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Effect of Locally Delivered Nimodipine Microparticles on Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage

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Abstract

Background

Recurrent spreading depolarizations (SDs) occur in patients after aneurysmal subarachnoid hemorrhage (aSAH), resulting in metabolic stress to brain. These events are closely associated with delayed cerebral ischemia. Preclinical data suggest that the beneficial effect of nimodipine demonstrated in clinical trials may be related to inhibition of SD rather than limitation of large artery vasospasm.

Methods

Subjects enrolled in a phase 3 trial of intraventricularly delivered, sustained-release nimodipine (EG-1962) versus standard of care oral nimodipine (NEWTON 2) who required surgical clipping had subdural strip electrodes implanted for monitoring of SD. SD was then scored blinded to NEWTON 2 allocation.

Results

Five subjects underwent electrocorticography monitoring of SD. Three of five patients had SD. There were fewer SDs, a lower rate of SD, and shorter depression durations in subjects treated with EG-1962 compared to standard of care. Outcomes were worse in the standard of care group, though there were baseline imbalances.

Conclusions

These results are consistent with a beneficial effect of locally delivered nimodipine (EG-1962) on SD after aSAH in more severely injured patients who are at risk of delayed cerebral ischemia related to SD. Larger studies are warranted to test this effect.

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Acknowledgements

The authors thank the NEWTON 2 steering committee and investigators as well as the COSBID (co-operative studies of brain injury depolarization) consortium for support with the project.

Funding

NEWTON 2 was funded fully by Edge Therapeutics, other funding from the department of neurosurgery at the University of New Mexico and an unrestricted educational Grant from Edge therapeutics.

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Authors and Affiliations

  1. Department of Neurosurgery, University of New Mexico School of Medicine, 1UNM, Albuquerque, NM, 87131, USA

    Andrew P. Carlson & Amal Alchbli

  2. Department of Neurosurgery, University Medical Center Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany

    Daniel Hänggi

  3. Department of Neurosurgery, University of California San Francisco Fresno, Fresno, USA

    R. Loch Macdonald

  4. University Neurosciences Institute, Fresno, USA

    R. Loch Macdonald

  5. Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada

    R. Loch Macdonald

  6. Department of Neuroscience, University of New Mexico School of Medicine, Albuquerque, USA

    C. William Shuttleworth

Authors
  1. Andrew P. Carlson
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  2. Amal Alchbli
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  3. Daniel Hänggi
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  4. R. Loch Macdonald
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  5. C. William Shuttleworth
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Contributions

Design, manuscript drafting and revisions were performed by APC. Conception of the study was performed by APC and RLM. Data analysis was performed by APC, AA and CWS. Review of the manuscript was performed by AA, DH and CWS. Conception of the parent study was performed by DH and RLM. Critical revisions of the manuscript was performed by RLM and CWS.

Corresponding author

Correspondence to Andrew P. Carlson.

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Conflict of interest

Carlson—unrestricted educational Grant from Edge Therapeutics. Hänggi—consulting fees for serving on the steering committee for Edge Therapeutics. Macdonald—Grant support from the Brain Aneurysm Foundation and the Canadian Institutes for Health Research; previously Chief Scientific Officer of Edge Therapeutics, Inc., Stock ownership of PDS Biotechnology, Shuttleworth—NINDS.

Informed Consent

All appropriate ethical guidelines were rigorously followed. Informed consent was prospectively used for both studies. Both the monitoring study and the parent RCT were approved by the local IRB (UNM-HRPO-10-159 and UNM-HRPO-16-074).

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Carlson, A.P., Alchbli, A., Hänggi, D. et al. Effect of Locally Delivered Nimodipine Microparticles on Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 34, 345–349 (2021). https://doi.org/10.1007/s12028-020-00935-1

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  • DOI: https://doi.org/10.1007/s12028-020-00935-1

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