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Purpose: Current Neurocritical Care Society guidelines on the management of cerebral edema recommend hypertonic saline (HTS) over mannitol in some scenarios, but practical questions remain regarding the appropriate administration method, concentration/dose, monitoring to ensure safe use, and storage. The aim of this article is to address these practical concerns based on the evidence currently available., Summary: Many different hypertonic solutions have been studied to define the optimal hyperosmolar substance to relieve acute cerebral edema in patients with conditions such as acute ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and traumatic brain injury. Mannitol and HTS are the main hyperosmolar therapies in use in contemporary neurocritical care practice. Contemporary use of HTS has followed a circuitous path in regards to the practical aspects of dosing and formulation, with evidence mainly consisting of retrospective or observational data. The effectiveness of bolus doses of HTS to lower acutely elevated intracranial pressure is well accepted. Adverse events with use of HTS are often mild and non-clinically significant if appropriate monitoring of serum sodium and chloride concentrations is performed. Available evidence shows that peripheral administration of HTS is likely safe in certain circumstances. Timely utilization of HTS is complicated by regulatory requirements for safe storage, but with appropriate safeguards HTS can be stored in patient care areas., Conclusion: HTS formulations, methods of administration, infusion rate, and storage vary by institution, and no practice standards exist. Central intravenous administration may be preferred for HTS, but peripheral intravenous administration is safe provided measures are undertaken to detect and prevent phlebitis and extravasation. The safe use of HTS is possible with proper protocols, education, and institutional safeguards in place., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)