Background: There exists the role for novel agents in the management of refractory intracranial pressure (ICP) via targeting cerebral acidosis, hyperemia, and excitotoxicity. Objective: We performed 4 separate systematic reviews to determine the effect of tromethamine (THAM), indomethacin, and ketamine on ICP. Methods: All articles from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to: February 2014 – THAM, July 2014 – Indomethacin, November 2013 - Ketamine), and gray literature were searched. The strength of evidence was adjudicated using both the Oxford and GRADE methodology. Results: Twelve articles were reviewed utilizing THAM while documenting ICP in neurosurgical patients. All but one study documented a decrease in ICP. Twelve original articles were reviewed utilizing indomethacin for ICP in neurological patients. All but one study documented a decrease in ICP. Seven articles were reviewed utilizing ketamine, documenting ICP in TBI patients, with 16 in non-trauma neurological patients. ICP did not increase in the studies during ketamine administration, and trended to decrease ICP. Conclusion: There exists Oxford level 2b, GRADE B evidence that THAM reduces ICP in the TBI and malignant ischemic infarct population. There exists Oxford level 2b, GRADE C evidence that indomethacin and ketamine reduce ICP in the adult severe TBI population.