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European Journal of Clinical Pharmacology

, Volume 75, Issue 1, pp 59–66 | Cite as

Prospective study of serum and ionized magnesium pharmacokinetics in the treatment of children with severe acute asthma

  • Sarah M. Becker
  • Kathleen M. Job
  • Kelly Lima
  • Ty J. Forbes
  • Jadon Wagstaff
  • Nam K. Tran
  • Catherine M. Sherwin
  • Douglas S. Nelson
  • Michael D. Johnson
  • Joseph E. Rower
Pharmacokinetics and Disposition

Abstract

Purpose

Intravenous (IV) magnesium sulfate (MgSO4) is clinically useful as adjunct therapy in treating acute asthma exacerbations. Despite its clinical utility, the disposition of magnesium in children is poorly described. The purpose of this study is to describe the pharmacokinetics (PK) of ionized and total serum magnesium following IV MgSO4 administration in children with severe acute asthma.

Methods

Thirty-two children receiving 50 mg/kg IV MgSO4 for acute asthma exacerbations at Primary Children’s Hospital in Salt Lake City, UT, were prospectively enrolled in the study. Blood samples were collected before, as well as 30 min and 2 h after each child’s IV MgSO4 dose, and used to determine total serum and ionized magnesium concentrations. The collected data were analyzed using population PK techniques using NONMEM® software.

Results

Total serum magnesium concentrations were used to externally validate our previously published model constructed with retrospective data (median prediction error 10.3%, median absolute prediction error 18.1%). The mean (%CV) observed endogenous ionized magnesium concentration was calculated to be 6.0 mg/L (12%), approximately one third of the same value for endogenous total serum magnesium (17.6 mg/L (22%)) in this dataset. Weight was a significant predictor of both clearance and volume in a population PK model describing ionized magnesium concentrations. No adverse events were observed in this pediatric cohort.

Conclusions

This prospective study supports and extends our previous PK analysis of total serum magnesium concentrations. Ionized and total serum magnesium followed similar PK profiles following IV MgSO4 administration in children. A single bolus infusion of IV MgSO4 was safe in this small sample of children receiving it for acute asthma.

Keywords

Intravenous magnesium sulfate Serum magnesium Ionized magnesium Population pharmacokinetics Acute asthma 

Notes

Acknowledgements

We would like to acknowledge the patients who participated in the study, as well as the University of California, Davis, Clinical Chemistry Section for performing the analysis of magnesium concentrations.

Contribution of authors

SB facilitated the IRB application and participant recruitment for the prospective clinical study, provided clinical care to the study participants, and was involved in the preparation of the manuscript. KJ facilitated the IRB application and participant recruitment for the prospective clinical study. KL and NKT did the laboratory analysis of the collected samples. TF and JW contributed to data cleaning, formatting, and analysis. CMS and DN were involved with study concept/design, and DN contributed to the clinical care of study participants. MDJ was involved with study concept/design, provided clinical care to study participants, and participated in preparing the manuscript. JER was involved with study concept/design, completed the described PK analysis, and wrote the manuscript. All authors participated in editing the manuscript prior to submission.

Funding information

Funding for this study was provided by the Primary Children’s Hospital Foundation, as well as the Division of Pediatric Clinical Pharmacology and the Division of Pediatric Emergency Medicine at the University of Utah.

Compliance with ethical standards

Study approval was granted by the University of Utah, Intermountain Health, and Primary Children’s Hospital Institutional Review Board.

Supplementary material

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Fig. 1

Diagnostic plots for the model describing ionized magnesium concentrations. Fig. 1A shows population predicted vs. observed concentrations, Fig. 1B shows the individual predicted vs. observed concentrations, Fig. 1C shows the conditional weighted residuals (CWRES) versus time after dose, and Fig. 1D shows CWRES versus population predicted concentration (PNG 865 kb)

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Fig. 2

Prediction corrected visual predictive check showing observed data concentrations (blue circles) and percentiles (red dashed lines: 5th and 95th percentile, red solid line: 50th percentile) versus time. Shaded area reflects the simulated concentrations and the respective 95% confidence interval at the 5th and 95th percentile (black dashed line, blue shading) and 50th percentile (black solid line, pink shading). The y-axis represents ionized magnesium concentrations in mg/L, while the x-axis represents the time after the previous dose in hours. (PNG 81 kb)

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References

  1. 1.
    Global Asthma Network (2014) The Global Asthma Report. http://www.globalasthmareport.org/burden/burden.php. Accessed 29 March 2016
  2. 2.
    Akinbami LJ, Bailey CM, Johnson CA, King ME, Liu X, Moorman JE, Zahran HS (2012) Trends in asthma prevalence, health care use, and mortality in the United States, 2001-2010. NICHS Data Brief (94):1–8Google Scholar
  3. 3.
    Sullivan PW, Ghushchyan V, Navaratnam P, Friedman HS, Kavati A, Ortiz B, Lanier B (2017) The national cost of asthma among school-aged children in the United States. Ann Allergy Asthma Immunol 119(3):246–252Google Scholar
  4. 4.
    Bichara MD, Goldman RD (2009) Magnesium for treatment of asthma in children. Can Fam Physician 55(9):887–889Google Scholar
  5. 5.
    Griffiths B, Kew KM, Michell CI, Kirtchuk L (2014) Intravenous magnesium sulfate for treating children with acute asthma in the emergency department. Cochrane Database Syst Rev 28(5):CD010909Google Scholar
  6. 6.
    Gontijo-Amaral C, Ribeiro MA, Gontijo LSC, Condino-Neto A, Ribeiro JD (2006) Oral magnesium supplementation in asthmatic children: a double-blind randomized placebo-controlled trial. Eur J Clin Nutr 61(1):54–60Google Scholar
  7. 7.
    Bois P (1963) Effect of magnesium deficiency on mast cells and urinary histamine in rats. Br J Exp Pathol 44(2):151–155Google Scholar
  8. 8.
    Del Castillo J, Engbaek L (1953) The nature of the neuromuscular block produced by magnesium. J Physiol 120 (4):54PGoogle Scholar
  9. 9.
    Ciarallo L, Sauer AH, Shannon MW (1996) Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial. J Pediatr 129(6):809–814Google Scholar
  10. 10.
    Ciarallo L, Brousseau D, Reinert S (2000) Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch Pediatr Adolesc Med 154(10):979–983CrossRefGoogle Scholar
  11. 11.
    Jones B, Paul A (2013) Management of acute asthma in the pediatric patient: an evidence-based review. Pediatr Emerg Med Pract 10(5):1–23Google Scholar
  12. 12.
    Rower JE, Liu X, Yu T, Mundorff M, Sherwin CM, Johnson MD (2017) Clinical pharmacokinetics of magnesium sulfate in the treatment of children with severe acute asthma. Eur J Clin Pharmacol 73(3):325–331CrossRefGoogle Scholar
  13. 13.
    Koch SM, Warters RD, Mehlhorn U (2002) The simultaneous measurement of ionized and total calcium and ionized and total magnesium in intensive care unit patients. J Crit Care 17(3):203–205CrossRefGoogle Scholar
  14. 14.
    Egelund TA, Wassil SK, Edwards EM, Linden S, Irazuzta JE (2013) High-dose magnesium sulfate infusion protocol for status asthmaticus: a safety and pharmacokinetics cohort study. Intensive Care Med 39(1):117–122CrossRefGoogle Scholar
  15. 15.
    Saris N-EL, Mervaala E, Karppanen H, Khawaja JA, Lewenstam A (2000) Magnesium: an update on physiological, clinical and analytical aspects. Clin Chim Acta 294(1–2):1–26Google Scholar
  16. 16.
    Taber EB, Tan L, Chao CR, Beall MH, Ross MG (2002) Pharmacokinetics of ionized versus total magnesium in subjects with preterm labor and preeclampsia. Am J Obstet Gynecol 186(5):1017–1021CrossRefGoogle Scholar
  17. 17.
    Irazuzta J, Egelund T, Wassil SK, Hampp C (2012) Feasibility of short-term infusion of magnesium sulfate in pediatric patients with status asthmaticus. J Pediatr Pharmacol Ther 17(2):150–154Google Scholar
  18. 18.
    Cadacio C, Nachamkin I (2017) A novel needle-free blood draw device for sample collection from short peripheral catheters. J Infus Nurs 40(3):156–162CrossRefGoogle Scholar
  19. 19.
    Beckman Coulter (2014) Synchron® System Chemistry Information SheetGoogle Scholar
  20. 20.
    Nova Biomedical. Stat Profile® pHOx® Ultra™. http://www.novabio.us/uk/phox-ultra/
  21. 21.
    Zhang W (2011) Point of care testing of ionized magnesium in blood with potentiometric sensors-opportunities and challenges. Am J Biomed Sci 3(4):301–312Google Scholar
  22. 22.
    Wu AH (2006) Tietz clinical guide to laboratory tests-E-book. Elsevier Health SciencesGoogle Scholar
  23. 23.
    Greenway DC, Hindmarsh JT, Wang J, Khodadeen JA, Hébert PC (1996) Reference interval for whole blood ionized magnesium in a healthy population and the stability of ionized magnesium under varied laboratory conditions. Clin Biochem 29(6):515–520CrossRefGoogle Scholar
  24. 24.
    Lanzinger MJ, Moretti EW, Wilderman RF, El-Moalem HE, Toffaletti JG, Moon RE (2003) The relationship between ionized and total serum magnesium concentrations during abdominal surgery. J Clin Anesth 15(4):245–249CrossRefGoogle Scholar
  25. 25.
    Sinert R, Spektor M, Gorlin A, Doty C, Rubin A, Altura B, Altura B (2005) Ionized magnesium levels and the ratio of ionized calcium to magnesium in asthma patients before and after treatment with magnesium. Scand J Clin Lab Invest 65(8):659–670CrossRefGoogle Scholar
  26. 26.
    Winkler AW, Smith PK, Hoff HE (1942) Intravenous magnesium sulfate in the treatment of nephritic convulsions in adults. J Clin Invest 21(2):207–216CrossRefGoogle Scholar
  27. 27.
    Russell EA, Woodford AL, Zorc JJ (2014) Intravenous magnesium for status asthmaticus in the emergency department: incidence of hypotension and other adverse events. Paper presented at the Pediatric Academic Society, Vancouver,Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Sarah M. Becker
    • 1
    • 2
  • Kathleen M. Job
    • 3
  • Kelly Lima
    • 4
  • Ty J. Forbes
    • 3
  • Jadon Wagstaff
    • 3
  • Nam K. Tran
    • 4
  • Catherine M. Sherwin
    • 3
    • 5
  • Douglas S. Nelson
    • 1
    • 2
  • Michael D. Johnson
    • 1
    • 2
  • Joseph E. Rower
    • 3
  1. 1.Primary Children’s Hospital, Intermountain HealthcareSalt Lake CityUSA
  2. 2.Division of Pediatric Emergency Medicine, Department of PediatricsUniversity of UtahSalt Lake CityUSA
  3. 3.Division of Clinical Pharmacology, Department of PediatricsUniversity of UtahSalt Lake CityUSA
  4. 4.Department of Pathology and Laboratory MedicineUniversity of California DavisDavisUSA
  5. 5.Department of Pharmacotherapy, College of PharmacyUniversity of UtahSalt Lake CityUSA

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