Bayesian hierarchical EMAX model for doseâ response in early phase efficacy clinical trials

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149669/1/sim8167_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149669/2/sim8167.pd

The Effect of Reductive Ventricular Osmotherapy on the Osmolarity of Artificial Cerebrospinal Fluid and the Water Content of Cerebral Tissue Ex Vivo

The purpose of this study was to explore a novel treatment involving removal of free water from ventricular cerebrospinal fluid (CSF) for the reduction of cerebra]l edema. The hypothesis is that removal of free water from the CSF will increase the osmolarity of the CSF, which will favor movement of tissue-bound water into the ventricles, where the water can be removed. Reductive ventricular osmotherapy (RVOT) was tested in a flowing solution of artificial CSF (aCSF) with two end-points: (1) the effect of RVOT on osmolarity of the CSF, and (2) the effect of RVOT on water content of ex vivo cerebral tissue. RVOT catheters are made up of membranes permeable only to water vapor. When a sweep gas is drawn through the catheter, free water in the form of water vapor is removed from the solution. With RVOT treatment, aCSF osmolarity increased from a baseline osmolarity of 318.8 ± 0.8 mOsm/L to 339.0 ± 3.3 mOsm/L (mean ± standard deviation) within 2 h. After 10 h of treatment, aCSF osmolarity approached an asymptote at 344.0 ± 4.2 mOsm/L, which was significantly greater than control aCSF osmolarity (p <<0.001 by t-test, n = 8). Water content at the end of 6 h of circulating aCSF exposure was 6.4 ± 0.9 g H2O (g dry wt)−1 in controls, compared to 6.1 ± 0.7 g H2O (g dry wt)− after 6 h of RVOT treatment of aCSF (p = 0.02, n = 24). The results support the potential of RVOT as a treatment for cerebral edema and intracranial hypertension