Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism.

BACKGROUND: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE). METHODS: Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation. RESULTS: Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysate sGC activity was increased with PE compared with controls. CONCLUSIONS: In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target.

Evaluation of the pulmonary embolism rule out criteria (PERC rule) in children evaluated for suspected pulmonary embolism.

BACKGROUND: The pulmonary embolism rule out criteria (PERC) reliably predicts a low probability of PE in adults. We examine the diagnostic accuracy of the objective components of the PERC rule in children previously tested for PE. METHODS: Children aged 5-17 who had a D-dimer or pulmonary vascular imaging ordered from 2004 to 2014 in a large multicenter hospital network were identified by query of administrative databases. Using explicit, predefined methods, trained abstracters selected charts of children clearly tested for PE, collected the 8 objective variables for PERC, and determined PE criterion standard status (image or autopsy confirmed PE or deep vein thrombosis within 30 days by query of the Indiana Network for Patient Care (INPC)). RESULTS: We identified 543 patients, including 56 (10.3%, 95% CI: 7.8-13.1%) who were PE+, with a mean and median age of 15 years. All 8 objective criteria from PERC were negative in 170 patients (31%), including one with PE (false negative rate 0.6%, 0-3.2%). Diagnostic sensitivity and specificity were 98.2% (90.5-100%), and 34.7 (30.5-39.1%), respectively, leading to a likelihood ratio negative = 0.05 (0.1-0.27). When treated as a diagnostic test based upon sum of criteria positive, PERC had good discrimination between PE+ vs PE- with an area under receiver operating characteristic curve 0.81 (0.75-0.86). CONCLUSIONS: In this sample of children and teenagers with suspected PE, the PERC rule was negative in 31%, and demonstrated good overall diagnostic accuracy, including a low false negative rate. These data support the need for a large, prospective diagnostic validation study of PERC in children.