Adoption of low tidal volume ventilation in the emergency department: A quality improvement intervention.

BACKGROUND: Ventilator tidal volumes of >8 mL/kg of predicted body weight (PBW) may increase the risk of lung injury. We sought to evaluate the impact of a quality improvement intervention among intubated Emergency Department (ED) patients to protocolize the prescription of low tidal volume ventilation. METHODS: In this before-and-after study, the average tidal volume delivered to ED patients receiving volume assist-control ventilation was compared before (2007-2014) and after (2015-2016) implementation of a ventilator initiation protocol (the quality improvement intervention). The intervention emphasized 1) measurement of the patient's height to calculate PBW and therefore tailor the tidal volume to estimated lung size (<8 mL/kg PBW), and 2) focused education and reference materials for ED physicians and respiratory therapists. RESULTS: Among ventilated ED patients meeting inclusion criteria in the before (N = 2185) and after (N = 774) cohorts, the mean (±SD) tidal volume decreased from 9.0 ±â€¯1.4 mL/kg to 7.2 ±â€¯0.9 mL/kg PBW following the intervention (absolute difference 1.8 mL/kg, 95% confidence interval 1.7 to 1.9 mL/kg, p < 0.001). The proportion of patients receiving low tidal volume ventilation increased after the intervention (72%), as compared to before (23%). Low tidal volume ventilation continued to be utilized at 24 h after ICU admission in patients who remained intubated in the cohort following the intervention (mean tidal volume 7.3 mL/kg PBW). CONCLUSIONS: Pairing a ventilator initiation protocol with focused education and resources for emergency physicians and respiratory therapists was associated with a significant reduction in tidal volume delivered to ED patients.

Longer upper airway lengths in Robin Sequence: A case-control study using computed tomography.

BACKGROUND: Direct laryngoscopy and intubation are often difficult in children with Robin Sequence. Previous research characterizing anatomic airway differences has focused on parameters influencing airway patency; there is a paucity of data pertaining to intubation trajectories and depth. Such information could impact airway management approaches and decrease the incidence of endotracheal tube malpositioning. AIM: The study goal was to examine whether longitudinal airway parameters pertaining to intubation are different in children with Robin Sequence compared with age-matched controls. METHOD: This case-control study compared patients with RS <4 years of age who had computed tomography scans of the head and neck to age- and sex-matched controls. Measurements were made of the nasopharynx, oropharynx, hypopharynx, tongue, hyoid, and the front teeth to vocal cord, nares to vocal cord, and nasion-basion distances. Statistical analysis was performed using multiple ANCOVA models with the categorical predictor of Robin Sequence vs control and potential covariates including subject height/length, weight, and age. RESULTS: Thirty-three patients with Robin Sequence and 33 control subjects were included. After controlling for subject height/length, mean front teeth to vocal cord distance was 1.2 cm longer (95% CI: 0.9 to 1.6 cm, P < .001) and mean nares to vocal cord distance was 0.8 cm longer (95% CI: 0.4 to 1.2 cm, P < .001) in patients with Robin Sequence than in controls. The tongue was positioned on average 0.5 cm higher (95% CI: 0.3 to 0.8, P < .001) and 0.9 cm more posterior (95% CI: 0.6 to 1.0 cm, P < .001) in cases than in controls. Moreover, in patients with Robin Sequence, the hyoid was positioned on average 0.5 cm more inferiorly (95% CI: 0.2 to 0.8 cm, P < .001) and 0.2 cm more posteriorly (95% CI: 0.1 to 0.4 cm, P < .01) than controls. CONCLUSION: In patients with Robin Sequence under 4 years of age, the mean front teeth to vocal cord distance was found to be 1.2 cm longer while the mean nares to vocal cord distance was found to be 0.8 cm longer controlling for subject length. Clinicians should account for these differences when selecting and placing endotracheal tubes, particularly those with a preformed bend.

Sodium nitroprusside in 2014: A clinical concepts review.

Sodium nitroprusside has been used in clinical practice as an arterial and venous vasodilator for 40 years. This prodrug reacts with physiologic sulfhydryl groups to release nitric oxide, causing rapid vasodilation, and acutely lowering blood pressure. It is used clinically in cardiac surgery, hypertensive crises, heart failure, vascular surgery, pediatric surgery, and other acute hemodynamic applications. In some practices, newer agents have replaced nitroprusside, either because they are more effective or because they have a more favorable side-effect profile. However, valid and adequately-powered efficacy studies are sparse and do not identify a superior agent for all indications. The cyanide anion release concurrent with nitroprusside administration is associated with potential cyanide accumulation and severe toxicity. Agents to ameliorate the untoward effects of cyanide are limited by various problems in their practicality and effectiveness. A new orally bioavailable antidote is sodium sulfanegen, which shows promise in reversing this toxicity. The unique effectiveness of nitroprusside as a titratable agent capable of rapid blood pressure control will likely maintain its utilization in clinical practice for the foreseeable future. Additional research will refine and perhaps expand indications for nitroprusside, while parallel investigation continues to develop effective antidotes for cyanide poisoning.

Inhibition of growth in medullary thyroid cancer cells with histone deacetylase inhibitors and lithium chloride.

BACKGROUND: While representing only 3% of thyroid malignancies, medullary thyroid cancer (MTC) accounts for 14% of thyroid cancer deaths. MTC has a high rate of recurrence and lacks effective treatments. The histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) activate the Notch1 signaling pathway, while lithium chloride inhibits the glycogen synthase kinase-3ss (GSK-3ss) pathway. These compounds have been shown to limit growth and suppress hormonal secretion; thus, targeting different signaling pathways may be an effective treatment. METHODS: MTC cells were treated with varying combinations of up to 20 mM lithium chloride with either 3 mM VPA or 20 muM SBHA for 48 h. Western analysis was used to measure the effects on Notch1, GSK-3ss, and neuroendocrine (NE) markers. Growth was assessed by a methylthiazolyldiphenyl-tetrazolium (MTT) bromide cellular proliferation assay. Western analysis was used to determine the mechanism of growth regulation. RESULTS: Combination therapy increased active Notch1, inhibited the GSK-3ss pathway, and decreased NE markers. Additive inhibition of growth was observed with combination therapy. Lower-dose combination therapy achieved greater decreases on NE markers and growth than treatment with any of the drugs alone. Moreover, an increase in the cleavage of the apoptotic markers caspase-3 and PARP was observed. CONCLUSIONS: Combination therapy with lithium chloride and HDAC inhibitors suppresses NE markers and decreases growth via apoptosis of MTC cells in vitro. With the possibility of increased efficacy and decreased toxicity, combination therapy may represent a new strategy to treat MTC.

Combination therapy with histone deacetylase inhibitors and lithium chloride: a novel treatment for carcinoid tumors.

In carcinoid cell lines, the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) activate the Notch1 pathway, whereas lithium inhibits glycogen synthase kinase-3beta (GSK-3beta). These compounds limit growth and decrease hormonal secretion in vitro. We hypothesized that lower-dose combination therapy of HDAC inhibitors and lithium chloride could achieve similar growth inhibition to that of the drugs alone. Gastrointestinal and pulmonary carcinoid cells were treated with either VPA or SBHA and lithium chloride for up to 48 hours. Western blot analysis was used to measure the effects on the Notch1 and GSK-3beta pathways and the neuroendocrine tumor marker chromogranin A (CgA). Growth was measured by a cellular proliferation assay. With lower-dose combination therapy, a decrease in CgA was observed. The HDAC inhibitors increased the amount of active Notch1 protein, whereas treatment with lithium was associated with inhibition of GSK-3beta. Moreover, growth was inhibited with lower-dose combination therapy. Treatment of carcinoid cells with either VPA or SBHA and lithium chloride suppresses the neuroendocrine marker CgA while upregulating Notch1 and inhibiting GSK-3beta. This combination effectively reduces growth. Thus, lower-dose combination therapy may be a viable therapeutic approach for carcinoid tumors.

Inhibition of the PI3K pathway suppresses hormonal secretion and limits growth in pheochromocytoma cells.

BACKGROUND: Operative resection is the only curative treatment for pheochromocytomas. Inhibition of the phosphatidylinositol-3 kinase (PI3K)-Akt pathway has been shown to be an effective treatment of neuroendocrine (NE) tumors in vitro. We hypothesized that inhibition of the PI3K-Akt pathway would be a viable strategy to inhibit growth and hormonal secretion in pheochromocytoma cells. METHODS: Sixteen pheochromocytomas were analyzed for expression of phosphorylated Akt and the NE marker achaete scute complex-like 1 (ASCL1). Pheochromocytoma PC-12 cells were treated with up to 100 microM of the PI3K-specific inhibitor LY294002 for 48 h. Western blot analysis was used to measure phosphorylated Akt, total Akt, ASCL1, chromogranin A (CgA), and markers of apoptosis. Growth was assessed by a methylthiazolyldiphenyl-tetrazolium (MTT) bromide cellular proliferation assay for six days. RESULTS: Human pheochromocytomas expressed significant amounts of phosphorylated Akt, and there was a significant correlation between malignant pheochromocytomas and the amount of expressed ASCL1. LY294002 significantly inhibited the PI3K-Akt pathway. Treatment led to a dose-dependent decrease in both ASCL1 and CgA, indicating an alteration in the NE phenotype and hormonal suppression. Treatment decreased cellular proliferation, and cleavage of the apoptotic markers caspase-3 and PARP was observed. CONCLUSIONS: Human pheochromocytoma tumor samples express high levels of phosphorylated Akt. LY294002 effectively inhibits the PI3K-Akt pathway, suppresses NE tumor markers, and decreases cellular proliferation via apoptosis in vitro. Inhibition of the PI3K pathway may represent a new strategy in the treatment of pheochromocytomas.

Incidence, Distribution, and Cost of Lawn-Mower Injuries in the United States, 2006-2013.

OBJECTIVES: Characterization of the epidemiology and cost of lawn-mower injuries is potentially useful to inform injury prevention and health policy efforts. We examined the incidence, distribution, types and severity, and emergency department (ED) and hospitalization charges of lawn-mower injuries among all age groups across the United States. METHODS: This retrospective, cross-sectional study used nationally representative, population-based (all-payer) data from the US Nationwide Emergency Department Sample for lawn-mower-related ED visits and hospitalizations from January 1, 2006, through December 31, 2013. Lawn-mower injuries were identified by using International Classification of Diseases, Ninth Revision, Clinical Modification code E920 (accidents caused by a powered lawn mower). We analyzed data on demographic characteristics, age, geographic distribution, type of injury, injury severity, and hospital charges. RESULTS: We calculated a weighted estimate of 51 151 lawn-mower injuries during the 8-year study period. The most common types of injuries were lacerations (n = 23 907, 46.7%), fractures (n = 11 433, 22.4%), and amputations (n = 11 013, 21.5%). The most common injury locations were wrist or hand (n = 33 477, 65.4%) and foot or toe (n = 10 122, 19.8%). Mean ED charges were $2482 per patient, and mean inpatient charges were $36 987 per patient. The most common procedures performed were wound irrigation or debridement (n = 1436, 29.9%) and amputation (n = 1230, 25.6%). CONCLUSIONS: Lawn-mower injuries occurred at a constant rate during the study period. Changes to nationwide industry safety standards are needed to reduce the frequency and severity of these preventable injuries.

Comparing phonation threshold flow and pressure by abducting excised larynges.

OBJECTIVES/HYPOTHESIS: This experiment studied a new aerodynamic parameter, phonation threshold flow, along with phonation threshold pressure, by varying prephonatory glottal width in canine larynges ex vivo. Goals were to examine phonation threshold flow as a measurable parameter sensitive to physiologic changes in the vocal folds and compare the relative sensitivities of phonation threshold flow and phonation threshold pressure. METHODS: Ten excised canine larynges were tested on a bench apparatus for subglottal pressure and airflow at phonation onset. Metal shims simulated abduction levels ranging from 0.0 to 4.0 mm. For each glottal configuration, airflow through the larynx was increased until the vocal folds began vibrating, and onset airflow and pressures were recorded. RESULTS: One-way analysis of variance (ANOVA) found significant differences in the aggregate phonation threshold flow means over the latter portion of the width domain (1.0-4.0 mm). Phonation threshold flow increased as posterior glottal width increased and was modeled linearly. One-way ANOVA of phonation threshold pressure means was insignificant, with a P value of .941. CONCLUSION: Results showed phonation threshold flow to be more sensitive to posterior glottal width changes than phonation threshold pressure. Therefore, phonation threshold flow could be a more effective indicator than phonation threshold pressure for those vocal diseases related to abduction.

Asymmetric airflow and vibration induced by the Coanda effect in a symmetric model of the vocal folds.

A model constructed from Navier-Stokes equations and a two-mass vocal fold description is proposed in this study. The composite model not only has the capability to describe the aerodynamics in a vibratory glottis but also can be used to study the vocal fold vibration under the driving of the complex airflow in the glottis. Numerical simulations show that this model can predict self-oscillations of the coupled glottal aerodynamics and vocal fold system. The Coanda effect could occur in the vibratory glottis even though the vocal folds have left-right symmetric prephonatory shape and tissue properties. The Coanda effect causes the asymmetric flow in the glottis and the difference in the driving force on the left and right vocal folds. The different pressures applied to the left and right vocal folds induce their displacement asymmetry. By using various lung pressures (0.6-2.0 kPa) to drive the composite model, it was found that the asymmetry of the vocal fold displacement is increased from 1.87% to 11.2%. These simulation results provide numerical evidence for the presence of asymmetric flow in the vibratory glottis; moreover, they indicate that glottal aerodynamics is an important factor in inducing the asymmetric vibration of the vocal folds.

Anti-nerve growth factor in pain management: current evidence.

There continues to be an unmet need for safe and effective pain medications. Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) dominate the clinical landscape despite limited effectiveness and considerable side-effect profiles. Although significant advancements have identified myriad potential pain targets over the past several decades, the majority of new pain pharmacotherapies have failed to come to market. The discovery of nerve growth factor (NGF) and its interaction with tropomyosin receptor kinase A (trkA) have been well characterized as important mediators of pain initiation and maintenance, and pharmacotherapies targeting this pathway have the potential to be considered promising methods in the treatment of a variety of nociceptive and neuropathic pain conditions. Several methodologic approaches, including sequestration of free NGF, prevention of NGF binding and trkA activation, and inhibition of trkA function, have been investigated in the development of new pharmacotherapies. Among these, NGF-sequestering antibodies have exhibited the most promise in clinical trials. However, in 2010, reports of rapid joint destruction leading to joint replacement prompted the US Food and Drug Administration (FDA) to place a hold on all clinical trials involving anti-NGF antibodies. Although the FDA has since lifted this hold and a number of new trials are under way, the long-term efficacy and safety profile of anti-NGF antibodies are yet to be established.

Building surgical capacity in developing countries: lessons from Haiti and Honduras.

The unmet burden of surgical disease in developing countries is large and growing. We successfully initiated two surgical field hospitals in austere environments. Similar problems were encountered in the areas of facility development, operations, and social considerations. A literature review was performed to contextualize our experience and compare it with that of others.

A case series of genital vascular anomalies in children and their management: lessons learned.

OBJECTIVE: To review our experience with genital vascular anomalies and discuss the management considerations for patients with associated genitourinary defects. METHODS: We reviewed the presentation, course, management considerations, surgical treatment, and follow-up of all cases of genital vascular anomalies treated at a single institution from January 2008 to October 2011. The lesions were classified according to the International Society for the Study of Vascular Anomalies. All patients were boys <18 years old. RESULTS: We identified 3 patients with genital vascular anomalies. Of these 3 patients, 2 had an infantile hemangioma and 1 had a venous malformation. All lesions were identifiable on physical examination, and 2 of the patients presented within a few months of birth. One patient had associated genitourinary abnormalities that complicated his treatment. Scrotal ultrasonography and pelvic magnetic resonance imaging consistently showed the vascular anomalies to be highly vascular and distinct from the underlying testes. Both intrascrotal lesions were excised, and the cutaneous lesion was excised as a part of a larger genitourinary reconstruction. At a mean follow-up of 33 months (range 23-42), the intrascrotal infantile hemangioma had recurred, requiring repeat intervention, but the cutaneous hemangioma had not. CONCLUSION: Vascular anomalies of the male genitalia are rare. Pelvic magnetic resonance imaging is useful for characterizing the internal extent of vascular anomalies and ultrasonography is useful in monitoring these lesions over time. The timing of surgery and the high recurrence rate are important considerations when planning surgical resection of genital vascular anomalies, especially when associated with concomitant genitourinary defects.

Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells.

BACKGROUND: The histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) have been demonstrated recently to be strong Notch-1 activators. Upregulation of the Notch-1 pathway has been shown to limit growth and suppress hormonal secretion in neuroendocrine (NE) neoplasms. We hypothesized that HDAC inhibition would be an effective strategy to activate the Notch-1 pathway and inhibit growth and hormonal secretion in pheochromocytoma cells. METHODS: Pheochromocytoma PC-12 cells were treated with up to 8 mmol/L VPA or 40 micromol/L SBHA for 2 days. NE tumor markers achaete-scute complex-like 1 (ASCL1) and chromogranin A (CgA) were measured by Western analysis after treatment. Growth was assessed by a cellular proliferation assay; Western analysis was used to determine the mechanism of growth regulation. RESULTS: HDAC inhibitor treatment caused a dose-dependent decrease in ASCL1 and CgA while increasing the amount of active Notch-1 protein; with a 6-day treatment, dose-dependent growth inhibition and cleavage of the apoptotic markers caspase-3 and poly-ADP ribose phosphate was observed. CONCLUSION: VPA and SBHA upregulate Notch-1 effectively, suppress NE tumor markers, and decrease growth via apoptosis of pheochromocytoma cells in vitro. Activation of the Notch-1 signaling pathway with HDAC inhibitors may represent a new strategy for treating pheochromocytomas.