Acute HBP is very frequent in patients admitted to ICU after aIS, ICH, aSAH and scheduled neurosurgical procedures [10, 12, 15, 17] causing complications like hemorrhagic transformation, hematoma expansion, brain swelling, rebleeding, prolonged hospital stays, worse functional outcomes and death [4, 10, 12]. Its exact pathophysiological mechanism is mostly unknown but increase of systemic vascular resistances because of damage of brain areas regulating arterial baroreceptor reflex and activation of renin-angiotensin-aldosterone, sympathetic autonomic and hypothalamic-pituitary-adrenal systems  probably plays a role. Cerebral autoregulation could be impaired in these patients causing vasoconstriction and ischemia or vasodilation and increase of cerebral blood flow volume and intracranial pressure , both associated with brain secondary injury. For this reason, its highly recommended a thoughtful management of acute HBP in these patients.
In this study we aimed to observe effectiveness and safety of clevidipine for acute HBP management in neurocritical patients admitted to ICU after aIS, ICH and aSAH requiring surgical management and scheduled neurosurgical procedures, because in Europe clevidipine is only approved for HBP management in perioperative setting . Study design was based in the unique profile of neurocritical patient requiring urgent and effective management of HBP to potentially prevent major neurological complications, reduce mortality and improve functional outcomes, making more powerful studies difficult to perform. This design permitted also to observe acute HBP management in a real theater, because guidelines suggest different antihypertensive drugs  making this decision on UCI doctors experience and preferences. Goal SBP is controversial also and current guidelines recommend different thresholds based on limited evidence and according neurocritical diagnosis [7, 8, 9, 11].
Our patients were median age, both gender with chronic HBP associated to other cardiovascular risk factors, as early published evidence regarding neurocritical population . Chronic treated HBP seen in a higher number of patients, none with history of uncontrolled HBP and probably unknown HBP in a lower number of patients, could influenced our results and be paradoxical because severe neurocritical diseases of our patients should be expected if uncontrolled or unknown HBP were higher.
Our study included neurocritical patients admitted to ICU with acute HBP requiring safe and fast control with intravenous treatment besides usual critical care management involving monitoring, airway control and thromboprophylaxis. Scheduled neurosurgical procedures, aIS, ICH and aSAH were most frequent diagnosis requiring individualized approaches for HBP management according to guidelines [7, 8, 9, 11] Neurological situation at admission with half of patients presenting moderate to deep disturbance of consciousness level probably resulting of severe neurocritical diagnosis as indicated for high-risk neurosurgical procedures, hematoma volumes, NIHHS and Fisher scales. Hematoma volumes were higher [17, 21] and similar  than previously published, including patients in a higher risk of severe complications. Major neurological complications seen in half of patients were IH secondary to rebleeding, hematoma expansion, brain swelling and vasospasm, probably explaining IMV requirement and a moderate to severe disability according mRS in a higher number of patients. Mortality was paradoxically lower than expected (30%) based on neurological situation at admission and major complications.
Clevidipine showed a higher global effectiveness of 73% for acute HBP treatment in this study. Several facts reflected its main advantages for HBP control in neurocritical patients: 97% of patients achieved goal SBP within 1 hour of treatment begin, maintained it for a media of 71 hours, corresponding to higher than 75% of infusion length, and 45 hours after stopping it without need of additional different intravenous antihypertensive drugs. Clevidipine treatment was highly safe in this study presenting 3% of transient adverse events. Fast and longer maintenance of goal SBP with one-drug presenting only a few transient adverse events could be good advantages of clevidipine for acute HBP management in neurocritical patients. Based on current guidelines choice of antihypertensive treatment should be decision of critical care doctors, probably resulting of preferences and usual practice among centers [7, 8, 9, 10, 11]. In Europe, Clevidipine is available in some centers only since a few years and different intravenous antihypertensive drugs like urapidil, nicardipine and labetalol are more used. This could explain that clevidipine was chosen after failure of different intravenous antihypertensive treatment in a higher number of our patients.
SBP thresholds requiring treatment are controversial also and vary according to neurocritical condition [7, 8, 9, 10, 11], making up to 160 mmHg or higher than 20% of preoperative basal values for 15 or more minutes a rational approach for acute HBP management. In this study, clevidipine treatment began with SBP higher than 160 mmHg and significantly decrease to goal at first hour without differences between effective and no effective groups. Minimum doses slightly lower than recommended for manufacturer (1 mg/h) and volumes than previously published  with infusion length not significantly different between effective and no effective groups achieved goal SBP. Clevidipine infusion began not significantly different between effective and no effective treatment groups could be paradoxical, because in a higher number of patients with rescue treatment would be expected a later began of infusion than first line group, but probably the variable onset of acute HBP requiring urgent treatment in each neurocritical disease explained this result. Transition to oral antihypertensive treatment required very frequently but not significantly different between effective and no effective treatment groups probably resulting of chronic HBP in a higher number of patients. A significantly longer time within goal SBP, requiring lower maximum doses (4 mg/h) without need of additional intravenous antihypertensive drugs seen only in effective group were also good advantages of clevidipine treatment in neurocritical patients.
Analysis of subgroups showed a higher effectiveness of clevidipine treatment in patients admitted to ICU after urgent embolization of aneurysm causing aSAH, mechanical thrombectomy for aIS, scheduled neurosurgical procedures and presenting poor prognosis factors like ICH volumes higher than 30 ml and Fisher scores up to 3 points. Clevidipine treatment as first line, beginning early within 24 hours of ICU admission, maintained for higher than 3 days with volumes up to 500 ml showed a higher effectiveness also. These results could partly be explained for higher number of patients admitted for aSAH, aIS and scheduled neurosurgical procedures in this study, but factors related to treatment like first line, early and longer treatment for patients with severe neurocritical diseases as indicated for poor prognosis factors probably played a role and was a very interesting finding of this study not previously published as far as we know. Moderate and lower effectiveness of clevidipine treatment were probably explained for higher severity of neurocritical disease as indicated for coma, aIS with NIHHS score higher than 10 points, ICH and IH. Effective treatment was safe with a lower number of adverse events like previously mentioned for a global group. Major neurological complications and mortality of patients with effective treatment were lower, but functional situation of moderate to severe disability was not different to global group.
Clevidipine was safe in subgroups of patients with early begin and effective treatment maintaining goal SBP higher than 48 hours, according to our study definitions. Adverse events were more frequent in patients with first line treatment but as mentioned above it was lower, transient, mild and dose related not requiring treatment stopped.
Major neurological complications were lower in subgroups of patients with early begin and effective treatment. Mortality was lower in subgroups of patients with first line and effective treatment. Maintenance of SBP higher than 48 hours showed a slightly higher number of adverse events, major neurological complications and mortality than global group. Functional situation of moderate to severe disability was seen in all subgroups of patients like than global group. These results seem to indicate the benefits of effective and early treatment with clevidipine more than maintenance of goal SBP after 48 hours to reduce mortality and major neurological complications, but without changes in functional situation. First line treatment showed a higher effectiveness and lower mortality with a higher number of adverse events, probably because of a lower number of patients included in this subgroup, making this result difficult to interpretate. Nevertheless, severity of neurocritical disease probably is the key factor in these outcomes, making treatment facts of limited impact but early begin of treatment and effectiveness more than a longer maintenance of goal SBP could be played a role.
Hematoma expansion was seen in a higher number of patients than previously reported [17, 21, 22] with higher mortality and severe disability. Our results could be paradoxical because we observed hematoma volumes lower than 30 ml in a higher number of patients and spot sign in angiography brain CT in neither patient with this complication, unlike published evidence had been showed [10, 17, 21, 22, 23]. All patients presented risk factors like SBP higher than 180 mmHg, history of chronic HBP and association with IH [3, 5, 8]. Clevidipine treatment effectiveness in a lower number of patients with this complication seems plausible since a lack of acute HBP control had been showed to be related with this complication [3, 5, 8].
Rebleeding was seen in a lower number of patients after aSAH probably because early embolization of ruptured brain aneurysm in our hospital as guidelines recommended , but this is a paradoxical result because a higher number of patients with Fisher scores of 4 points with higher risk of this complication included in this study. Risk factors previously associated with rebleeding like SBP higher than 160 mmHg, Fisher score of 4 points and aneurysms of posterior brain circulation were seen in a higher number of our patients [4, 11, 24] with mortality and moderate to severe disability like global group. An interesting finding of this study was that clevidipine treatment was effective in a higher number of patients, probably indicating that early embolization and effective management of acute HBP with clevidipine should reduce this complication as evidence had been showed .
Vasospasm was seen also in a lower number of patients with aSAH probably because of early prophylaxis treatment with nimodipine in all patients in accordance with guidelines recommendations . Mortality was very low and functional situation was highly variable between mild symptoms to moderate disability. SBP higher than 160 mmHg, Fisher score of 4 points and effective treatment with clevidipine was seen in all patients with this complication. These results could be partly explained because this study included a higher number of patients with Fisher of 4 points whom are less prone to vasospasm, but additional effects of effective treatment with a calcium channel blocker like clevidipine and a lack of hypotension as indicated for SBP higher than 160 mmHg in all patients could contribute to reduce this complication. Nevertheless, the exact role of clevidipine for vasospasm prevention is difficult to observe since a higher mortality and disability related to this complication making difficult to perform more powerful studies to explore its benefits.
Our study has limitations related mainly to its little size and design. This retrospective and observational study made possible to describe the real theater of acute HBP management in neurocritical patients admitted to ICU. Our study showed a typical neurocritical population requiring urgent and effective treatment of acute HBP using clevidipine mainly as a rescue therapy, but these patients probably take advantages of a higher effectiveness and safety observed with early began of treatment. Additionally, our interesting findings related to effective and early treatment with clevidipine for reduce mortality and major neurological complications should be considered with caution because concerns about study design.
In conclusion, we observed that clevidipine was effective and safe treatment in neurocritical patients with acute HBP requiring urgent treatment with potential benefits related to mortality and major neurological complications. Clevidipine has pharmacological advantages in this population based on its shorter acting and smooth control of acute HBP. Observational design of our study in a real theater of neurocritical patients admitted to ICU prevent us to make stronger recommendations. Nevertheless, this original study including larger population than previously published as far as we know underscore advantages of clevidipine for acute HBP management in neurocritical patients.