Analytical Post-Embedding Immunogold-Electron Microscopy with Direct Gold-Labelled Monoclonal Primary Antibodies against RIBEYE A- and B-Domain Suggests a Refined Model of Synaptic Ribbon Assembly.

Synaptic ribbons are the eponymous specializations of continuously active ribbon synapses. They are primarily composed of the RIBEYE protein that consists of a unique amino-terminal A-domain and carboxy-terminal B-domain that is largely identical to the ubiquitously expressed transcriptional regulator protein CtBP2. Both RIBEYE A-domain and RIBEYE B-domain are essential for the assembly of the synaptic ribbon, as shown by previous analyses of RIBEYE knockout and knockin mice and related investigations. How exactly the synaptic ribbon is assembled from RIBEYE subunits is not yet clear. To achieve further insights into the architecture of the synaptic ribbon, we performed analytical post-embedding immunogold-electron microscopy with direct gold-labelled primary antibodies against RIBEYE A-domain and RIBEYE B-domain for improved ultrastructural resolution. With direct gold-labelled monoclonal antibodies against RIBEYE A-domain and RIBEYE B-domain, we found that both domains show a very similar localization within the synaptic ribbon of mouse photoreceptor synapses, with no obvious differential gradient between the centre and surface of the synaptic ribbon. These data favour a model of the architecture of the synaptic ribbon in which the RIBEYE A-domain and RIBEYE B-domain are located similar distances from the midline of the synaptic ribbon.

Standardized versus custom parenteral nutrition: impact on clinical and cost-related outcomes.

PURPOSE: Results of a study comparing clinical and cost outcomes with the use of standardized versus custom-prepared parenteral nutrition (PN) in an acute care setting are reported. METHODS: In a retrospective pre-post analysis, nutritional target attainment, electrolyte abnormalities, and other outcomes were compared in patients 15 years of age or older who received custom PN (n = 49) or a standardized PN product (n = 57) for at least 72 hours at a large medical center over a 13-month period; overall, 45% of the cases were intensive care unit (ICU) admissions. A time-and-motion assessment was conducted to determine PN preparation times. RESULTS: There were no significant between-group differences in the percentage of patients who achieved estimated caloric requirements or in mean ICU or hospital length of stay. However, patients who received standardized PN were significantly less likely than those who received custom PN to achieve the highest protein intake goal (63% versus 92%, p = 0.003) and more likely to develop hyponatremia (37% versus 14%, p = 0.01). Pharmacy preparation times averaged 20 minutes for standardized PN and 80 minutes for custom PN; unit costs were $61.06 and $57.84, respectively. CONCLUSION: A standardized PN formulation was as effective as custom PN in achieving estimated caloric requirements, but it was relatively less effective in achieving 90% of estimated protein requirements and was associated with a higher frequency of hyponatremia. The standardized PN product may be a cost-effective formulation for institutions preparing an average of five or fewer PN orders per day.

Impact of a protocol advocating dexmedetomidine over propofol sedation after robotic-assisted direct coronary artery bypass surgery on duration of mechanical ventilation and patient safety.

BACKGROUND: Controversy remains whether propofol or dexmedetomidine is the preferred sedative following cardiac surgery. Dexmedetomidine may offer advantages over propofol among patients undergoing robotic-assisted, minimally invasive, direct coronary artery bypass (MIDCAB) surgery given the rapidity with which this population is usually extubated after surgery. OBJECTIVE: To measure the impact of a surgery protocol advocating use of dexmedetomidine rather than propofol after MIDCAB surgery on discontinuation of mechanical ventilation and patient safety. METHODS: The records on consecutive adults undergoing MIDCAB surgery who received postoperative sedation with propofol or dexmedetomidine at a 508-bed academic medical center were analyzed before and after implementation of a post-MIDCAB surgery protocol advocating dexmedetomidine use. RESULTS: Seventy-three propofol patients were compared with 53 dexmedetomidine patients. The groups were similar, except propofol patients were older (p = 0.002) and more likely to have underlying heart failure that was either moderate or severe (New York Heart Association class III or IV) (p = 0.0001). Time (median [interquartile range]) to extubation (hours) was shorter in the dexmedetomidine group (5.0 [3.6-7.0] vs 9.8 [5.0-16.3]; p = 0.0001). A Cox proportional hazards model revealed that patient age (p = 0.001) and duration of surgery (p = 0.003) influenced time to extubation between the dexmedetomidine and propofol groups but the presence of moderate or severe heart failure (p = 0.438), the number of coronary vessels operated on (p = 0.130), use of an opioid (p = 0.791), or the total dose of morphine administered (p = 0.215) did not. During sedation administration, more propofol-treated patients experienced 1 or more episodes of hypotension (systolic blood pressure ≤80 mm Hg, 11.6% vs 0%; p = 0.02), tachycardia (heart rate ≥120 beats/min, 8.6% vs 0%; p = 0.04), and unarousability (Sedation Agitation Scale score ≤2, 30.0% vs 9.4%; p = 0.03). CONCLUSIONS: Use of a protocol promoting dexmedetomidine, rather than propofol sedation, after MIDCAB surgery facilitates faster discontinuation of mechanical ventilation and is associated with greater hemodynamic stability and arousability.

Local antimicrobial administration for prophylaxis of surgical site infections.

Despite a lack of consensus guidelines, local antibiotic administration for prophylaxis of surgical site infections is used during many surgical procedures. The rationale behind this practice is to provide high antibiotic concentrations at the site of surgery while minimizing systemic exposure and adverse effects. Local antibiotic administration for surgical site prophylaxis has inherent limitations in that antibiotics are applied after the incision is made, rather than the current standard for surgical site prophylaxis that recommends providing adequate antibiotic concentrations at the site before the incision. The efficacy and safety of local application of antibiotics for surgical site prophylaxis have been assessed in different types of surgery with a variety of antibiotic agents and methods of application. We identified 22 prospective, randomized, controlled trials that evaluated local application of antibiotics for surgical site prophylaxis. These trials were subsequently divided and analyzed based on the type of surgical procedure: dermatologic, orthopedic, abdominal, colorectal, and cardiothoracic. Methods of local application analyzed included irrigations, powders, ointments, pastes, beads, sponges, and fleeces. Overall, there is a significant lack of level I evidence supporting this practice for any of the surgical genres evaluated. In addition, the literature spans several decades, and changes in surgical procedures, systemic antibiotic prophylaxis, and microbial flora make conclusions difficult to determine. Based on available data, the efficacy of local antibiotic administration for the prophylaxis of surgical site infections remains uncertain, and recommendations supporting this practice for surgical site prophylaxis cannot be made.

Use of airway pressure release ventilation is associated with a reduced incidence of ventilator-associated pneumonia in patients with pulmonary contusion.

BACKGROUND: Past studies suggest that airway pressure release ventilation (APRV) is associated with reduced sedative requirements and increased recruitment of atelectatic lung, two factors that might reduce the risk for ventilator-associated pneumonia (VAP). We investigated whether APRV might be associated with a decreased risk for VAP in patients with pulmonary contusion. MATERIALS: Retrospective cohort study. RESULTS: Of 286, 64 (22%) patients requiring mechanical ventilation for >48 hours met criteria for pulmonary contusion and were the basis for this study. Subjects with pulmonary contusion had a significantly higher rate of VAP than other trauma patients, [VAP rate contusion patients: 18.3/1,000, non-contusion patients: 7.7/1,000, incidence rate ratio 2.37 (95% confidence interval [CI], 1.11-4.97), p=0.025]. Univariate analysis showed that APRV (hazard ratio, 0.15 [0.03-0.72; p=0.018]) was associated with a decreased incidence of VAP. Cox proportional hazards regression, using propensity scores for APRV to control for confounding, supported a protective effect of APRV from VAP (hazard ratio, 0.10 [95% CI, 0.02-0.58]; p=0.01). Pao2/FiO2 ratios were higher during APRV compared with conventional ventilation (p<0.001). Subjects attained the goal Sedation Agitation Score for an increased percentage of time during APRV (median [interquartile range (IQR)] 72.7% [33-100] of the time) compared with conventional ventilation (47.2% [0-100], p=0.044), however, dose of sedatives was not different between these subjects. APRV was not associated with hospital mortality (odds ratio 0.57 [95% CI, 0.06-5.5]; p=0.63) or ventilator-free days (No APRV 15.4 vs. APRV 13.7 days, p=0.49). CONCLUSION: Use of APRV in patients with pulmonary contusion is associated with a reduced risk for VAP.

Controversies of anticoagulation reversal in life-threatening bleeds.

Therapeutic anticoagulation with heparins, warfarin, and anti-Xa inhibitors carry an inherent risk of complications due to their multifaceted pharmacokinetic and pharmacodynamic properties as well as narrow therapeutic ranges. When an anticoagulated patient presents with a major or life-threatening bleed, immediate and effective therapy may be necessary to reverse the effects of the anticoagulant, minimize blood loss, and reduce patient morbidity and mortality. Optimal agents and strategies for anticoagulant reversal are limited, particularly for newer anticoagulants. The literature describing such strategies available to reverse the effects of anticoagulants in the setting of a bleed is limited, and therefore many controversies exist. Thus, as new anticoagulants become available, without a specific agent for reversal, the concerns and controversies related to this topic must be addressed. The purpose of this review is to discuss the management of major or life-threatening bleeds by addressing the following controversies: (1) the use of recombinant factor VIIa for rapid reversal of warfarin in patients with intracerebral hemorrhage, (2) the role of prothrombin complex concentrate in emergent warfarin reversal, and (3) the optimal approach to reverse newer anticoagulants such as low molecular weight heparins, fondaparinux, and direct thrombin inhibitors.

Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study.

INTRODUCTION: While propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol. METHODS: Critically ill adults from 11 academic medical centers administered an infusion of propofol for [>or=] 24 hours were monitored at baseline and then on a daily basis until propofol was discontinued for the presence of 11 different PRIS-associated clinical manifestations and risk factors derived from 83 published case reports of PRIS. RESULTS: Among 1017 patients [medical (35%), neurosurgical (25%)], PRIS (defined as metabolic acidosis plus cardiac dysfunction and [>or=] 1 of: rhabdomyolysis, hypertriglyceridemia or renal failure occurring after the start of propofol therapy) developed in 11 (1.1%) patients an average of 3 (1-6) [median (range)] days after the start of propofol. While most (91%) of the patients who developed PRIS were receiving a vasopressor (80% initiated after the start of propofol therapy), few received a propofol dose >83 mcg/kg/min (18%) or died (18%). Compared to the 1006 patients who did not develop PRIS, the APACHE II score (25 +/- 6 vs 20 +/- 7, P = 0.01) was greater in patients with PRIS but both the duration of propofol use (P = 0.43) and ICU length of stay (P = 0.82) were similar. CONCLUSIONS: Despite using a conservative definition for PRIS, and only considering new-onset PRIS clinical manifestations, the incidence of PRIS slightly exceeds 1%. Future controlled studies focusing on evaluating whether propofol manifests the derangements of critical illness more frequently than other sedatives will need to be large. These studies should also investigate the mechanism(s) and risk factors for PRIS.

The impact of delirium on clinical outcomes in mechanically ventilated surgical and trauma patients.

OBJECTIVE: Previously, delirium has been identified as an independent risk factor for mortality in critically ill medical patients. We undertook this study to examine the relationships among medication usage, delirium, and clinical outcomes in a critically ill surgical/trauma population. DESIGN: Prospective, multicentered, observational study. SETTING: Two surgical intensive care units in level 1 trauma centers. PATIENTS: One hundred thirty-four consecutive surgical adult patients requiring mechanical ventilation (MV) for greater than 24 hours. INTERVENTIONS: Daily delirium assessment with the Confusion Assessment Method-Intensive Care Unit tool, outcomes assessment, and prospective data collection. MEASUREMENT AND MAIN RESULTS: Of the 134 patients who met inclusion criteria, 84 patients (63%) developed delirium at some point during their intensive care unit (ICU) stay. Delirium was associated with more MV days (9.1 vs. 4.9 days, p < 0.01), longer ICU stay (12.2 vs. 7.4 days, p < 0.01), longer hospital stay (20.6 vs. 14.7 days, p < 0.01). Additionally, greater cumulative lorazepam dose (p = 0.012), and higher cumulative fentanyl dose (p = 0.035) were administered in the delirium group. CONCLUSIONS: Delirium in the surgical/trauma ICU cohort is independently associated with more days requiring MV, longer ICU length of stay, and longer hospital length of stay. Additionally, greater amounts of lorazepam and fentanyl were administered to patients with delirium.

Fondaparinux as a treatment option for heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated complication that can occur after exposure to heparin products. Because patients with HIT are at increased risk for thrombosis, anticoagulation is warranted. The direct thrombin inhibitors lepirudin and argatroban are approved by the United States Food and Drug Administration (FDA) for this indication. Bivalirudin, another direct thrombin inhibitor, is approved for use in patients with HIT who must undergo percutaneous coronary intervention. The synthetic pentasaccharide fondaparinux lacks FDA approval for treating patients with HIT; however, a few published reports describe its use. Furthermore, various small-scale, in vitro studies have demonstrated a lack of cross-reactivity between fondaparinux and HIT antibodies. Large, in vivo comparison trials must be performed before fondaparinux can become a standard treatment option in the setting of HIT.

You can withdraw from that? The effects of abrupt discontinuation of medications.

Obtaining complete medication histories from patients and reinitiating home medications on hospital admission or when clinically appropriate will help prevent unnecessary complications secondary to abrupt discontinuation.

Rhabdomyolysis during therapy with daptomycin.

The use of daptomycin has been associated with an elevation in creatine phosphokinase level, with a reported incidence of 2.8% in phase III clinical trials. Published case reports have documented the presence of myopathy in patients who received daptomycin; however, there have been no previously reported cases of rhabdomyolysis in animals or humans to date. We describe a case of rhabdomyolysis during therapy with daptomycin.