Delayed CPAP-Induced Pneumocephalus and Meningitis Posttranssphenoidal Surgery.

Transsphenoidal surgery (TSS) is a frequently used technique to remove pituitary adenomas. Rare complications of TSS include development of postoperative pneumocephalus. Many patients undergoing TSS also suffer from obstructive sleep apnea (OSA) and thus require positive pressure ventilation. The exact timing of when to safely reintroduce the CPAP machine in this subset of patients is presently not exactly known but is most often cited as being two to four weeks postoperatively. In this case, we describe the story of a 69-year-old female who underwent TSS for a nonsecreting pituitary adenoma in April 2012 and went on to develop pneumocephalus five weeks postoperatively after reintroduction of her CPAP machine. This is the latest presentation of pneumocephalus after reintroduction of CPAP documented in present literature. The case reopens the debate as to how many weeks postoperatively positive pressure ventilation should be withheld to prevent the development of pneumocephalus in patients having undergone TSS with simultaneous OSA.

Incidence and characteristics of cerebral hypoxia after craniectomy in brain-injured patients: a cohort study.

OBJECTIVE: After craniectomy, although intracranial pressure (ICP) is controlled, episodes of brain hypoxia might still occur. Cerebral hypoxia is an indicator of poor outcome independently of ICP and cerebral perfusion pressure. No study has systematically evaluated the incidence and characteristics of brain hypoxia after craniectomy. The authors' objective was to describe the incidence and characteristics of brain hypoxia after craniectomy. METHODS: The authors included 25 consecutive patients who underwent a craniectomy after traumatic brain injury or intracerebral hemorrhage and who were monitored afterward with a brain tissue oxygen pressure monitor. RESULTS: The frequency of hypoxic values after surgery was 14.6% despite ICP being controlled. Patients had a mean of 18 ± 23 hypoxic episodes. Endotracheal (ET) secretions (17.4%), low cerebral perfusion pressure (10.3%), and mobilizing the patient (8.6%) were the most common causes identified. Elevated ICP was rarely identified as the cause of hypoxia (4%). No cause of cerebral hypoxia could be determined 31.2% of the time. Effective treatments that were mainly used included sedation/analgesia (20.8%), ET secretion suctioning (15.4%), and increase in fraction of inspired oxygen or positive end-expiratory pressure (14.1%). CONCLUSIONS: Cerebral hypoxia is common after craniectomy, despite ICP being controlled. ET secretion and patient mobilization are common causes that are easily treatable and often not identified by standard monitoring. These results suggest that monitoring should be pursued even if ICP is controlled. The authors' findings might provide a hypothesis to explain the poor functional outcome in the recent randomized controlled trials on craniectomy after traumatic brain injury where in which brain tissue oxygen pressure was not measured.

Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.

Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p.) administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0) but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67), cortex (AUC0-t, i.n./AUC0-t, i.p. = 46) and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3). Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies support intranasal delivery of 2-PMPA to deliver therapeutic concentrations in the brain and may facilitate its clinical development.

Rapid formation of hindered cores using an oxidative Prins process.

An unprecedented oxidative Prins transformation on phenol derivatives mediated by a hypervalent iodine reagent has been developed. This method allows a rapid access to highly substituted compact systems present in several natural products via a carbon-based addition on an aromatic core. Substitution at each ring position has been demonstrated, enabling synthesis of molecules with up to two contiguous quaternary carbon centers in good yield.

An unprecedented oxidative Wagner-Meerwein transposition.

An oxidative Wagner-Meerwein transposition involving different functionalities mediated by a hypervalent iodine reagent has been accomplished. The strategy fits within the concept of "aromatic ring umpolung" and allows rapid access to highly functionalized cores.

Assessing a whiplash management model: a population-based non-randomized intervention study.

OBJECTIVE: To evaluate the effectiveness of a multidisciplinary clinical management approach for whiplash-associated disorders (WAD) following a motor vehicle injury in Quebec. METHODS: A clinical management model was implemented in 5 geographic regions of the Province of Quebec, Canada, in 7 hospitals and 19 clinics. A 2-group population-based parallel design was used to assess its effectiveness. All patients with a new whiplash injury seen in these 26 centers between March and September, 2001 were entered into the Whiplash Management Model (experimental group). A reference group included all subjects who had a whiplash injury during this same period but were not seen in these 26 intervention centers. All subjects were followed for up to a year. The outcome variables were time on compensation, time to file closure, and total direct costs. RESULTS: A total of 288 patients with WAD were identified in the experimental group and 1,875 patients in the reference group. The rate of ending of compensation was significantly higher in patients who received the experimental treatment model than those receiving the reference treatment approach (rate ratio, RR: 3.2; 95% confidence interval, CI: 2.8-3.6). The rate of file closure was also significantly higher with the experimental treatment (RR: 1.5; 95% CI: 1.2-1.8). The average cost per patient was significantly reduced with the experimental intervention. CONCLUSION: A coordinated whiplash management approach can lead to earlier return to work and lower costs for patients who have sustained a whiplash injury.