Introduction: Although oxygen administration is fundamental in the management of aneurysmal subarachnoid hemorrhage (SAH) patients in the acute stage, hyperoxia has harmful effects. The effects of hyperoxia on neurological outcomes in SAH patients are unclear. We aimed to examine the association of hyperoxia during the first 24 h in the intensive care unit (ICU) with unfavorable neurological outcomes in SAH patients. Methods: We retrospectively selected consecutive adult patients admitted to ICU for SAH between January 2009 and April 2018. We defined normoxia during the first 24 h in ICU as PaO₂ of 60 mm Hg to 120 mm Hg, mild hyperoxia as PaO₂ of 121 mm Hg to 200 mm Hg, moderate hyperoxia as PaO₂ of 201 mm Hg to 300 mm Hg, and severe hyperoxia as PaO₂ of >300 mm Hg. Univariate and multivariate analyses were performed to examine the association between hyperoxia during the first 24 h in ICU and unfavorable neurological outcomes (i.e., modified Rankin scale score of 3–6 at hospital discharge). Results: Among 196 SAH patients, 90 had unfavorable neurological outcomes. Hyperoxia was observed in 93.4% of patients. No significant association was observed between unfavorable neurological outcomes and hyperoxia in overall patients. However, we found that early hyperoxia in ICU was significantly associated with unfavorable neurological outcomes in SAH patients with Hunt and Kosnik (H&K) grades I to III (Relative risk, 1.84; 95% confidence interval, 1.10–2.94; P = 0.02). Conclusions: Early hyperoxia was not associated with unfavorable neurological outcomes in overall SAH patients, but it was associated with unfavorable neurological outcomes in those with H&K grades I to III.

Background:Erythropoietin (EPO) has antiapoptotic and tissue-protective effects, but previous clinical studies using high-dose EPO have not shown cardioprotective effects, probably because of platelet activation and a lack of knowledge regarding the optimal dose. In contrast, a small pilot study using low-dose EPO has shown improvement in left ventricular function without adverse cardiovascular events. Methods and Results:We performed a multicenter (25 hospitals), prospective, randomized, double-blind, placebo-controlled, dose-finding study to clarify the efficacy and safety of low-dose EPO in patients with ST-segment elevation myocardial infarction (STEMI) under the Evaluation System of Investigational Medical Care of the Ministry of Health, Labor and Welfare of Japan. In total, 198 STEMI patients with low left ventricular ejection fraction (LVEF <50%) were randomly assigned to receive intravenous administration of EPO (6,000 or 12,000 IU) or placebo within 6 h of successful percutaneous coronary intervention. At 6 months, there was no significant dose-response relationship in LVEF improvement among the 3 groups tested (EPO 12,000 IU: 5.4±9.3%, EPO 6,000 IU: 7.3±7.7%, Placebo: 8.1±8.3%, P=0.862). Low-dose EPO also did not improve cardiac function, as evaluated by ^{99 m}Tc-MIBI SPECT or NT-proBNP at 6 months and did not increase adverse events. Conclusions:Administration of low-dose EPO did not improve LVEF at 6 months in STEMI patients (UMIN000005721).

Both ischemia and hypoxia increase adenosine production in the heart. This study tested whether hypoxia increases adenosine production in the coronary artery via ecto-5′-nucleotidase and the role of protein kinase C in this condition. Canine left circumflex coronary artery was rapidly removed and incubated in 10 mL Krebs-Henseleit solution for 30 minutes. The Krebs-Henseleit solution contained 5′-iodotubercidin and 2′-deoxycoformycin, which inhibit adenosine kinase and adenosine deaminase, respectively. Adenosine production was measured in intact coronary arteries under normoxic conditions (16.2±1.2 pmol/mg protein). Adenosine production was reduced by 27% after removal of endothelium. Ecto-5′-nucleotidase activity of coronary arteries with and without endothelium was 51±6 and 41±4 nmol/mg protein per minute under normoxic conditions. Hypoxia increased adenosine production to 27.0±2.3 and 20.0±0.8 pmol/mg protein with and without endothelium. Hypoxia also increased ecto-5′-nucleotidase activity of coronary arteries with and without endothelium (74±8 and 53±5 nmol/mg protein per minute;P<.05). Increases in adenosine production under hypoxic conditions were blunted by both an inhibitor of ecto-5′-nucleotidase and inhibitors of protein kinase C. Activation of ecto-5′-nucleotidase was blunted by an inhibitor of protein kinase C. These results indicate that hypoxia increased extracellular adenosine production and activated ecto-5′-nucleotidase via activation of protein kinase C in coronary arterial smooth muscle and endothelial cells. Increased adenosine production in coronary arteries during hypoxia may contribute to coronary vasodilation and cardioprotection against ischemic injury.