RESUMO
Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration-response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10-10 to 10-5 M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration-response curve to the α1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (- logEC50: - 5.73 ± 0.25 vs. - 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (- logEC50: - 6.62 ± 0.21 vs. - 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r2 = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS.
Assuntos
Choque Hemorrágico , Gabexato/farmacologia , Gabexato/uso terapêutico , Choque Hemorrágico/tratamento farmacológico , Choque Hemorrágico/enzimologia , Endotélio/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacologia , Inibidores de Serina Proteinase/uso terapêutico , Ratos Wistar , Masculino , Animais , RatosRESUMO
OBJECTIVE: Many emergency department (ED) transfers of children may be avoidable. Identifying hospital-level variables associated with avoidable transfers may guide system-level interventions to improve pediatric emergency care. We sought to examine hospital characteristics associated with ED transfers deemed "probably avoidable" in a large state Medicaid program. METHODS: We performed a retrospective cohort study using 2009 to 2013 claims data for Pennsylvania Medicaid beneficiaries. We categorized all ED transfers of children < 17 years old as "probably avoidable," "possibly avoidable", or "unavoidable" based on ultimate disposition and procedures (including subspecialty consultations) at the receiving ED. Using descriptive statistics and multivariable regression, we examined hospital characteristics associated with probably avoidable transfers. RESULTS: Among 2,839,379 pediatric visits to EDs across 158 Pennsylvania hospitals, 20,304 resulted in transfer. Among these, 3,764 (18.5%) were categorized as probably avoidable and 6,091 (30.0%) as possibly avoidable transfers. In adjusted analysis, compared to hospitals with no pediatric-specific capabilities, probably avoidable transfers were less likely from referring hospitals with pediatric-specific EDs and no other pediatric-specific capabilities (adjusted odds ratio [aOR] = 0.38, 95% confidence interval [CI] = 0.21-0.71) and from referring hospitals with pediatric-specific EDs and inpatient capabilities (aOR = 0.36, 95% CI = 0.20-0.64). Probably avoidable transfers were more likely from referring hospitals in large metropolitan areas (aOR = 2.64, 95% CI = 1.46-4.80) compared to those in rural areas. CONCLUSIONS: Among pediatric emergency transfers in a large state Medicaid program with a nearly 20% probably avoidable transfer rate, there was significant hospital-level variation in the proportion of probably avoidable transfers. Transfers from hospitals in large metropolitan areas and transfers from hospitals without pediatric-specific capabilities had increased odds of being probably avoidable transfers, such that these hospitals may represent targets for interventions to reduce these transfers.