Background-Transnasal evaporative cooling has sufficient heat transfer capacity for effective intra-arrest cooling and improves survival in swine. The aim of this study was to determine the safety, feasibility, and cooling efficacy of prehospital transnasal cooling in humans and to explore its effects on neurologically intact survival to hospital discharge. Methods and Results-Witnessed cardiac arrest patients with a treatment interval Յ20 minutes were randomized to intra-arrest cooling with a RhinoChill device (treatment group, nϭ96) versus standard care (control group, nϭ104). The final analysis included 93 versus 101 patients, respectively. Both groups were cooled after hospital arrival. The patients had similar demographics, initial rhythms, rates of bystander cardiopulmonary resuscitation, and intervals to cardiopulmonary resuscitation and arrival of advanced life support personnel. Eighteen device-related adverse events (1 periorbital emphysema, 3 epistaxis, 1 perioral bleed, and 13 nasal discolorations) were reported. Time to target temperature of 34°C was shorter in the treatment group for both tympanic (102 versus 282 minutes, Pϭ0.03) and core (155 versus 284 minutes, Pϭ0.13) temperature. There were no significant differences in rates of return of spontaneous circulation between the groups (38% in treated subjects versus 43% in control subjects, Pϭ0.48), in overall survival of those admitted alive (44% versus 31%, respectively, Pϭ0.26), or in neurologically intact survival to discharge (Pittsburgh cerebral performance category scale 1 to 2, 34% versus 21%, Pϭ0.21), although the study was not adequately powered to detect changes in these outcomes. Conclusions-Prehospital

IMPORTANCE Therapeutic hypothermia may increase survival with good neurologic outcome after cardiac arrest. Trans-nasal evaporative cooling is a method used to induce cooling, primarily of the brain, during cardiopulmonary resuscitation (ie, intra-arrest). OBJECTIVE To determine whether prehospital trans-nasal evaporative intra-arrest cooling improves survival with good neurologic outcome compared with cooling initiated after hospital arrival. DESIGN, SETTING, AND PARTICIPANTS The PRINCESS trial was an investigator-initiated, randomized, clinical, international multicenter study with blinded assessment of the outcome, performed by emergency medical services in 7 European countries from July 2010 to January 2018, with final follow-up on April 29, 2018. In total, 677 patients with bystander-witnessed out-of-hospital cardiac arrest were enrolled. INTERVENTIONS Patients were randomly assigned to receive trans-nasal evaporative intra-arrest cooling (n = 343) or standard care (n = 334). Patients admitted to the hospital in both groups received systemic therapeutic hypothermia at 32°C to 34°C for 24 hours. MAIN OUTCOMES AND MEASURES The primary outcome was survival with good neurologic outcome, defined as Cerebral Performance Category (CPC) 1-2, at 90 days. Secondary outcomes were survival at 90 days and time to reach core body temperature less than 34°C. RESULTS Among the 677 randomized patients (median age, 65 years; 172 [25%] women), 671 completed the trial. Median time to core temperature less than 34°C was 105 minutes in the intervention group vs 182 minutes in the control group (P < .001). The number of patients with CPC 1-2 at 90 days was 56 of 337 (16.6%) in the intervention cooling group vs 45 of 334 (13.5%) in the control group (difference, 3.1% [95% CI, −2.3% to 8.5%]; relative risk [RR], 1.23 [95% CI, 0.86-1.72]; P = .25). In the intervention group, 60 of 337 patients (17.8%) were alive at 90 days vs 52 of 334 (15.6%) in the control group (difference, 2.2% [95% CI, −3.4% to 7.9%]; RR, 1.14 [95% CI, 0.81-1.57]; P = .44). Minor nosebleed was the most common device-related adverse event, reported in 45 of 337 patients (13%) in the intervention group. The adverse event rate within 7 days was similar between groups. CONCLUSIONS AND RELEVANCE Among patients with out-of-hospital cardiac arrest, trans-nasal evaporative intra-arrest cooling compared with usual care did not result in a statistically significant improvement in survival with good neurologic outcome at 90 days.

Background-Colony-stimulating factors (CSFs) have been shown to effectively induce arteriogenesis in the hindlimb.Moreover, clinical trials demonstrated positive effects of CSFs on arteriogenesis in patients with coronary artery disease. However, patients with cerebrovascular disease have not yet profited from treatments aimed at the growth of brain vessels. Thus far, angiogenesis studies have failed to demonstrate improvement of stroke outcome. Arteriogenesis differs from angiogenesis in that it substitutes arterial collaterals for the occluded artery. Methods and Results-We tested in a novel brain arteriogenesis rat model (occlusion of vertebral plus left carotid artery ) the application of CSFs or saline over 7 or 21 days. On 3-VO postmortem, latex perfusion demonstrated a timeand treatment-dependent arteriogenesis of the posterior cerebral artery (PCA). In saline-treated animals, the PCA diameter increased by 39%; in granulocyte-macrophage (GM)-CSF-treated animals, this increase was significantly faster (72% after 1 week). Functionally, saline-treated animals exhibited a decline of CO 2 reactivity (mm Hg) from 1.48% to 0.1% compared with GM-CSF-treated animals (1.43% arterial pCO 2 change after 1 week). This difference remained significant after 3 weeks. This functional improvement correlated with increased numbers of CD68-positive macrophages in histological sections of the PCA in GM-CSF-treated animals and only a few macrophages in saline-treated animals. Conclusions-To the best of our knowledge, this is the first report of stimulation of arteriogenesis in the brain. Key Words: arteries Ⅲ stroke Ⅲ cerebrovascular circulation Ⅲ drugs T he adaptive proliferation of preexisting collateral pathways (arteriogenesis) is an effective biological rescue system against detrimental effects of arterial stenosis. We have recently demonstrated that occlusion of the left carotid artery (CA) and both vertebral arteries induced a significant redistribution of blood flow via the left posterior cerebral artery (PCA), which increased its diameter 2-fold. Importantly, the induced hemispheric hypoperfusion was not severe enough to produce expression of the angiogenic factor VEGF (vascular endothelial growth factor) or histological injury. On the functional level, we demonstrated that this adaptive arteriogenesis led to a significant improvement of the hemodynamic capacity of the hypoperfused brain. Thus, we proposed a novel concept of brain protection by arteriogenesis: collateral artery growth as a means to prevent cerebral ischemia during progressing cerebrovascular disease. 1 Several experimental studies have shown that the speed of arteriogenesis is not limited to its natural time course. The infusion of CC chemokines (monocyte chemotactic protein-1), 2 fibroblast growth factors, 3 or granulocyte-macrophage colony-stimulating factor (GM-CSF) into the peripheral or coronary collateral circulation led to a significant increase in collateral conductance compared with untreated animals. The proarteriogenic effect of the latter ...

Summary:Experimental and clinical studies have provided evidence for spontaneous and therapeutically induced arteriogenesis after occlusion of major peripheral or cardiac vessels. Such evidence is lacking for the cerebrovascular system. In halothane-anesthetized rats, different degrees of brain hypoperfusion were induced by one-to four-vessel occlusion, that is, one or both common carotid arteries in combination with or without bilateral vertebral artery occlusion. The flow decline was monitored by laser Doppler flowmetry, the residual hemodynamic reserve by testing flow reactivity to ventilation with 6% CO 2 and arteriogenesis by intravascular latex infusion and immunohistochemistry of vascular proliferation and monocyte adhesion. The optimum condition for induction of arteriogenesis was three-vessel (one carotid plus both vertebral arteries) occlusion, which led to reduction of blood flow to about 50% and complete suppression of CO 2 reactivity, but no histologic injury. One week after three-vessel occlusion, the ipsilateral posterior cerebral artery significantly enlarged by 39%, and after 3 weeks by 72%, paralleled by the partial return of CO 2 reactivity and the appearance of immunohistochemical markers of arteriogenesis. Three-vessel occlusion is a reliable model for the induction of arteriogenesis in the adult brain and is a new approach for exploring the potentials of arteriogenesis for the prevention of progressing brain ischemia.