Comparison of Clinical Outcomes with Initial Norepinephrine or Epinephrine for Hemodynamic Support After Return of Spontaneous Circulation.

BACKGROUND: The optimal vasoactive agent for management of patients with return of spontaneous circulation (ROSC) after cardiac arrest has not yet been identified. The Advanced Cardiac Life Support guidelines recommend initiation of either norepinephrine (NE), epinephrine (EPI), or dopamine (DA) to maintain adequate hemodynamics after ROSC is achieved. The goal of this study is to retrospectively assess the impact of initial vasopressor agent on incidence rate of rearrest, death, or need for additional vasopressor in post-cardiac arrest emergency department (ED) patients. METHODS: A retrospective review of electronic medical records was conducted at a tertiary care, academic medical center over a 32-month period. Inclusion criteria were any patient who received vasopressors in the ED after achieving ROSC from out-of-hospital cardiac arrest, or in ED cardiac arrest. The incidence of the primary outcome was assessed during care within the ED, at 6 h regardless of location (early resuscitation period), and throughout the entire hospitalization. Secondary outcomes included incidence of tachyarrhythmia while on vasopressor, type of additional therapy needed for refractory shock, and functional status at discharge as determined by discharge location (discharged home without assistance, or discharged to long-term care facility, subacute rehabilitation, or assisted living). RESULTS: A total of 93 patients were included for analysis; 45 received NE, 42 EPI, and six DA. Due to small sample size, DA was excluded from reporting post hoc. Significantly more EPI patients met the primary outcome of refractory hypotension, rearrest, or death in the emergency department (EPI 21/42, 50% vs. NE 10/45, 22.2%; P = 0.008). The incidence was no longer significantly different during the early resuscitation period of 6 h (EPI 30/42, 71.4% vs. NE 25/45, 55.6%; P = 0.182), or during the entire hospitalization (EPI 40/42, 95.2% vs. NE 36/45, 80.0%; P = 0.051). Notably, the EPI group had higher rates of rearrest prior to vasopressor initiation, potentially signaling more severe illness despite other prognostic variables being similarly distributed. In an adjusted regression model, which included adjustment for rearrest prior to vasopressor initiation, the odds of reaching the primary outcome in the ED were 3.94 [95%CI 1.38-12.2] (P = 0.013) times higher in the EPI group compared to NE treated patients. No difference in tachyarrhythmia or functional status at discharge was detected between groups. CONCLUSION: These data suggest prospective study of initial vasopressors used for hemodynamic support after ROSC may be warranted. Rates of intra-emergency department refractory shock, rearrest, or death were higher among epinephrine treated patients compared to norepinephrine treated patients in this population. However, inability to control for potential confounding variables in retrospective studies limits the findings. These results are hypothesis generating and further study is warranted.

Association between Pre-Operative Cefazolin Dose and Surgical Site Infection in Obese Patients.

BACKGROUND: A fixed dose of cefazolin results in serum concentrations that decrease as body mass increases. Current national guidelines suggest a pre-operative cefazolin dose of two grams may be insufficient for patients ≥120 kg; thus a three gram dose is recommended. These recommendations, however, are based on pharmacokinetic rather than outcome data. We evaluate the efficacy of pre-operative cefazolin two gram and three gram doses as measured by the rate of surgical site infection (SSI). PATIENTS AND METHODS: We conducted a retrospective review of adult patients ≥100 kg who were prescribed cefazolin as surgical prophylaxis between September 1, 2012 and May 31, 2013 at an academic medical center. Patients were excluded if cefazolin was prescribed but not administered, had a known infection at the site of surgery, or inappropriately received cefazolin prophylaxis based on surgical indication. The SSIs were identified by documentation of SSI in the medical record or findings consistent with the standard Centers for Disease Control and Prevention definition. Inpatient and outpatient records up to 90 days post-operative were reviewed for delayed SSI. RESULTS: Four hundred eighty-three surgical cases were identified in which pre-operative cefazolin was prescribed. Forty-seven patients were excluded leaving a total of 436 patients for final analysis: 152 in the cefazolin two gram group and 284 in the three gram group. Baseline demographics were similar between groups with a mean follow-up duration of 77 days for both groups. Unadjusted SSI rates were 7.2% and 7.4% (odds ratio [OR] 0.98, p = 0.95), for the two gram and three gram groups, respectively. When differences in follow-up between groups were considered and logistic regression was adjusted with propensity score, there remained no difference in SSI rates (OR 0.87, 95% confidence interval 0.36-2.06, p = 0.77). CONCLUSION: In otherwise similar obese surgical patients weighing ≥100 kg, the administration of a pre-operative cefazolin two gram dose is associated with a similar rate of SSI compared with patients who received a three gram dose.

The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth.

Chronic mechanical loading (CML) of skeletal muscle induces compensatory growth and the drug rapamycin has been reported to block this effect. Since rapamycin is considered to be a highly specific inhibitor of the mammalian target of rapamycin (mTOR), many have concluded that mTOR plays a key role in CML-induced growth regulatory events. However, rapamycin can exert mTOR-independent actions and systemic administration of rapamycin will inhibit mTOR signalling in all cells throughout the body. Thus, it is not clear if the growth inhibitory effects of rapamycin are actually due to the inhibition of mTOR signalling, and more specifically, the inhibition of mTOR signalling in skeletal muscle cells. To address this issue, transgenic mice with muscle specific expression of various rapamycin-resistant mutants of mTOR were employed. These mice enabled us to demonstrate that mTOR, within skeletal muscle cells, is the rapamycin-sensitive element that confers CML-induced hypertrophy, and mTOR kinase activity is necessary for this event. Surprisingly, CML also induced hyperplasia, but this occurred through a rapamycin-insensitive mechanism. Furthermore, CML was found to induce an increase in FoxO1 expression and PKB phosphorylation through a mechanism that was at least partially regulated by an mTOR kinase-dependent mechanism. Finally, CML stimulated ribosomal RNA accumulation and rapamycin partially inhibited this effect; however, the effect of rapamycin was exerted through a mechanism that was independent of mTOR in skeletal muscle cells. Overall, these results demonstrate that CML activates several growth regulatory events, but only a few (e.g. hypertrophy) are fully dependent on mTOR signalling within the skeletal muscle cells.

Novel insights into the regulation of skeletal muscle protein synthesis as revealed by a new nonradioactive in vivo technique.

In this study, the principles of surface sensing of translation (SUnSET) were used to develop a nonradioactive method for ex vivo and in vivo measurements of protein synthesis (PS). Compared with controls, we first demonstrate excellent agreement between SUnSET and a [(3)H]phenylalanine method when detecting synergist ablation-induced increases in skeletal muscle PS ex vivo. We then show that SUnSET can detect the same synergist ablation-induced increase in PS when used in vivo (IV-SUnSET). In addition, IV-SUnSET detected food deprivation-induced decreases in PS in the heart, kidney, and skeletal muscles, with similar changes being visualized with an immunohistochemical version of IV-SUnSET (IV-IHC-SUnSET). By combining IV-IHC-SUnSET with in vivo transfection, we demonstrate that constitutively active PKB induces a robust increase in skeletal muscle PS. Furthermore, transfection with Ras homolog enriched in brain (Rheb) revealed that a PKB-independent activation of mammalian target of rapamycin is also sufficient to induce an increase in skeletal muscle PS. Finally, IV-IHC-SUnSET exposed the existence of fiber type-dependent differences in skeletal muscle PS, with PS in type 2B and 2X fibers being significantly lower than that in type 2A fibers within the same muscle. Thus, our nonradioactive method allowed us to accurately visualize and quantify PS under various ex vivo and in vivo conditions and revealed novel insights into the regulation of PS in skeletal muscle.

A phosphatidylinositol 3-kinase/protein kinase B-independent activation of mammalian target of rapamycin signaling is sufficient to induce skeletal muscle hypertrophy.

It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used rapamycin to inhibit mTOR; yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB-independent activation of mTOR signaling, and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants also were used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy, and the kinase activity of mTOR is necessary for this event.