Edited by: Tae-Hee Cho, Hospices Civils de Lyon, France
Reviewed by: Simone Beretta, Azienda Ospedaliera San Gerardo, Italy; Richard Leigh, National Institutes of Health, United States
Specialty section: This article was submitted to Stroke, a section of the journal Frontiers in Neurology
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In unsuccessful vessel recanalization, clinical outcome of acute stroke patients depends on early improvement of penumbral perfusion. So far, mean arterial blood pressure (MAP) is the target hemodynamic parameter. However, the correlations of MAP to cardiac output (CO) and cerebral perfusion are volume state dependent. In severe subarachnoid hemorrhage, optimizing CO leads to a reduction of delayed ischemic neurological deficits and improvement of clinical outcome. This study aims to investigate the effect of standard versus advanced cardiac monitoring with optimization of CO on the clinical outcome in patients with large ischemic stroke.
The OPTIMAL study is a prospective, multicenter, open, into two arms (1:1) randomized, controlled trial.
The results of this trial will provide data on the safety and efficacy of advanced hemodynamic monitoring on clinical outcome.
The trial was approved by the leading ethics committee of Freiburg University, Germany (438/14, 2015) and the local ethics committees of the participating centers. The study is performed in accordance with the Declaration of Helsinki and the guidelines of Good Clinical Practice. It is registered in the German Clinical Trial register (DRKS; DRKS00007805). Dissemination will include submission to peer-reviewed professional journals and presentation at congresses. Hemodynamic monitoring may be altered in a specific stroke patient cohort if the study shows that advanced monitoring is safe and improves the functional outcome.
Acute therapy in stroke focuses on restoring and optimizing the cerebral perfusion (CP) to reduce the final infarction volume and improve the clinical outcome (
However, former studies have shown that correlation of MAP, and organ perfusion depends on volume state (
In patients with severe subarachnoid hemorrhage (SAH) increased CO during constant, MAP levels lead to a higher cerebral blood flow reducing the rate of delayed cerebral ischemia (
The Optimizing cardiac out-Put To Increase cerebral penumbral perfusion in large Middle cerebral Artery ischemic Lesion (OPTIMAL) study aims to investigate the effect of advanced cardiac monitoring with optimization of CO levels in stroke patients. We hypothesize that advanced monitoring reduces the infarction volume and improves clinical outcome.
The OPTIMAL study is a prospective, multicenter, open, two-armed, randomized, and outcome-blinded trial. The participating centers are part of the IGNITE network.
All subjects with an ischemic stroke are eligible for participation if the following inclusion criteria are met:
Ischemic stroke ≥30% of the territory of the middle cerebral artery (visual assessment of CT or MR scans). Age between 18 and 85 years. Within 12 h of symptom onset/12 h from time last seen well. Patients without recanalization measures: inclusion within 3 h after hospital admission. Patients with recanalization therapy (i.v. thrombolysis, thrombectomy, or both): inclusion within 3 h after cessation of recanalization measures and persistent neurological deficit [with National Institute of Health Stroke Scale (NIH-SS) >10 points]. If patients are in a sedated state and cannot be clinically monitored, the vessel occlusion must be persistent (depicted by angiography or sonography). Written informed consent by the subject herself/himself, her/his legal representative or written/oral consent by a close relative or friend according to the patient’s presumed will and interest of participating in this study.
Subjects will be excluded from the trial if any of the following criteria is fulfilled:
Patients receiving recanalization measures: patients presenting with NIH-SS ≤10 points during recanalization measures or within 3 h after cessation of recanalization measures. Intracerebral hemorrhage. Premorbid modified Rankin (mRS) score ≥2. Severe comorbidities or malignant disease leading to a relevant impact on the 3 months outcome.
Subjects are randomly assigned to standard monitoring or standard plus advanced monitoring using an online-randomization tool (
All participating centers have adequate experience in the intensive care management of acute ischemic stroke.
All patients receive best medical care according to the standards based on the recommendations of the German stroke association. MAP levels of ≥80 mmHg have to be achieved for 48 h; volume (crystalloids) or catecholamines (noradrenaline and dobutamine) are to be administered if needed. According to our hospital standard of care, systolic blood pressure levels are limited to 160 mmHg in patients who underwent recanalization measures.
Patients receive standard plus advanced cardiac monitoring. Those monitoring systems (“Vigileo,” “PiCCO”) perform an analysis of the arterial pulse contour and calculate a cardiac index (CI; index results from CO and stroke volume related to body surface). Optimizing both parameters with MAP levels ≥80 mmHg and CI ranging between ≥3.0 and ≤4.5 has to be achieved for 48 h with volume (crystalloids) or catecholamines (noradrenaline and dobutamine) administration if necessary. According to our hospital standard of care, systolic blood pressure levels are limited to 160 mmHg in patients who underwent recanalization measures.
The monitoring systems calculate further parameters, which can be used to guide hemodynamic therapy: as a preload indicator the stroke volume variety (SVV) is calculated by (SVmax − SVmin)/SVmean with SVV >10% being a sign of volume depletion. The SVR index indicates vessel dilation and/or volume depletion [normal SVRI levels 1,700–2,400 dyn s/cm5/m2 (
The primary outcome is a dichotomized mRS score after 3 months score 0–3 versus 4–6 is compared within the treatment groups.
Dichotomized outcome of mRS score 0–3 versus 4–6 after 6 months, as well as 0–2 versus 3–6 after 3 and 6 months, change of NIH-SS on day 1, 2, 3, and 10 ± 3 are analyzed. Final infarction volume is calculated. Monitoring parameters (CI and MAP levels) as well as amount of fluid administration and catecholamines are analyzed. Furthermore, safety assessments include the following: in hospital mortality, days of hospital stay, number of secondary intracerebral hemorrhages, and duration and quantity of catecholamine treatment.
Data will be recorded in every participating center, and all data will be finally analyzed in the principle center (University Freiburg). Safety parameters will be thoroughly assessed (c.f. secondary outcomes).
Sample size calculations are based on the study of Mutoh et al. (
Statistical analysis will be performed as intention to treat. Summary statistics will be used for descriptive analysis.
The steering committee consists of the project leader Wolf-Dirk Niesen and the principle investigators of the participating centers. The study received funding for the patient randomization by the German Society for Neurointensive Care and Emergency Medicine (DGNI). Besides this, the study is exclusively driven by internal means of the participating centers.
Patients with acute ischemic stroke are screened for in- and exclusion criteria when admitted to the hospital. Randomization takes place within 3 h when no acute recanalization measures take place or within 3 h after cessation of recanalization measures. From then on, monitoring and optimizing of hemodynamic parameters are applied for the next 48 h in both groups. Data of NIH-SS scores are collected on day 1, 2, 3, and 10 ± 3, the data of mRS scores at time of discharge and after 3 and 6 months. A follow-up MRI is performed on day 10 ± 3.
The OPTIMAL study aims to investigate the effect of advanced hemodynamic monitoring with optimization of CO levels in stroke patients. We anticipate an advanced monitoring to improve clinical long-term outcome and reduce the infarction volume.
The penumbra concept describes tissue at risk due to hypoxemia around the infarction core. The fate of the penumbral tissue seems to be individually variable and depends on slight differences in perfusion (
Patients being treated with an i.v. thrombolysis and/or thrombectomy are excluded from this study within the first 3 h after completion of recanalization therapy due to the increased risk of secondary hemorrhages (
With focus on outcome parameters and since there are no hemodynamic data on severely ill stroke patients, we based our study on data of Ref. (
We believe that results of OPTIMAL will provide reliable data on hemodynamic monitoring and functional outcome in large ischemic stroke, thereby forming the basis of subsequent future studies.
The trial was approved by the leading ethics committee of Freiburg University, Germany (Reference Number: 438/14, date of approval: 29.01.2015) and the local ethics committees of the participating centers. The study is performed in accordance with the Declaration of Helsinki and its subsequent amendments and the guidelines of Good Clinical Practice. The study is registered in the German Clinical Trial register (DRKS; DRKS00007805). Dissemination will include submission of study results to peer-reviewed professional journals and presentation at congresses. Hemodynamic monitoring may be altered in stroke patients or in a specific stroke patient cohort if the study shows that advanced monitoring is safe and improves the functional outcome.
HF has performed literature research and put the topic in perspective of current knowledge. HF and W-DN have created the study design. AG and JZ gave support of creating the study design. Writing of the article has been performed by AG and JZ, as well of HF and W-DN.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.