Effect of a pharmacist on timing of postintubation sedative and analgesic use in trauma resuscitations.

PURPOSE: Pharmacists' impact in reducing the time interval from intubation to sedative and analgesic use during trauma patient resuscitations is investigated. METHODS: A retrospective cohort study was conducted at a level 1 trauma center to compare medication-use outcomes in consecutive cases in which trauma patients underwent rocuronium-assisted rapid-sequence intubation (RSI) and subsequent sedation and analgesia with or without a pharmacist's participation on the resuscitation team. The primary and secondary outcomes were, respectively, the time to sedative provision and the time to analgesic provision after intubation. RESULTS: Relative to resuscitation cases not involving a pharmacist, the presence of the pharmacist during RSI was associated with decreased mean times to provision of postintubation sedation (9 minutes versus 28 minutes, p = 0.007) and analgesia (21 minutes versus 44 minutes, p = 0.057). The cumulative proportions of patients receiving appropriate sedation 5, 10, and 15 minutes after intubation were 11%, 26%, and 41% in the pharmacist-absent group and 33%, 53%, and 63% in the pharmacist-present group (p = 0.009, 0.008, and 0.045, respectively); for postintubation analgesic use, the corresponding figures were 9%, 14%, and 23% in the pharmacist-absent group and 17%, 30%, and 43% in the pharmacist-present group (p = 0.236, 0.066, and 0.039, respectively). CONCLUSION: The presence of a pharmacist during RSI procedures was associated with decreased times to postintubation sedative and analgesic use, indicating that pharmacist participation in trauma-resuscitation responses can facilitate appropriate drug therapy.

Effect of paralytic type on time to post-intubation sedative use in the emergency department.

OBJECTIVE: To determine the difference between rocuronium and succinylcholine with regard to post-intubation sedative initiation in the emergency department. METHDS: This was a retrospective cohort study conducted in a tertiary care emergency department (ED) in the USA. Consecutive adult patients intubated in the ED using succinylcholine or rocuronium for paralysis were included. Data collected included patient demographics, vital signs, medications used post-intubation and times of drug administration. Patients were divided into two groups based on the type of paralytic used for rapid sequence intubation: (1) rocuronium or (2) succinylcholine. All patients received etomidate for induction of sedation. Time between intubation and post-intubation sedative use was compared between the two groups using an unpaired Student's t test. MAIN RESULTS: A total of 200 patients were included in the final analyses (100 patients in each group). There were no significant differences between the groups with regard to patient demographics, vital signs or other baseline characteristics. After intubation, 77.5% (n=155) of patients were initiated on a sedative infusion of propofol (n=148) or midazolam (n=7). The remaining patients received sedation as bolus doses only. Mean time between intubation and post-intubation sedative use was significantly greater in the rocuronium group compared with the succinylcholine group (27 min vs 15 min, respectively; p<0.001). CONCLUSIONS: Patients intubated with rocuronium had greater delays in post-intubation sedative initiation compared with succinylcholine.

Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase.

Mice with heterozygous deletion of the PTEN tumor suppressor gene develop a range of epithelial neoplasia as well as lymphoid hyperplasia. Previous studies suggest that PTEN suppresses tumor formation by acting as a phosphoinositide phosphatase to limit signaling by phosphoinositide 3-kinase (PI3K). Here, we examined the effect of deleting various regulatory subunits of PI3K (p85alpha and p85beta) on epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice. Interestingly, we found the loss of one p85alpha allele with or without the loss of p85beta led to increased incidence of intestinal polyps. Signaling downstream of PI3K was enhanced in the PTEN+/-p85alpha+/-p85beta-/- polyps, as judged by an increased fraction of both cells with cytoplasmic staining of the transcription factor FKHR and cells with positive staining for the proliferation marker Ki-67. In contrast, the incidence of prostate intraepithelial neoplasia was not significantly altered in PTEN+/- mice heterozygous for p85alpha or null for p85beta, whereas the fraction of proliferating cells in prostate intraepithelial neoplasia was reduced in mice lacking p85beta. Finally, there was no significant change in T lymphocyte hyperplasia in the PTEN+/- mice with various p85 deletions, although anti-CD3-stimulated AKT activation was somewhat reduced in the p85alpha+/- background. These results indicate that decreasing the levels of different p85 regulatory subunits can result in enhanced PI3K signaling in some tissues and decreased PI3K signaling in others, supporting the model that, although p85 proteins are essential for class I(A) PI3K signaling, they can function as inhibitors of PI3K signaling in some tissues and thus suppress tumor formation.

Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase.

On the basis of ex vivo studies using insulin-responsive cells, activation of a Class IA phosphoinositide 3-kinase (PI3K) seems to be required for a wide variety of cellular responses downstream of insulin. The Class IA PI3K enzymes are heterodimers of catalytic and regulatory subunits. In mammals, insulin-responsive tissues express both the p85alpha and p85beta isoforms of the regulatory subunit. Surprisingly, recent studies have revealed that disruption of the p85alpha gene in the mouse (p85alpha(-/-) mice) results in hypoglycemia with decreased plasma insulin, and the p85alpha(+/-) mice exhibit significantly increased insulin sensitivity. These results suggest either that p85alpha negatively regulates insulin signaling, or that p85beta, which mediates the major fraction of Class IA PI3K signaling in the absence of p85alpha, is more efficient than p85alpha in mediating insulin responses. To address this question, we have generated mice in which the p85beta gene is deleted (p85beta(-/-) mice). As with the p85alpha(-/-) mice, the p85beta(-/-) mice showed hypoinsulinemia, hypoglycemia, and improved insulin sensitivity. At the molecular level, PI3K activity associated with phosphotyrosine complexes was preserved despite a 20-30% reduction in the total protein level of the regulatory subunits. Moreover, insulin-induced activation of AKT was significantly up-regulated in muscle from the p85beta(-/-) mice. In addition, insulin-dependent tyrosine phosphorylation of insulin receptor substrate-2 was enhanced in the p85beta(-/-) mice, a phenotype not observed in the p85alpha(-/-) mice. These results indicate that in addition to their roles in recruiting the catalytic subunit of PI3K to the insulin receptor substrate proteins, both p85alpha and p85beta play negative roles in insulin signaling.