTS The MgSO4 group had shorter postoperative mechanical ventilation, lower postoperative morphine requirements and lower postoperative pain scores. Also, 24 h postoperative NT Pro-BNP levels were significantly lower in the MgSO4 group. CONCLUSION Administration of MgSO4 in elective CABG with CPB can decrease the postoperative NT Pro-BNP levels; also, it decreases their time of postoperative mechanical ventilation.
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Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study.
Rex, DK, Katz, PO, Bertiger, G, Vanner, S, Hookey, LC, Alderfer, V, Joseph, RE
Gastrointestinal endoscopy. 2013;(1):132-41
Abstract
BACKGROUND New bowel cleansers for colonoscopy that lead to improved efficacy, safety, and tolerability are needed. OBJECTIVE This study evaluated a nonphosphate, dual-action, low-volume, orange-flavored preparation containing sodium picosulfate and magnesium citrate (P/MC). DESIGN Multicenter, assessor-blinded, randomized, noninferiority study. SETTING University hospitals, academic medical centers, and private clinics across the United States. PATIENTS Adults preparing for colonoscopy. INTERVENTIONS P/MC versus 2 L of polyethylene glycol solution (2L PEG-3350) and two 5-mg bisacodyl tablets. MAIN OUTCOME MEASUREMENTS This phase 3 study investigated the efficacy, safety, and tolerability of split-dose administration of P/MC versus day-before dosing of 2L PEG-3350 and two 5-mg bisacodyl tablets (SEE CLEAR I study). Efficacy was evaluated by using the Aronchick and Ottawa scales; noninferiority and superiority analyses were performed. Safety was assessed by monitoring adverse events (AEs). Tolerability was measured via a patient questionnaire. RESULTS The intent-to-treat population consisted of 601 patients who self-administered P/MC (n = 304) or 2L PEG-3350 and bisacodyl tablets (n = 297). P/MC was superior to 2L PEG-3350 and bisacodyl tablets in overall colon cleansing (84.2% vs 74.4%; 1-sided 97.5% confidence interval [CI], 3.4) (Aronchick scores of excellent or good) and in cleansing of the ascending (89.5% vs 78.8%; 1-sided 97.5% CI, 4.9), mid (transverse and descending) (92.4% vs 85.9%; 1-sided 97.5% CI, 1.6), and rectosigmoid (92.4% vs 87.2%; 1-sided 97.5% CI, 0.4) segments of the colon (Ottawa scores of excellent, good, or fair). Commonly reported AEs related to the bowel preparations were nausea, vomiting, headache, and chills. Patient-reported tolerability, including ease of consumption and taste, was significantly higher for P/MC than 2L PEG-3350 and bisacodyl tablets (P < .0001). LIMITATIONS Because of differences in administration and volume of the bowel preparations, the study was designed to be a single-assessor, blinded study. CONCLUSIONS The bowel-cleansing effects and patient acceptability of split-dose P/MC were superior to day-before dosing with 2L PEG-3350 and bisacodyl tablets.
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Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial.
Dorhout Mees, SM, Algra, A, Vandertop, WP, van Kooten, F, Kuijsten, HA, Boiten, J, van Oostenbrugge, RJ, Al-Shahi Salman, R, Lavados, PM, Rinkel, GJ, et al
Lancet (London, England). 2012;(9836):44-9
Abstract
BACKGROUND Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia. We did a trial to test whether magnesium therapy improves outcome after aneurysmal subarachnoid haemorrhage. METHODS We did this phase 3 randomised, placebo-controlled trial in eight centres in Europe and South America. We randomly assigned (with computer-generated random numbers, with permuted blocks of four, stratified by centre) patients aged 18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging who were admitted to hospital within 4 days of haemorrhage, to receive intravenous magnesium sulphate, 64 mmol/day, or placebo. We excluded patients with renal failure or bodyweight lower than 50 kg. Patients, treating physicians, and investigators assessing outcomes and analysing data were masked to the allocation. The primary outcome was poor outcome-defined as a score of 4-5 on the modified Rankin Scale-3 months after subarachnoid haemorrhage, or death. We analysed results by intention to treat. We also updated a previous meta-analysis of trials of magnesium treatment for aneurysmal subarachnoid haemorrhage. This study is registered with controlled-trials.com (ISRCTN 68742385) and the EU Clinical Trials Register (EudraCT 2006-003523-36). FINDINGS 1204 patients were enrolled, one of whom had his treatment allocation lost. 606 patients were assigned to the magnesium group (two lost to follow-up), 597 to the placebo (one lost to follow-up). 158 patients (26·2%) had poor outcome in the magnesium group compared with 151 (25·3%) in the placebo group (risk ratio [RR] 1·03, 95% CI 0·85-1·25). Our updated meta-analysis of seven randomised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0·96, 95% CI 0·86-1·08). INTERPRETATION Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage, therefore routine administration of magnesium cannot be recommended. FUNDING Netherlands Heart Foundation, UK Medical Research Council.
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Placental secretion of interleukin-1 and interleukin-1 receptor antagonist in preeclampsia: effect of magnesium sulfate.
Amash, A, Holcberg, G, Sapir, O, Huleihel, M
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2012;(9):432-41
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Preeclampsia is a pregnancy-specific disorder characterized by hypertension and systemic endothelial dysfunction. Interleukin (IL)-1β is a possible mediator of maternal endothelial dysfunction in preeclampsia. Serum IL-1β as well as its natural inhibitor IL-1 receptor antagonist (IL-1Ra) were reported to be increased in women with preeclampsia. In the current study, we addressed the role of the placenta in controlling the circulatory levels of IL-1β and its natural inhibitor IL-1Ra in preeclampsia, and the possible effect of magnesium sulfate (MgSO(4)) on these levels. Using an ex vivo placental perfusion system, placentas from preeclamptic (n = 9) and normotensive (n = 6) pregnancies were perfused in presence or absence of MgSO(4). Perfusate samples were collected from the maternal and the fetal circulations of the perfusion system, and IL-1β and IL-1Ra were examined by enzyme-linked immunoassay (ELISA). Preeclamptic placentas secreted higher levels of IL-1β (P < 0.001), and a tendentious higher levels of IL-1Ra, mainly into the maternal circulation, as compared with normotensive placentas, although no differences in IL-1β:IL-1Ra ratio were detected. However, there was only tendentious increase in the secretion levels of IL-1β or IL-1Ra into the fetal circulation of preeclamptic placentas, when compared with normotensive placentas. Administration of MgSO(4) to preeclamptic placentas resulted in an attenuation of the increased secretion of IL-1β into the maternal circulation (P < 0.001), and in a tendentious reduction in IL-1Ra. However, IL-1β:IL-1Ra ratio in preeclamptic placentas was not affected by MgSO(4). Interestingly, exposure of normotensive placenta to MgSO(4) resulted only in increased levels of IL-1Ra in the maternal circulation, without affecting IL-1β levels or IL-1β:IL-1Ra ratio. These findings suggest that the placenta may contribute to the elevation in serum IL-1β and IL-1Ra in preeclampsia by increased secretion of these cytokines into the maternal circulation, and that MgSO(4) is able to attenuate this increased secretion of IL-1β, and possibly IL-1Ra, in preeclampsia.
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Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7.
Grothey, A, Nikcevich, DA, Sloan, JA, Kugler, JW, Silberstein, PT, Dentchev, T, Wender, DB, Novotny, PJ, Chitaley, U, Alberts, SR, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;(4):421-7
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PURPOSE Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT. METHODS Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect. RESULTS Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo. CONCLUSION Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer.
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Intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage (IMASH): a randomized, double-blinded, placebo-controlled, multicenter phase III trial.
Wong, GK, Poon, WS, Chan, MT, Boet, R, Gin, T, Ng, SC, Zee, BC, ,
Stroke. 2010;(5):921-6
Abstract
BACKGROUND AND PURPOSE Pilot clinical trials using magnesium sulfate in patients with acute aneurysmal subarachnoid hemorrhage have reported trends toward improvement in clinical outcomes. This Phase III study aimed to compare intravenous magnesium sulfate infusion with saline placebo among such patients. METHODS We recruited patients with aneurysmal subarachnoid hemorrhage within 48 hours of onset from 10 participating centers. The patients were randomly assigned to magnesium sulfate infusion titrated to a serum magnesium concentration twice the baseline concentration or saline placebo for 10 to 14 days. Patients and assessors were blinded to treatment allocation. The study is registered at www.strokecenter.org/trials (as Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Hemorrhage [IMASH]) and www.ClinicalTrials.gov (NCT00124150). RESULTS Of the 327 patients recruited, 169 were randomized to receive treatment with intravenous magnesium sulfate and 158 to receive saline (placebo). The proportions of patients with a favorable outcome at 6 months (Extended Glasgow Outcome Scale 5 to 8) were similar, 64% in the magnesium sulfate group and 63% in the saline group (OR, 1.0; 95% CI, 0.7 to 1.6). Secondary outcome analyses (modified Rankin Scale, Barthel Index, Short Form 36, and clinical vasospasm) also showed no significant differences between the 2 groups. Predefined subgroups included age, admission World Federation of Neurological Surgeons grade, pre-existing hypertension, intracerebral hematoma, intraventricular hemorrhage, location of aneurysm, size of aneurysm, and mode of aneurysm treatment. In none of the subgroups did the magnesium sulfate group show a better outcome at 6 months. CONCLUSIONS The results do not support a clinical benefit of intravenous magnesium sulfate infusion over placebo infusion in patients with acute aneurysmal subarachnoid hemorrhage.
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Use of calcium and magnesium infusions in prevention of oxaliplatin induced sensory neuropathy.
Chay, WY, Tan, SH, Lo, YL, Ong, SY, Ng, HC, Gao, F, Koo, WH, Choo, SP
Asia-Pacific journal of clinical oncology. 2010;(4):270-7
Abstract
AIM: Oxaliplatin-related neurotoxicity is frequently dose-limiting. Following retrospective studies suggesting neuroprotective effects of calcium and magnesium (Ca and Mg), we conducted a prospective study using nerve conduction studies (NCS) to evaluate the effectiveness of such infusions in oxaliplatin-related neuropathy. METHODS Colorectal cancer patients receiving FOLFOX-4 or capecitabine plus oxaliplatin were randomized to (Arm A) calcium gluconate 1g +15% magnesium sulphate 1g diluted in 100 mL of dextrose 5% or (Arm B) placebo. Neuropathy was assessed using the National Cancer Center common toxicity criteria, oxaliplatin-specific scale and NCS. RESULTS This study was terminated prematurely based on the initial negative results of the CONcePT trial. Median follow up was 8.7 months. Overall 22 out of 27 patients experienced neuropathy. The subjective neuropathy rate was 77% in Arm A and 86% in Arm B, (P = 0.6). At the end of treatment, three patients in Arm A and 0 in Arm B had grade 3 numbness (P = 0.09). There was no significant difference in neuropathy between arms, whether during or at the end of treatment. Median objective neuropathy score was 6 in Arm A and 0 in Arm B, (P = 0.02). CONCLUSION Premature closure of this study limits the interpretation of results. While there was a trend towards reduced subjective acute sensory neuropathy with Ca and Mg, this was not significant. Ca and Mg failed to reduce the rate of cumulative sensory neuropathy and instead increased the rate of abnormal NCS, suggesting a significant difference in perceived sensory and objective neuropathy.
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Plasma magnesium concentrations and clinical outcomes in aneurysmal subarachnoid hemorrhage patients: post hoc analysis of intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage trial.
Wong, GK, Poon, WS, Chan, MT, Boet, R, Gin, T, Ng, SC, Zee, BC
Stroke. 2010;(8):1841-4
Abstract
BACKGROUND AND PURPOSE Conflicting data have been obtained on optimal plasma magnesium concentrations for clinical outcomes in patients with aneurysmal subarachnoid hemorrhage. METHODS Adults (aged 18 years or older) who had acute aneurysmal subarachnoid hemorrhage diagnosed were randomly assigned to receive either an intravenous MgSO(4) infusion (80 mmol in 500 mL normal saline per day) or a placebo (500 mL normal saline per day) for up to 14 days. Post hoc multivariable binary logistic regression analyses were performed by dividing mean plasma magnesium concentrations into 4 quartiles according to treatment group and then comparing with the lowest quartiles. RESULTS The worst clinical outcomes at 6 months were seen in MgSO(4) group patients, with mean plasma magnesium concentrations in the fourth quartile, and in placebo group patients, with mean such concentrations in the third and fourth quartiles. CONCLUSIONS No evidence was found to suggest that a higher mean plasma magnesium concentration improves clinical outcomes. On the contrary, we found an association between high plasma magnesium concentration and worse clinical outcomes.