Yusuke Hagiwara

Association Between Repeated Intubation Attempts and Adverse Events in Emergency Departments: An Analysis of a Multicenter Prospective Observational Study

STUDY OBJECTIVE Although repeated intubation attempts are believed to contribute to patient morbidity, only limited data characterize the association between the number of emergency department (ED) laryngoscopic attempts and adverse events. We seek to determine whether multiple ED intubation attempts are associated with an increased risk of adverse events. METHODS We conducted an analysis of a multicenter prospective registry of 11 Japanese EDs between April 2010 and September 2011. All patients undergoing emergency intubation with direct laryngoscopy as the initial device were included. The primary exposure was multiple intubation attempts, defined as intubation efforts requiring greater than or equal to 3 laryngoscopies. The primary outcome measure was the occurrence of intubation-related adverse events in the ED, including cardiac arrest, dysrhythmia, hypotension, hypoxemia, unrecognized esophageal intubation, regurgitation, airway trauma, dental or lip trauma, and mainstem bronchus intubation. RESULTS Of 2,616 patients, 280 (11%) required greater than or equal to 3 intubation attempts. Compared with patients requiring 2 or fewer intubation attempts, patients undergoing multiple attempts exhibited a higher adverse event rate (35% versus 9%). After adjusting for age, sex, principal indication, method, medication, and operator characteristics, intubations requiring multiple attempts were associated with an increased odds of adverse events (odds ratio 4.5; 95% confidence interval 3.4 to 6.1). CONCLUSION In this large Japanese multicenter study of ED patients undergoing intubation, we found that multiple intubation attempts were independently associated with increased adverse events.

Emergency airway management in Japan: Interim analysis of a multi-center prospective observational study ,

OBJECTIVES Emergency medicine is increasingly recognized as a medical specialty in Japan. However, comprehensive studies evaluating emergency airway management practice are lacking. We describe emergency department (ED) airway management using a large multi-center registry. METHODS We formed the Japanese Emergency Airway Network, a consortium of 10 academic and community medical centers in Japan, and prospectively collected data on ED intubations from April 2010 to February 2011. All patients undergoing emergency intubation were eligible for inclusion. Data were entered in real time by the intubator using a standardized data form. Variables included patients age, sex, weight, indication for intubation, methods of intubation, drugs, level of training and specialty of the intubator, number of attempts, success or failure, and adverse events. We present descriptive data as proportions with 95% confidence intervals. RESULTS We recorded 1486 intubations (compliance rate 99%). Intubation was ultimately successful in 99.7%. The initial method of intubation varied substantially among the hospitals, including rapid sequence intubation (0-79%), sedation without paralysis (4-88%), paralysis without sedation (0-18%), and oral without medication (12-67%), in non-cardiac arrest encounters. Success rates in first and ≤3 attempts ranged from 40 to 83% and from 74 to 100%, respectively. The overall adverse event rate was 11%, without significant difference by the method used. CONCLUSIONS In this multi-center study characterizing ED airway management across Japan, we observed a high overall success rate but a high degree of variation among hospitals in the methods of intubation and success rates.

Analysis of αSMA-Labeled Progenitor Cell Commitment Identifies Notch Signaling as an Important Pathway in Fracture Healing

Fracture healing is a regenerative process that involves coordinated responses of many cell types, but characterization of the roles of specific cell populations in this process has been limited. We have identified alpha smooth muscle actin (αSMA) as a marker of a population of mesenchymal progenitor cells in the periosteum that contributes to osteochondral elements during fracture healing. Using a lineage tracing approach, we labeled αSMA‐expressing cells, and characterized changes in the periosteal population during the early stages of fracture healing by histology, flow cytometry, and gene expression profiling. In response to fracture, the αSMA‐labeled population expanded and began to differentiate toward the osteogenic and chondrogenic lineages. The frequency of mesenchymal progenitor cell markers such as Sca1 and PDGFRα increased after fracture. By 6 days after fracture, genes involved in matrix production and remodeling were elevated. In contrast, genes associated with muscle contraction and Notch signaling were downregulated after fracture. We confirmed that activating Notch signaling in αSMA‐labeled cells inhibited differentiation into osteogenic and adipogenic lineages in vitro and ectopic bone formation in vivo. By characterizing changes in a selected αSMA‐labeled progenitor cell population during fracture callus formation, we have shown that modulation of Notch signaling may determine osteogenic potential of αSMA‐expressing progenitor cells during bone healing.

Lineage tracing of resident tendon progenitor cells during growth and natural healing.

Unlike during embryogenesis, the identity of tissue resident progenitor cells that contribute to postnatal tendon growth and natural healing is poorly characterized. Therefore, we utilized 1) an inducible Cre driven by alpha smooth muscle actin (SMACreERT2), that identifies mesenchymal progenitors, 2) a constitutively active Cre driven by growth and differentiation factor 5 (GDF5Cre), a critical regulator of joint condensation, in combination with 3) an Ai9 Cre reporter to permanently label SMA9 and GDF5-9 populations and their progeny. In growing mice, SMA9+ cells were found in peritendinous structures and scleraxis-positive (ScxGFP+) cells within the tendon midsubstance and myotendinous junction. The progenitors within the tendon midsubstance were transiently labeled as they displayed a 4-fold expansion from day 2 to day 21 but reduced to baseline levels by day 70. SMA9+ cells were not found within tendon entheses or ligaments in the knee, suggesting a different origin. In contrast to the SMA9 population, GDF5-9+ cells extended from the bone through the enthesis and into a portion of the tendon midsubstance. GDF5-9+ cells were also found throughout the length of the ligaments, indicating a significant variation in the progenitors that contribute to tendons and ligaments. Following tendon injury, SMA9+ paratenon cells were the main contributors to the healing response. SMA9+ cells extended over the defect space at 1 week and differentiated into ScxGFP+ cells at 2 weeks, which coincided with increased collagen signal in the paratenon bridge. Thus, SMA9-labeled cells represent a unique progenitor source that contributes to the tendon midsubstance, paratenon, and myotendinous junction during growth and natural healing, while GDF5 progenitors contribute to tendon enthesis and ligament development. Understanding the mechanisms that regulate the expansion and differentiation of these progenitors may prove crucial to improving future repair strategies.

GDF5 PROGENITORS GIVE RISE TO FIBROCARTILAGE CELLS THAT MINERALIZE VIA HEDGEHOG SIGNALING TO FORM THE ZONAL ENTHESIS

The sequence of events that leads to the formation of a functionally graded enthesis is not clearly defined. The current study demonstrates that clonal expansion of Gdf5 progenitors contributes to linear growth of the enthesis. Prior to mineralization, Col1+ cells in the enthesis appose Col2+ cells of the underlying primary cartilage. At the onset of enthesis mineralization, cells at the base of the enthesis express alkaline phosphatase, Indian hedgehog, and ColX as they mineralize. The mineralization front then extends towards the tendon midsubstance as cells above the front become encapsulated in mineralized fibrocartilage over time. The hedgehog (Hh) pathway regulates this process, as Hh-responsive Gli1+ cells within the developing enthesis mature from unmineralized to mineralized fibrochondrocytes in response to activated signaling. Hh signaling is required for mineralization, as tissue-specific deletion of its obligate transducer Smoothened in the developing tendon and enthesis cells leads to significant reductions in the apposition of mineralized fibrocartilage. Together, these findings provide a spatiotemporal map of events - from expansion of the embryonic progenitor pool to synthesis of the collagen template and finally mineralization of this template - that leads to the formation of the mature zonal enthesis. These results can inform future tendon-to-bone repair strategies to create a mechanically functional enthesis in which tendon collagen fibers are anchored to bone through mineralized fibrocartilage.

Quality of Care for Acute Asthma in Emergency Departments in Japan: A Multicenter Observational Study

BACKGROUND Little is known about the quality of acute asthma care in emergency departments (EDs) outside of North America. OBJECTIVE We evaluated concordance of acute asthma management in Japanese EDs with recommendations in the 2007 National Institutes of Health asthma guidelines and investigated whether guideline concordance was associated with risk of hospital admission. METHODS We conducted a multicenter chart review study in 23 EDs across Japan. We identified ED patients aged 18 to 54 years with acute asthma between 2009 and 2011. Concordance with evidence-based guideline recommendations was evaluated by using item-by-item quality measures and composite concordance scores both at patient and ED levels. These scores ranged from 0 to 100. RESULTS Among 1380 patients, the median age was 35 years and 11% were hospitalized. Overall guideline concordance score was suboptimal both at the patient level (mean ± SD, 72 ± 14) and ED level (mean ± SD, 72 ± 6). Specifically, asthma care at the patient level was suboptimal in several areas: inhaled anticholinergics in ED (2%), systemic corticosteroid in ED (56%) and at discharge (36%), and peak flow assessment (9%). A multivariable model that adjusted for severity at presentation and several ED characteristics showed that higher guideline concordance was associated with significantly lower risk of hospital admission (odds ratio, 0.70 per 10-unit increase in composite score; 95% CI, 0.62-0.79 per 10-unit increase in composite score). CONCLUSION The management of acute asthma in Japanese EDs is suboptimal. Greater concordance with guideline-recommended management might reduce unnecessary hospitalizations. Knowledge translation initiatives are warranted to increase adherence with best practice in acute asthma management.

Emergency airway management in geriatric and younger patients: analysis of a multicenter prospective observational study ☆,☆☆,☆☆☆,★,★★

OBJECTIVES There is little information on geriatric emergency airway management. We sought to describe intubation practices and outcomes for emergency department (ED) geriatric and younger patients in Japan. METHOD We formed the Japanese Emergency Airway Network, a consortium of 11 medical centers, and prospectively collected data on ED intubations between 2010 and 2011. All patients 18 years or older who underwent emergent airway management were included in our study. Patients were divided to into 2 groups: 18 to 64-year olds and 65 years or older. We present descriptive data as proportions with 95% confidence intervals (CI). RESULTS The database recorded 3277 patients (capture rate 96%), and 3178 met the inclusion criteria. Of 3178 patients, 1844 (58%) were 65 years or older, 1334 (42%) were 18 to 64 years old, 809 (25%) were 80 years or older, and 407 (50%) of them were in the state of cardiac arrest. The geriatric group, compared to the younger group, had a higher success rate on the initial attempt (71% vs 64%; difference 7%; 95% CI 4%-10%;) and in 2 attempts (90% vs 88%; difference 3%; 95% CI 1%-5%) or less. There was no significant difference in the adverse event rates by age group (difference 0%; 95% CI -2% to 3%). CONCLUSION In our multicenter study involving a large geriatric population, we found that geriatric patients were intubated with a higher success rate, compared to younger patients. These data provide implications for the geriatric ED airway practice that may lead to better patient-centered emergency care.

Multiple failed intubation attempts are associated with decreased success rates on the first rescue intubation in the emergency department: a retrospective analysis of multicentre observational data

BackgroundAlthough the international guidelines emphasize early and systematic use of rescue intubation techniques, there is little evidence to support this notion. We aimed to test the hypothesis that preceding multiple failed intubation attempts are associated with a decreased success rate on the first rescue intubation in emergency departments (EDs).MethodsWe analysed data from two multicentre prospective registries designed to characterize current ED airway management in Japan between April 2010 and June 2013. All patients who underwent a rescue intubation after a failed attempt or a series of failed attempts were included for the analysis. Multiple failed intubation attempts were defined as ≥2 consecutive failed intubation attempts before a rescue intubation. Primary outcome measure was success rate on the first rescue intubation attempt.ResultsOf 6,273 consecutive patients, 1,151 underwent a rescue intubation. The success rate on the first rescue intubation attempt declined as the number of preceding failed intubation attempts increased (81% [95% CI, 79%-84%] after one failed attempt; 71% [95% CI, 66%-76%] after two failed attempts; 67% [95% CI, 55%-78%] after three or more failed attempts; Ptrend <0.001). In the multivariable analysis adjusting for age, sex, principal indication, change in methods, devices, and intubator specialty, and clustering of patients within EDs, success rate on the first rescue intubation after two failed attempts was significantly lower (OR, 0.56; 95% CI, 0.41-0.77) compared to that after one failed attempt. Similarly, success rate on the first rescue intubation attempt after three or more failed attempts was significantly lower (OR, 0.49; 95% CI, 0.25-0.94) compared to that after one failed attempt.ConclusionPreceding multiple failed intubation attempts was independently associated with a decreased success rate on the first rescue intubation in the ED.

Prospective validation of the modified LEMON criteria to predict difficult intubation in the ED

BACKGROUND Evidence to predict difficult intubation remains scarce in the emergency department (ED) setting. A previously defined clinical decision rule, the modified LEMON criteria, may provide a reliable and reproducible means of identifying difficult intubations. We aimed to prospectively evaluate the external validity of the modified LEMON criteria in the EDs. METHODS We conducted a 13-center prospective observational study, the second Japanese Emergency Airway Network study. We prospectively collected data on all patients undergoing intubations in the ED from February 2012 through September 2014. The primary outcomes were sensitivity, specificity, and predictive values of the modified LEMON criteria for predicting difficult intubation (≥2 attempts by emergency attending physicians or anesthesiologists). RESULTS The database recorded a total of 4034 encounters (capture rate, 96%) in the EDs. Of these, 3313 patients (84%) underwent the intubation attempt with a direct laryngoscope and 610 patients (16%) with a video laryngoscope. The proportion of difficult intubation was 5.4% (95% confidence interval [CI], 4.7%-6.2%) in the direct laryngoscope group and 7.4% (95% CI, 5.6%-9.7%) in the video laryngoscope group. The sensitivity was 85.7% (95% CI, 79.3%-90.4%) with direct laryngoscope and 94.9% (95% CI, 83.5%-98.6%) with video laryngoscope. The specificity was 47.6% (95% CI, 47.2%-47.9%) and 40.3% (95% CI, 39.4%-40.6%), respectively. The negative predictive value was 98.2% (95% CI, 97.5%-98.8%) and 99.0% (95% CI, 96.6%-99.7%), respectively. CONCLUSIONS In this multicenter prospective study, we found a high sensitivity and a negative predictive value of the modified LEMON criteria for predicting difficult intubation. The modified LEMON might assist ED providers in better identifying difficult intubations.

Response of knee fibrocartilage to joint destabilization

OBJECTIVE A major challenge to understanding osteoarthritis (OA) pathology is identifying the cellular events that precede the onset of cartilage damage. The objective of this study is to determine the effect of joint destabilization on early changes to fibrocartilage in the joint. DESIGN/METHODS The anterior cruciate ligament was transected in collagen reporter mice (Col1CFP and ColXRFP). Mineralization labels were given every 2 weeks to measure new mineralized cartilage apposition. Novel fluorescent histology of mineralized tissue was used to characterize the changes in fibrocartilage at 2 and 4 weeks post-injury. RESULTS Changes in fibrocartilaginous structures of the joint occur as early as 2 weeks after injury and are well developed by 4 weeks. The alterations are seen in multiple entheses and in the medial surface of the femoral and tibial condyles. In the responding entheses, mineral apposition towards the ligament midsubstance results in thickening of the mineralize fibrocartilage. These changes are associated with increases in ColX-RFP, Col1-CFP reporter activity and alkaline phosphatase enzyme activity. Mineral apposition also occurs in the fibrocartilage of the non-articular regions of the medial condyles by 2 weeks and develops into osteophytes by 4 weeks post-injury. An unexpected observation is punctate expression of tartrate resistant acid phosphatase activity in unmineralized fibrochondrocytes adjacent to active appositional mineralization. DISCUSSION These observations suggest that fibrocartilage activates prior to degradation of the articular cartilage. Thus clinical and histological imaging of fibrocartilage may be an earlier indicator of disease initiation and may indicate a more appropriate time to start preventative treatment.