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Rapid Treatment with Intramuscular Magnesium Sulfate During Cardiopulmonary Resuscitation Does Not Provide Neuroprotection Following Cardiac Arrest

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Abstract

Brain injury is the most common cause of death for patients resuscitated from cardiac arrest. Magnesium is an attractive neuroprotective compound which protects neurons from ischemic injury by reducing neuronal calcium overload via NMDA receptor modulation and preventing calcium-induced mitochondrial permeability transition. Intramuscular (IM) delivery of MgSO4 during CPR has the potential to target these mechanisms within an early therapeutic window. We hypothesize that IM MgSO4 administrated during CPR could achieve therapeutic serum magnesium levels within 15 min after ROSC and improve neurologic outcomes in a rat model of asphyxial cardiac arrest. Male Long Evans rats were subjected to 8-min asphyxial cardiac arrest and block randomized to receive placebo, 107 mg/kg, 215 mg/kg, or 430 mg/kg MgSO4 IM at the onset of CPR. Serum magnesium concentrations increased rapidly with IM delivery during CPR, achieving twofold to fourfold increase by 15 min after ROSC in all magnesium dose groups. Rats subjected to cardiac arrest or sham surgery were block randomized to treatment groups for assessment of neurological outcomes. We found that IM MgSO4 during CPR had no effect on ROSC rate (p > 0.05). IM MgSO4 treatment had no statistically significant effect on 10-day survival with good neurologic function or hippocampal CA1 pyramidal neuron survival compared to placebo treatment. In conclusion, a single dose IM MgSO4 during CPR achieves up to fourfold baseline serum magnesium levels within 15 min after ROSC; however, this treatment strategy did not improve survival, recovery of neurologic function, or neuron survival. Future studies with repeated dosing or in combination with hypothermic targeted temperature management may be indicated.

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Data Availability

The data and materials used in the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the American Heart Association, Strategically Focused Research Network grant (19SFRN34830008) (RWN, THS). This work has also been supported in part by NIH R01 NS091242 and NS120322 (THS), NIH T32HL007853 (TB), and the China Scholarship Council (201806220219) (RZ).

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Authors and Affiliations

  1. Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Rui Zhang, Timothy D. Bryson, Garrett M. Fogo, Jinhui Liao, Sarita Raghunayakula, Jennifer Mathieu, Joseph M. Wider, Xiaodan Ren, Kathleen J. Maheras, Katlynn J. Emaus, Erin Gruley, Robert W. Neumar & Thomas H. Sanderson

  2. Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China

    Rui Zhang & Yuguo Chen

  3. Department of Cardiology, Weifang People’s Hospital, Weifang, 261000, China

    Rui Zhang

  4. Frankel Cardiovascular Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Timothy D. Bryson & Thomas H. Sanderson

  5. Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Garrett M. Fogo, Katlynn J. Emaus & Thomas H. Sanderson

  6. Michigan Center for Integrative Research in Critical Care, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Joseph M. Wider, Robert W. Neumar & Thomas H. Sanderson

  7. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA

    Thomas H. Sanderson

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  1. Rui Zhang
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  2. Timothy D. Bryson
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Contributions

Robert W. Neumar and Thomas H. Sanderson designed the research. Rui Zhang, Timothy D. Bryson, Garrett M. Fogo, Jinhui Liao, Sarita Raghunayakula, Jennifer Mathieu, Joseph M. Wider, Xiaodan Ren, Kathleen J. Maheras, Katlynn J. Emaus, and Erin Gruley performed the research. Rui Zhang, Timothy D. Bryson, Garrett M. Fogo, Robert W. Neumar, Thomas H. Sanderson, and Yuguo Chen analyzed and interpreted data. Rui Zhang, Timothy D. Bryson, Thomas H. Sanderson, and Robert W. Neumar drafted and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Robert W. Neumar or Thomas H. Sanderson.

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Thomas H. Sanderson and Robert W. Neumar are co-senior authors.

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Zhang, R., Bryson, T.D., Fogo, G.M. et al. Rapid Treatment with Intramuscular Magnesium Sulfate During Cardiopulmonary Resuscitation Does Not Provide Neuroprotection Following Cardiac Arrest. Mol Neurobiol 59, 1872–1881 (2022). https://doi.org/10.1007/s12035-021-02645-x

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