Continuous Albuterol in Pediatric Acute Care: Study Demonstrates Safety Outside the Intensive Care Unit.

There are little data to support the use of continuous aerosolized albuterol (CAA) in the non-intensive care unit (ICU) or non-emergency department (ED) setting for pediatric asthma patients. A 2014 study demonstrated low rates of adverse outcomes associated with administration of CAA on the acute care unit; however, the authors do not describe additional outcomes. We sought to determine whether administration of CAA within a respiratory cohort on an acute care floor was feasible and safe. METHODS: This quasi-experimental study evaluates data 1 year before and after (2014-2016) the initiation of CAA on the acute care inpatient unit for asthma patients 2-18 years of age. Outcome measures included ED and hospital length of stay (LOS), readmission rate, rapid response team activations, and transfers to ICU. Use of chest x-rays, viral studies, and hospital charges were also studied. RESULTS: Seven hundred thirty-two patients met study criteria. Population demographics and severity of acute presentation were similar pre- and poststudy. ED LOS decreased poststudy, whereas overall hospital LOS was unchanged. Fifteen-day readmission rate decreased in the poststudy group. Only 4 rapid response activations occurred in the poststudy population. The poststudy group utilized fewer chest x-rays and viral studies. There was no change in overall hospital charges. CONCLUSIONS: With appropriate resources and safety processes in place, care of pediatric patients with status asthmaticus receiving CAA on an acute care unit, outside of the ICU, resulted in improved ED LOS with evidence of lower resource utilization and rare adverse outcomes.

Discharging Asthma Patients on 3-Hour ß-Agonist Treatments: A Quality Improvement Project.

OBJECTIVES: Asthma exacerbations are a leading cause of hospitalization among children. Despite the existence of hospital protocols and national guidelines, little guidance is available regarding appropriate short-acting ß-agonist (SABA) frequency discharge criteria. Our aim was to reduce the median length of stay (LOS) for children hospitalized with asthma exacerbations by 4 hours by changing the discharge requirement SABA frequency. METHODS: Multiple plan-do-study-act cycles based on findings in our key driver diagram were used to decrease LOS. Our primary intervention was reducing the SABA administration frequency discharge requirement from every 4 hours to every 3 hours. After a feasibility pilot, this change was implemented throughout the hospital. Our intervention bundle included updating our evidence-based guidelines, electronic health record order sets and note templates, house-wide education, and a new process for respiratory therapists to notify physicians of discharge readiness. Our primary metric was LOS, with 3-, 7-, and 14-day same-cause emergency department (ED) revisits and hospital readmissions as balancing metrics. Statistical process control charts and nonparametric testing were performed for data analysis. RESULTS: Median hospital LOS was significantly lower in the postintervention period compared with the preintervention period (30.18 vs 36.14 hours respectively; P < .001). Statistical process control charts indicated special cause variation was achieved. No significant differences were observed in rates of ED revisits or hospital readmissions. CONCLUSIONS: Reducing the discharge requirement of SABA frequency from every 4 hours to every 3 hours resulted in a reduction in LOS, with no increase in ED recidivism or hospital readmission rates.

Resident Workshop Standardizes Patient Handoff and Improves Quality, Confidence, and Knowledge.

OBJECTIVES: Residency programs are required to instruct residents in handoff; however, a handoff curriculum endorsed by the Accreditation Council for Graduate Medical Education does not exist. Although curricula are available, we preferred to use a curriculum that could be taught quickly, was easy to implement, and used a mnemonic that resembled current practices at our institution. We designed and implemented a novel handoff educational workshop intended to improve resident confidence and performance. METHODS: In this observational study, pediatric residents across postgraduate training years during winter 2014-spring 2015 participated in two study segments: a handoff workshop with questionnaires and handoff observations. Co-investigators developed and led an interactive workshop for residents that emphasized a standardized approach using the SIGNOUT mnemonic (see text for definition). The effect of workshop participation on handoff abilities was evaluated using a validated, handoff evaluation tool administered before and after the workshop. Qualitative feedback was obtained from residents using pre- and postworkshop surveys. RESULTS: Forty-three residents participated in the workshop; 41 residents completed handoff observations. Improvements were noted in clinical judgment (P = 0.02) and organization/communication (P = 0.005). Pre- and postworkshop surveys demonstrated self-perceived increases in confidence, comfort, and knowledge (P < 0.001). CONCLUSIONS: Improvements in handoffs, particularly in clinical judgment and organization/communication domains, suggest that a more standardized handoff approach is beneficial, especially for postgraduate year 1 residents. The novel, interactive workshop we developed can be taught quickly, is easy to implement, is appropriate for all resident training levels, and improves resident confidence and skill. This workshop can be implemented by training programs across all disciplines, possibly leading to improved patient safety.

Quantifying vitamin K-dependent holoprotein compaction caused by differential γ-carboxylation using high-pressure size exclusion chromatography.

This study uses high-pressure size exclusion chromatography (HPSEC) to quantify divalent metal ion (X(2+))-induced compaction found in vitamin K-dependent (VKD) proteins. Multiple X(2+) binding sites formed by the presence of up to 12 γ-carboxyglutamic acid (Gla) residues are present in plasma-derived FIX (pd-FIX) and recombinant FIX (r-FIX). Analytical ultracentrifugation (AUC) was used to calibrate the Stokes radius (R) measured by HPSEC. A compaction of pd-FIX caused by the filling of Ca(2+) and Mg(2+) binding sites resulted in a 5 to 6% decrease in radius of hydration as observed by HPSEC. The filling of Ca(2+) sites resulted in greater compaction than for Mg(2+) alone where this effect was additive or greater when both ions were present at physiological levels. Less X(2+)-induced compaction was observed in r-FIX with lower Gla content populations, which enabled the separation of biologically active r-FIX species from inactive ones by HPSEC. HPSEC was sensitive to R changes of approximately 0.01nm that enabled the detection of FIX compaction that was likely cooperative in nature between lower avidity X(2+) sites of the Gla domain and higher avidity X(2+) sites of the epidermal growth factor 1 (EGF1)-like domain.

The mechanism underlying activation of factor IX by factor XIa.

Factor XI (fXI) is the zymogen of a plasma protease, factor XIa (fXIa), that contributes to thrombin generation during blood coagulation by proteolytic conversion of factor IX (fIX) to factor IXaß (fIXaß). There is considerable interest in fXIa as a therapeutic target because it contributes to thrombosis, while serving a relatively minor role in hemostasis. FXI/XIa has a distinctly different structure than other plasma coagulation proteases. Specifically, the protein lacks a phospholipid-binding Gla-domain, and is a homodimer. Each subunit of a fXIa dimer contains four apple domains (A1 to A4) and one trypsin-like catalytic domain. The A3 domain contains a binding site (exosite) that largely determines affinity and specificity for the substrate fIX. After binding to fXIa, fIX undergoes a single cleavage to form the intermediate fIXα. FIXα then rebinds to the A3 domain to undergo a second cleavage, generating fIXaß. The catalytic efficiency for the second cleavage is ~7-fold greater than that of the first cleavage, limiting fIXα accumulation. Residues at the N-terminus and C-terminus of the fXIa A3 domain likely form the fIX binding site. The dimeric conformation of fXIa is not required for normal fIX activation in solution. However, monomeric forms of fXI do not reconstitute fXI-deficient mice in arterial thrombosis models, indicating the dimer is required for normal function in vivo. FXI must be a dimer to be activated normal by the protease fXIIa. It is also possible that the dimeric structure is an adaptation that allows fXI/XIa to bind to a surface through one subunit, while binding to its substrate fIX through the other.

Structural and functional studies of γ-carboxyglutamic acid domains of factor VIIa and activated Protein C: role of magnesium at physiological calcium.

Crystal structures of factor (F) VIIa/soluble tissue factor (TF), obtained under high Mg(2+) (50mM Mg(2+)/5mM Ca(2+)), have three of seven Ca(2+) sites in the γ-carboxyglutamic acid (Gla) domain replaced by Mg(2+) at positions 1, 4, and 7. We now report structures under low Mg(2+) (2.5mM Mg(2+)/5mM Ca(2+)) as well as under high Ca(2+) (5mM Mg(2+)/45 mM Ca(2+)). Under low Mg(2+), four Ca(2+) and three Mg(2+) occupy the same positions as in high-Mg(2+) structures. Conversely, under low Mg(2+), reexamination of the structure of Gla domain of activated Protein C (APC) complexed with soluble endothelial Protein C receptor (sEPCR) has position 4 occupied by Ca(2+) and positions 1 and 7 by Mg(2+). Nonetheless, in direct binding experiments, Mg(2+) replaced three Ca(2+) sites in the unliganded Protein C or APC. Further, the high-Ca(2+) condition was necessary to replace Mg4 in the FVIIa/soluble TF structure. In biological studies, Mg(2+) enhanced phospholipid binding to FVIIa and APC at physiological Ca(2+). Additionally, Mg(2+) potentiated phospholipid-dependent activations of FIX and FX by FVIIa/TF and inactivation of activated factor V by APC. Since APC and FVIIa bind to sEPCR involving similar interactions, we conclude that under the low-Mg(2+) condition, sEPCR binding to APC-Gla (or FVIIa-Gla) replaces Mg4 by Ca4 with an attendant conformational change in the Gla domain ω-loop. Moreover, since phospholipid and sEPCR bind to FVIIa or APC via the ω-loop, we predict that phospholipid binding also induces the functional Ca4 conformation in this loop. Cumulatively, the data illustrate that Mg(2+) and Ca(2+) act in concert to promote coagulation and anticoagulation.

A sequential mechanism for exosite-mediated factor IX activation by factor XIa.

During blood coagulation, the protease factor XIa (fXIa) activates factor IX (fIX). We describe a new mechanism for this process. FIX is cleaved initially after Arg(145) to form fIXα, and then after Arg(180) to form the protease fIXaß. FIXα is released from fXIa, and must rebind for cleavage after Arg(180) to occur. Catalytic efficiency of cleavage after Arg(180) is 7-fold greater than for cleavage after Arg(145), limiting fIXα accumulation. FXIa contains four apple domains (A1-A4) and a catalytic domain. Exosite(s) on fXIa are required for fIX binding, however, there is lack of consensus on their location(s), with sites on the A2, A3, and catalytic domains described. Replacing the A3 domain with the prekallikrein A3 domain increases K(m) for fIX cleavage after Arg(145) and Arg(180) 25- and ≥ 90-fold, respectively, and markedly decreases k(cat) for cleavage after Arg(180). Similar results were obtained with the isolated fXIa catalytic domain, or fXIa in the absence of Ca(2+). Forms of fXIa lacking the A3 domain exhibit 15-fold lower catalytic efficiency for cleavage after Arg(180) than for cleavage after Arg(145), resulting in fIXα accumulation. Replacing the A2 domain does not affect fIX activation. The results demonstrate that fXIa activates fIX by an exosite- and Ca(2+)-mediated release-rebind mechanism in which efficiency of the second cleavage is enhanced by conformational changes resulting from the first cleavage. Initial binding of fIX and fIXα requires an exosite on the fXIa A3 domain, but not the A2 or catalytic domain.