Factors Influencing Discontinuation of Clazosentan Therapy in Elderly Patients with Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study from a Japanese Single Center.

BACKGROUND Clazosentan is an endothelin receptor antagonist approved in Japan for preventing cerebral vasospasm and vasospasm-associated cerebral ischemia and infarction. This study included elderly patients aged ≥75 years with aneurysmal subarachnoid hemorrhage (SAH) and aimed to evaluate the factors associated with discontinuing anti-vasospasm therapy with clazosentan. MATERIAL AND METHODS In this single-center retrospective observational study, we extracted diagnostic and therapeutic work-up data of consecutive 40 patients with SAH treated with clazosentan infusion (10 mg/h) as first-line anti-vasospasm therapy between May 2022 and August 2023. Patient data were compared between the discontinued and completed groups, and related factors for the discontinuation were further analyzed. RESULTS Clazosentan was discontinued in 22% (n=9) of patients due to intolerable dyspnea accompanied by hypoxemia at 5±3 days after therapy initiation, in which 44% (n=4) were elderly (≥75 years). Patients who discontinued clazosentan therapy showed significantly lower urine volumes compared with those who completed the therapy (P<0.05). Multivariate regression analysis revealed that day-to-day urine volume variance and older age were independent risk factors for drug cessation (P<0.05). The cut-off value for predicting clazosentan discontinuation was -0.7 mL/kg/h with sensitivity of 86% and specificity of 75% (area under the curve: 0.76±0.10; 95% confidence interval: 0.56-0.96; P=0.035). CONCLUSIONS Our results suggest that approximately 20% of SAH patients suffered from intolerable respiratory symptoms attributable to hypoxemia. We found that both reduced day-to-day urine volume variation and older age are independent risk factors for drug discontinuation.

Cardiopulmonary Events of the Elderly (≥75 Years) during Clazosentan Therapy after Subarachnoid Hemorrhage: A Retrospective Study from a Tertiary Stroke Center in Japan.

Clazosentan has been shown to prevent vasospasm and reduce mortality in patients after aneurysmal subarachnoid hemorrhage (SAH) and has been approved for clinical use in Japan; however, its systemic events in the elderly (aged ≥ 75 years) have not been well-documented. Here, we report serious/intolerable cardiopulmonary complications requiring discontinuation of drug therapy in elderly SAH patients. In this single-center case series study, medical records of consecutive SAH patients treated postoperatively with clazosentan (10 mg/h) between June 2022 and May 2023 were reviewed retrospectively. Thirty-three patients received clazosentan therapy, of whom six were elderly with a mean age of 80.3 ± 5.2 (range 75-89) years. Among them, despite no obvious medical history of systemic abnormalities, clazosentan was discontinued in three (50%) patients due to pleural effusion and hypoxemia with or without hypotension at 5 ± 3 days after therapy initiation, which was higher than the incidence for younger patients (15%). The elderly patients had significantly lower urine output (1935 ± 265 vs. 1123 ± 371 mL/day, p = 0.03) and greater weight gain (2.1 ± 1.1 vs. 4.2 ± 1.9 kg from baseline, p = 0.04) than patients who completed the therapy. One 89-year-old female developed congestive heart failure and hydrostatic pulmonary edema associated with increased intravascular and lung volumes even after therapy was discontinued, while the remaining two cases recovered within 2 days after drug cessation. These results suggest that elderly patients are more vulnerable to fluid retention and have a higher risk of cardiopulmonary complications during clazosentan therapy than younger patients. Careful monitoring of urine volume and weight gain and caution regarding age- and therapy-related hemodynamic insufficiencies are required.

Pretreatment with tadalafil attenuates cardiotoxicity induced by combretastatin A4 disodium phosphate in rats.

Combretastatin A4 disodium phosphate (CA4DP) is a prodrug of combretastatin A4 (CA4), a microtubule-disassembling agent that exhibits antitumor effects by inhibiting tumor cell proliferation and inducing morphological changes and apoptosis in vascular endothelial cells in tumors. However, cardiotoxicity induced by ischemia and hypertension is a severe adverse event. In this study, we focused on the fact that phosphodiesterase (PDE) 5 inhibitors dilate the heart and peripheral blood vessels and aimed to investigate whether co-administration of tadalafil, a PDE5 inhibitor, can attenuate cardiotoxicity without altering the antitumor effect of CA4DP. To investigate cardiotoxicity, CA4DP and/or tadalafil were administered to rats, and blood pressure, echocardiography, histopathology, and cGMP concentration in the myocardium were examined. Administration of CA4DP increased systolic blood pressure, decreased cardiac function, lowered cGMP levels in the myocardium, and led to necrosis of myocardial cells. Co-administration of tadalafil attenuated these CA4DP-induced changes. To investigate the antitumor effect, canine mammary carcinoma cell lines (CHMp-13a) and human umbilical vein endothelial cells were cultured with CA4 and/or tadalafil, and cell proliferation and endothelial vascular tube disruption were examined. CHMp-13a cells were transplanted into nude mice and treated with CA4DP and/or tadalafil. CA4-induced inhibition of cell proliferation and disruption of the endothelial vascular tube were not affected by co-treatment with tadalafil, and the antitumor effects of CA4DP in xenograft mice were not reduced by co-administration of tadalafil. These results revealed that myocardial damage induced by CA4DP was attenuated by co-administration of tadalafil while maintaining antitumor efficacy.

Alzheimer's Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet.

Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated with Alzheimer's disease (AD). This is partly due to insulin resistance in the brain. Insulin signaling and the number of insulin receptors may decline in the brain of T2DM patients, resulting in impaired synaptic formation, neuronal plasticity, and mitochondrial metabolism. In AD patients, hypometabolism of glucose in the brain is observed before the onset of symptoms. Amyloid-ß accumulation, a main pathology of AD, also relates to impaired insulin action and glucose metabolism, although ketone metabolism is not affected. Therefore, the shift from glucose metabolism to ketone metabolism may be a reasonable pathway for neuronal protection. To promote ketone metabolism, medium-chain triglyceride (MCT) oil and a ketogenic diet could be introduced as an alternative source of energy in the brain of AD patients.

Hypoperfusion in the posterior cingulate cortex is associated with lower bone mass density in elderly women with osteopenia and Alzheimer's disease.

Accelerated bone loss is closely associated with Alzheimer's disease (AD), but the relationship between bone mineral density (BMD) and imaging markers of neurodegeneration remains uncertain. We examined the effect of low bone mass (osteopenia) on regional cerebral blood flow (rCBF) in patients with AD (n = 19) and non-demented aging (n = 12). We enrolled 31 female outpatients diagnosed with osteopenia (age ≥ 65 years) who had both a single-photon emission computed tomography brain scan and dual-energy X-ray absorptiometry bone scan taken at their initial investigation. We analyzed the relationship between osteopenia (-2.5 < T-score < -1) and rCBF in 62 cortical areas measured using the stereotactic extraction estimation analysis on single-photon emission computed tomography (SPECT) (mean Z-scores). We found that the mean Z-scores of 14 cerebral subregions, most of which are often affected early in AD, were significantly lower in the AD group than the non-demented group (P < .001). The age-stratified multivariate regression analysis showed that the decreased rCBF in the left posterior cingulate cortex (PCC) was an independent predictor of osteopenia (r = -0.395; P = .005). BMD and rCBF in the left PCC were significantly correlated in the overall population (r = -0.54; P = .001), as well as the AD group (r = -0.514; P = .02). These imaging data suggest that osteopenia may contribute to neurodegeneration of a brain network hub associated with AD.

Alzheimer's Disease and Specialized Pro-Resolving Lipid Mediators: Do MaR1, RvD1, and NPD1 Show Promise for Prevention and Treatment?

Alzheimer's disease (AD) is a common neurodegenerative disease and a major contributor to progressive cognitive impairment in an aging society. As the pathophysiology of AD involves chronic neuroinflammation, the resolution of inflammation and the group of lipid mediators that actively regulate it-i.e., specialized pro-resolving lipid mediators (SPMs)-attracted attention in recent years as therapeutic targets. This review focuses on the following three specific SPMs and summarizes their relationships to AD, as they were shown to effectively address and reduce the risk of AD-related neuroinflammation: maresin 1 (MaR1), resolvin D1 (RvD1), and neuroprotectin D1 (NPD1). These three SPMs are metabolites of docosahexaenoic acid (DHA), which is contained in fish oils and is thus easily available to the public. They are expected to become incorporated into promising avenues for preventing and treating AD in the future.

Non-invasive three-dimensional power Doppler imaging for the assessment of acute cerebral blood flow alteration in a mouse model of subarachnoid haemorrhage.

We aimed to evaluate the feasibility of a non-invasive method of cerebral blood flow (CBF) measurement using high-frequency power Doppler ultrasound imaging in a mouse model of subarachnoid haemorrhage (SAH). The 3-dimensionally (3D) reconstructed blood flow signals (%vascularity) within the brain volume of the middle cerebral artery territory correlated well with reference parameters, baseline carotid artery blood flow (r2  = 0.52, P < 0.0001) and normalized CBF changes (r2  = 0.74 P < 0.0001). These data suggest that the 3D power Doppler analysis may have the potential for reflecting real-time CBF changes during the acute phase of experimental SAH, which may be applicable to preclinical studies on early brain injury.

Effect of hippotherapy on gait symmetry in children with cerebral palsy: A pilot study.

We aimed to investigate the effect of hippotherapy on gait symmetry in children with cerebral palsy (CP). Twelve children with Gross Motor Function Classification System (GMFCS) levels II-IV received weekly hippotherapy lesson for 1 year. Gait analyses were performed during a 5-m walking test, using a portable, tri-axial accelerometer-based motion recorder. The baseline symmetry index derived from the Lissajous index (LI) figure before hippotherapy was greater than the LI in age-matched normal subjects (P < 0.01). Hippotherapy was associated with a decreased LI (-10.4 ± 4.9%, P = 0.018) and an improved GMFCS score (-0.6 ± 0.7, P = 0.02). These data suggest that hippotherapy has a beneficial effect on symmetry of the trunk movement in children with CP.

Clinical Utility of a Semiquantitative Method Using Lumbar Radiography as a Screening Tool for Osteoporosis in Elderly Subjects.

BACKGROUND Osteoporosis is a major global public health problem in the current aging era. Osteoporosis is often diagnosed only after patients have a fracture that causes a severe decline in ability to perform activities of daily life. Although the current criterion standard for diagnosing osteoporosis is dual-energy X-ray absorptiometry (DXA), this modality remains less prevalent among general practitioners in geriatric medicine. The aim of this study was to determine the diagnostic utility of visual inspection of lumbar radiography in detecting bone mineral density (BMD) decline. MATERIAL AND METHODS We retrospectively reviewed medical data of 78 patients who underwent both lateral lumbar radiography and DXA. Board-certified radiologists determined the clinical grade of each patient's condition according to the semiquantitative (SQ) method of lumbar fracture assessment. We compared the grades and young adult means of BMD in the lumbar spine and hips as measured using DXA. RESULTS BMD of the femoral neck was significantly lower in patients with severe osteoporosis (grades 2 and 3 as classified using the SQ method) than in those with mild osteoporosis (grades 0 and 1; P<0.05). A receiver operating characteristic curve analysis showed that the SQ method can help predict the decrease in BMD (young adult mean score of <70%) in the femoral neck with moderate accuracy (sensitivity, 0.621; specificity, 0.829; area under the curve, 0.742). CONCLUSIONS These results suggest that lateral lumbar radiography can provide useful information about bone mineral status and can serve as a tool for osteoporosis screening by general practitioners.

Assessment of Gait Symmetry in Elderly Women with Low Bone Mineral Density Using a Portable Trunk Accelerometer: A Pilot Study.

BACKGROUND Convincing evidence regarding gait and balance function in elderly women with low bone mineral density (BMD) and/or osteoporosis is limited. In the present study, we aimed to compare the gait characteristics in elderly women with and without low BMD and to analyze plausible parameter(s) for predicting low BMD. MATERIAL AND METHODS We retrospectively analyzed prospectively collected data of 26 consecutive postmenopausal women aged >65 years who were admitted to our geriatric outpatient service. They were assigned to 2 groups, with (n=14) and without (n=12) low BMD based on T-score (0.05). Receiver operating characteristic curve analysis demonstrated that LI can predict low BMD in the femur neck with moderate accuracy (area under the curve=0.75, 95% confidence interval 0.55-0.95; P=0.031). The optimal cut-off value was 17%, with 67% specificity and 86% sensitivity. CONCLUSIONS These results suggest that elderly women with low BMD may walk with asymmetrical trunk movement, but they are able to generate gait patterns similar to healthy peers. The LI may provide valuable quantitative information for preventing fractures in subjects with osteoporosis.

Common Data Element for Unruptured Intracranial Aneurysm and Subarachnoid Hemorrhage: Recommendations from Assessments and Clinical Examination Workgroup/Subcommittee.

BACKGROUND: Clinical studies of subarachnoid hemorrhage (SAH) and unruptured cerebral aneurysms lack uniformity in terms of variables used for assessments and clinical examination of patients which has led to difficulty in comparing studies and performing meta-analyses. The overall goal of the National Institute of Health/National Institute of Neurological Disorders and Stroke Unruptured Intracranial Aneurysms (UIA) and subarachnoid hemorrhage (SAH) Common Data Elements (CDE) Project was to provide common definitions and terminology for future unruptured intracranial aneurysm and SAH research. METHODS: This paper summarizes the recommendations of the subcommittee on SAH Assessments and Clinical Examination. The subcommittee consisted of an international and multidisciplinary panel of experts in UIA and SAH. Consensus recommendations were developed by reviewing previously published CDEs for other neurological diseases including traumatic brain injury, epilepsy and stroke, and the SAH literature. Recommendations for CDEs were classified by priority into "core," "supplemental-highly recommended," "supplemental" and "exploratory." RESULTS: We identified 248 variables for Assessments and Clinical Examination. Only the World Federation of Neurological Societies grading scale was classified as "Core." The Glasgow Coma Scale was classified as "Supplemental-Highly Recommended." All other Assessments and Clinical Examination variables were categorized as "Supplemental." CONCLUSION: The recommended Assessments and Clinical Examination variables have been collated from a large number of potentially useful scales, history, clinical presentation, laboratory, and other tests. We hope that adherence to these recommendations will facilitate the comparison of results across studies and meta-analyses of individual patient data.

Positron emission tomography/computed tomography as a clinical diagnostic tool for anterior mediastinal tumors.

PURPOSE: The purpose of this study was to assess the usefulness of positron emission tomography/computed tomography (PET/CT) in the differential diagnosis of anterior mediastinal tumors. METHODS: A total of 94 patients with anterior mediastinal masses or nodules (male, n = 41; female, n = 53; age, 17-84 years) were retrospectively evaluated. All patients were evaluated by PET/CT and the masses or nodules were histologically diagnosed in our institution. RESULTS: Anterior mediastinal masses and nodules were classified into two disease categories: Low (thymic hyperplasia, thymoma, mature teratoma, and MALT lymphoma) and High (thymic carcinoid, thymic cancer, diffuse large B-cell lymphoma, T-cell lymphoblastic lymphoma, Hodgkin's lymphoma, and malignant germ cell tumors) groups. The sensitivity and specificity of maximum standardized uptake value (SUVmax) 7.5 for the detection of High group were 77% and 100%, respectively. The SUVmax distributions of the WHO histological thymoma types and Masaoka stage thymomas extensively overlapped. Masaoka stage III thymomas had significantly higher SUVmax than Masaoka stage I thymomas. Regarding the TNM classification, the SUVmax of T3 and T1b thymomas was higher than T1a thymoma. CONCLUSION: Although the SUVmax of each disease overlapped, PET/CT findings provided useful information for the differential diagnosis of anterior mediastinal masses.

Development and exploration of a Japanese version of the cerebral palsy quality of life for children questionnaire for primary caregivers: a pilot study.

[Purpose] We aimed to translate and validate a Japanese language version of the cerebral palsy quality of life for children questionnaire for primary caregivers and assess the relationship between quality of life of Japanese parents and their children's motor skills. [Participants and Methods] Fifty children (aged 4 to 12 years) and their parents (mothers) were enrolled. The parent-proxy version of the cerebral palsy quality of life for children questionnaire translated to Japanese was administered, and a validation study was performed using Cronbach's α as the key metric. The relationships between the parents' quality of life and children's Gross Motor Function Classification Scale levels were analyzed. [Results] We found that the age of the children and their parents and gender of the children were not significant factors affecting the quality of life domains. Significantly high values of internal consistency were detected among items within each quality of life domain, wherein Cronbach's α was between 0.72 and 0.89. Two quality of life domains (Emotional well-being and Feeling about functioning) were significantly associated with Gross Motor Function Classification Scale levels. [Conclusion] Our data suggest that the original English version of the cerebral palsy quality of life for children questionnaire for primary caregivers was successfully translated to Japanese for use by Japanese-speaking parents caring for their children.

Evaluation of mitochondrial respiratory function in rat cardiomyocytes under different glucose conditions, using an extracellular flux analysis method.

We studied the effect of glucose supply on mitochondrial respiratory function (MRF) of neonatal rat cardiomyocytes, using a novel extracellular flux analysis. Fundamental respiratory parameters regarding oxygen consumption rate in mitochondria showed glucose concentration-dependent changes, where a significant increase or decrease in these parameters was observed to be associated with glucose concentrations ranging between 10% and 1000% of the concentration used in standard medium (3151 mg/L), respectively. By contrast, the extracellular acidification rate, a parameter of anaerobic activity, was shown to decrease under low-glucose conditions, whereas it increased after inhibiting complex V (ATP synthase) under the same glucose conditions. These findings provide a beneficial basis for various experimental studies on mitochondrial metabolism in cardiomyocytes.

Utility of electrical velocimetry-based noninvasive stroke volume variation in predicting fluid responsiveness under different ventilation modes in anaesthetized dogs.

We evaluated the utility of noninvasive stroke volume variation (SVV) as a functional haemodynamic predictor for fluid responsiveness under different ventilation modes [assist control (A/C), synchronized intermittent mandatory ventilation (SIMV), and continuous positive airway pressure (CPAP)] in 45 anaesthetized dogs, using an electrical velocimetry device. Receiver operating curve analysis confirmed the best predictive value during SVVA/C (12.5% of cut-off value; 75% sensitivity and 86% specificity) followed by SVVSIMV (13.5% of cut-off value; 75% sensitivity and 75% specificity), while no statistically significance detected during SVVCPAP (P > .05). These data suggest that SVV is useful for the prediction of fluid responsiveness in laboratory dogs during A/C and SIMV, while its reliability during CPAP is poor. This article is protected by copyright. All rights reserved.

Preceding functional tooth loss delays recovery from acute cerebral hypoxia and locomotor hypoactivity after murine subarachnoid haemorrhage.

Tooth loss and related changes in the functionality may lead to worse outcome of stroke patients, but the effect on hemorrhagic stroke remains unclear. This study aimed to determine the impact of impaired masticatory function on acute cerebral oxygenation and locomotor activity after experimental subarachnoid haemorrhage (SAH). Twenty C57BL/6 mice with (MC-treated group) or without (control group) prior treatment of cutting off the upper molars were subjected to SAH by endovascular perforation. Grading of SAH and acute cerebral infarction were assessed by MR images. Brain tissue oxygen saturation (SbtO2 ) by photoacoustic imaging and parameters related to locomotor activity by open-field test were analyzed serially after SAH. In all mice, global SbtO2 depression was notable immediately after SAH induction (P <.001), which recovered close to the baseline levels until day 3. However, MC-treated mice demonstrated a prolonged relative cerebral hypoxia (<40% of the baseline SbtO2) as compared to the control (3 ± 1 vs 1 ± 1 days; P <.05). The average distance travelled on day 7 and the ratio of central-area distance/total travelled distance by open-field test between days 7 and 14 were significantly lower in MC-treated mice than in the control mice (P <.05), although the occurrences of new infarction were not statistically different (P >.05). These data suggest a possible link between preceding masticatory impairment and early brain injury to deteriorate neurobehavioural function in patients after SAH.

Rapamycin protects against early brain injury independent of cerebral blood flow changes in a mouse model of subarachnoid haemorrhage.

We evaluated the neuroprotective role of rapamycin, a mammalian target of rapamycin (mTOR) kinase inhibitor, in cerebral ischaemia and locomotor function in a mouse model of subarachnoid haemorrhage (SAH). Pretreatment with rapamycin, an mTOR kinase inhibitor, resulted in better recovery from cerebral hypoxia early after SAH than control (P < .05), while the values of peak flow velocity in the middle cerebral artery did not change significantly (P > .05). Average distance travelled and the ratio of central-area distance/total travelled distance determined by open-field test after day 14 was significantly higher in mice pretreated with rapamycin than in control mice (P < .05). Inhibition of the mTOR pathway could be protective against post-SAH early brain injury, ameliorating brain tissue hypoxia and locomotor hypoactivity.

Reduced CBF recovery detected by longitudinal 3D-SSP SPECT analyses predicts outcome of postoperative patients after subarachnoid haemorrhage.

The aim of this study was to evaluate the impact of cerebral blood flow (CBF) recovery obtained from brain single-photon emission computed tomography (SPECT) images on postoperative outcome after aneurysmal subarachnoid haemorrhage (SAH). Twenty-nine patients who had undergone surgical clipping for ruptured anterior communicating artery aneurysms were analyzed prospectively. Routine measurements of CBF were performed using technetium-99 m hexamethyl propyleneamine oxine SPECT on days 4 and 14 after SAH. Regional voxel data analyzed by three dimensional stereotactic surface projection (3D-SSP) were compared between patients and age-matched normal database (NDB). In 3D-SSP analysis of all patients, cortical hypoperfusion around the surgical site in bilateral frontal lobes was evident on day 4 (P < .05 vs NDB), which was improved significantly on day 14. However, the recovery was less complete in patients with poor clinical grades (P < .05) and presenting symptoms attributable to delayed cerebral ischaemia (DCI) (P < .05) than those without. Multivariate analysis showed that patients with mild to moderate CBF recovery (relative Z-score differences of <4) (P = .014; odds ratio, 2.5; 95% confidence interval, 1.93-3.31) was independently associated with poor functional outcome at 3 months. We conclude that reduced CBF recovery detected by serial 3D-SSP SPECT image analyses can be a potential predictor of poor prognosis in postoperative patients after SAH.

Comparison of Noninvasive Dynamic Indices of Fluid Responsiveness Among Different Ventilation Modes in Dogs Recovering from Experimental Cardiac Surgery.

BACKGROUND Fluid resuscitation is a cornerstone of minimizing morbidity and mortality in critically ill patients, but the techniques for predicting fluid responsiveness is still a matter of debate. In this study, we aimed to evaluate the utility of noninvasive stroke volume variation (SVV), pulse pressure variation (PPV), and systolic pressure variation (SPV) as a dynamic predictor for assessing fluid responsiveness during different ventilation modes in anaesthetized, intubated dogs recovering from cardiac surgery. MATERIAL AND METHODS Thirty-six adult Beagle dogs undergoing experimental surgery for isolated right ventricular failure were monitored for SVV, PPV, and SPV simultaneously using electrical velocimetry device. The relationships between each indicator and SVI before and after volume loading were compared in 3 ventilatory modes: assist control (A/C), synchronized intermittent mandatory ventilation (SIMV), and continuous positive airway pressure (CPAP). Responders were defined as those whose stroke volume index increased by ≥10%. RESULTS In all of the indices, the baseline values were greater in responders than in nonresponders (P<0.01) under A/C and SIMV. Receiver operating curve analysis confirmed the best predictive value during A/C [area under the curve (AUC): SVV, 0.90; PPV, 0.88; SPV, 0.85; P<0.05] followed by SIMV (AUC: SVV, 0.86; PPV, 0.83; CPAP, 0.80; P<0.05), with their sensitivities and specificities of ≥7 5%. By contrast, no statistically significance detected in any parameter during CPAP (AUC: SVV, 0.71; PPV, 0.66; CPAP, 0.65; P>0.05). CONCLUSIONS SVV, PPV, and SVV are all useful to predict cardiac response to fluid loading in dogs during A/C and SIMV, while their reliabilities during CPAP are poor.

Acute cardiac support with intravenous milrinone promotes recovery from early brain injury in a murine model of severe subarachnoid haemorrhage.

Early brain injury/ischaemia (EBI) is a serious complication early after subarachnoid haemorrhage (SAH) that contributes to development of delayed cerebral ischaemia (DCI). This study aimed to determine the role of inotropic cardiac support using milrinone (MIL) on restoring acute cerebral hypoperfusion attributable to EBI and improving outcomes after experimental SAH. Forty-three male C57BL/6 mice were assigned to either sham surgery (SAH-sham), SAH induced by endovascular perforation plus postconditioning with 2% isoflurane (Control), or SAH plus isoflurane combined with MIL with and without hypoxia-inducible factor inhibitor (HIF-I) pretreatment. Cardiac output (CO) during intravenous MIL infusion (0.25-0.75 µg/kg/min) between 1.5 and 2.5 hours after SAH induction was monitored with Doppler echocardiography. Magnetic resonance imaging (MRI)-continuous arterial spin labelling was used for quantitative cerebral blood flow (CBF) measurements. Neurobehavioral function was assessed daily by neurological score and open field test. DCI was analyzed 3 days later by determining infarction on MRI. Mild reduction of cardiac output (CO) and global cerebral blood flow (CBF) depression were notable early after SAH. MIL increased CO in a dose-dependent manner (P<.001), which was accompanied by improved hypoperfusion, incidence of DCI and functional recovery than Control (P<.05). The neuroprotective effects afforded by MIL or Control were attenuated by hypoxia-inducible factor (HIF) inhibition (P<.05). These results suggest that MIL improves acute hypoperfusion by its inotropic effect, leading to neurobehavioral improvement in mice after severe SAH, in which HIF may be acting as a critical mediator.