Blood pressure augmentation in acute ischemic stroke

Journal of the Neurological Sciences 261 (2007) 63 – 73 www.elsevier.com/locate/jns

Blood pressure augmentation in acute ischemic stroke Robert J. Wityk ⁎ Associate Professor of Neurology, Johns Hopkins University School of Medicine, Co-Director, Cerebrovascular Division, Johns Hopkins Hospital, Phipps 126 B, 600 North Wolfe Street, Baltimore, MD 21287, United States Available online 19 June 2007

Abstract Although control of hypertension is established as an important factor in the primary and secondary prevention of stroke, management of blood pressure in the setting of acute ischemic stroke remains controversial. Given limited data, the general consensus is that there is no proven benefit to lowering blood pressure in the first hours to days after acute ischemic stroke. Instead, there is concern that relative hypotension may lead to worsening of cerebral ischemia. For many years, the use of blood pressure augmentation (“induced hypertension”) has been studied in animal models and in humans as a means of maintaining or improving perfusion to ischemic brain tissue. This approach is now widely used in neurocritical care units to treat delayed neurological deficits after subarachnoid hemorrhage, but its use in ischemic stroke patients remains anecdotal. This article reviews the cerebral physiology, animal models and human studies of induced hypertension as a treatment for acute ischemic stroke. Although there has not been a large, randomized clinical trial of this treatment, the available clinical data suggests that induced hypertension can result in at least short-term neurological improvement, with an acceptable degree of safety. © 2007 Elsevier B.V. All rights reserved. Keywords: Acute ischemic stroke; Blood pressure; Induced hypertension; Ischemic penumbra; Magnetic resonance imaging

1. Introduction Hypertension is a well-recognized risk factor for ischemic stroke. In the primary prevention of stroke, treatment of elevated blood pressure (BP) with antihypertensive medications is effective in reducing the risk of ischemic stroke [1,2]. In patients with cerebrovascular disease, however, the use of antihypertensive medication could theoretically precipitate ischemia in the setting of impaired cerebral perfusion. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) randomized both hypertensive and normotensive subjects who had recent stroke or transient ischemic attack (TIA) to either placebo or one of two treatment arms of antihypertensive medications [3]. In this large study of 6105 subjects, the risk of stroke over 4 years of follow-up was 10% in the active treatment group and 14% in the placebo group, with a relative risk reduction of 28% (95% CI 17–38, p b 0.0001). An important point is that patients were enrolled in the study no sooner than 2 weeks after stroke ⁎ Tel.: +1 410 955 2228; fax: +1 410 614 9807. E-mail address: [email protected]. 0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2007.04.033

onset. The appropriate treatment of BP in the setting of acute ischemic stroke (e.g. in the first few days after onset) remains unclear [4,5]. The exception is the management of BP in patients treated with intravenous (IV) thrombolytic therapy, where the currently accepted protocol recommends strict BP control below defined guidelines [6]. Over the past few decades, the concept of an “ischemic penumbra” in the setting of acute stroke has influenced our thinking about new stroke therapies [7]. In animal experiments, Astrup et al. [8] demonstrated a critical threshold of cerebral blood flow (CBF) below which neurons cease to function, but continue to survive for a period of time. These neurons potentially can return to a normal state of function with restoration of blood flow. Jones et al. [9] replicated these findings and suggested that the time window in which ischemia is reversible is in the range of several hours. Our current concept of the ischemic penumbra is a region of brain with a gradient of depressed CBF, in which the core of the infarct has the lowest flow and is irreversibly damaged (Fig. 1) [10,11]. The regions surrounding the core, the “penumbra,” are ischemic and dysfunctional, but could potentially survive hours. The length of time the ischemic

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Fig. 1. Ischemic penumbra. This diagram indicates two regions within an acute ischemic infarct — a smaller core of irreversibly infracted tissue surrounded by a penumbra of hypoperfused and dysfunctional tissue. Timely reperfusion of the region of hypoperfusion outside of the core region may result in rescue of brain tissue and improvement in neurological function.

penumbra persists is controversial, but is likely highly individualized from patient to patient, and dependent upon the location of cerebral vessel occlusion, the rapidity of occlusion, and the adequacy of collateral blood flow [10]. With timely reperfusion, the region of ischemic penumbra may be rescued from infarction. This hypothesis also suggests that BP reduction in the setting of acute ischemic stroke may lead to hypoperfusion of the penumbra and hasten extension of the infarct [12]. The traditional approach to the study of stroke treatment is to use animal models with either transient or temporary cerebral artery occlusion. This allows for quantitation of cerebral blood flow and cerebral infarction in a controlled setting. Newer neuro-imaging techniques have allowed a window into understanding some of these factors in humans with stroke, using a variety of techniques to identify and follow the fate of the ischemic penumbra. Logistical problems and the constraints of a very short time window to study human stroke have limited such studies, but diffusionweighted and perfusion-weighted magnetic resonance im-

aging (MRI) has become one of the most widely used techniques. Diffusion-weighted imaging (DWI) reveals areas of cerebral injury within minutes to hours after onset of ischemia. Although reversible in exceptional circumstances, the DWI lesion represents for practical purposes the core of the infarct. Perfusion-weighted MRI (PWI) utilizes tracking of a bolus of gadolinium to generate relative CBF maps and represents the region of hypoperfusion. The difference between the PWI lesion and the DWI lesion (the “diffusion– perfusion mismatch”) can be operationally used as a representation of the ischemic penumbra (Fig. 2) [13]. This review will briefly examine the natural history of BP changes after ischemic stroke, review selected animal studies of the effect of BP manipulation on cerebral blood flow, and finally review the human studies reported to date of induced hypertension used as a treatment for ischemic stroke. The recent use of diffusion- and perfusion-weighted MRI in patients during induced hypertension has opened a new means of studying brain function, and may also provide a useful tool in applying this treatment to stroke patients. 2. Natural history of blood pressure after ischemic stroke An increased BP is common in patients presenting with acute stroke, particularly in patients with pre-existing hypertension [14]. In most cases, BP spontaneously declines in the first few days after stroke onset, but a significant decline can be seen even in the first few hours after onset in about a third of patients [15]. A number of studies have examined the relationship of admission BP (or BP changes in the first few days) with subsequent patient outcome [16–23]. These studies do not provide a clear consensus. Many studies note an association of poor outcome with patients with high admission BP [16,21]. Others have noted a smaller chance of progressive stroke with higher BP [18], and worse outcome with a drop in BP after admission [20]. The argument can be made that higher BP may be a consequence of more severe stroke, rather than higher BP causing worse outcomes [24]. For example, Mattle et al. [23] reported that there was a

Fig. 2. MRI of diffusion–perfusion mismatch. Image A is a diffusion-weighted MRI showing minimal signal change (bright region) in the left basal ganglia and temporal lobe. Image B taken on the same date is a perfusion-weighted MRI showing a large area of hypoperfusion (dark region, arrow) in the left temporal lobe. Attempts at reperfusion were not successful, and the final infarct was demonstrated in image C (FLAIR) several weeks later.

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greater spontaneous drop in BP after admission in patients who had good recanalization after intra-arterial thrombolysis, as compared to patients with inadequate recanalization. In the largest study to date, over 17,000 patients in the International Stroke Trial were analyzed, correlating admission systolic BP with the risk of a poor outcome (defined as death or dependent status at 6 months) [25]. This study showed a “U”-shaped curve, where either very low or very high admission BP was associated with poor outcome (Fig. 3). These findings were subsequently replicated in a hospital-based stroke registry [26]. Only a few studies have examined the effect of BP reduction in patients with acute ischemic stroke [27–30]. The Cochrane Review found five trials with a total of 218 subjects studied [31]. The data was felt to be too limited to establish the effect of BP reduction on clinical outcome. The American Stroke Association Guidelines suggest that in most cases, it is not imperative to lower BP in the acute setting [5]. From a clinical perspective, there are a number of case reports and series describing clinical worsening with excessive BP lowering [32,33]. The opposite approach – pharmacologic elevation of BP as a treatment for stroke – has been studied intermittently for a number of decades. In 1952, Derek Denny-Brown noted in his Shattuck Lecture on current stroke research that, “In carotid insufficiency the most physiologic treatment is one that maintains or raises the level of blood pressure yet obtains some measure of cerebral vasodilatation” [34]. 3. Induced hypertension — animal studies Early experimental stroke studies in animals revealed factors that influenced CBF in the normal animal and in animals with ischemia produced by large vessel occlusion. Changes in mean arterial blood pressure (MAP) within a range of about 50 to 150 mm Hg did not affect CBF in

Fig. 3. Admission blood pressure and outcome. Data from the International Stroke Trial demonstrates increased poor outcome (death — solid line, death plus dependency — dashed line) at lower and higher admission blood pressures (Adapted with permission from [25].).

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normal animals due to cerebral autoregulation [35]. However, cerebral autoregulation is impaired in ischemic brain, with ischemic regions having virtually no autoregulation at all [36]. As a result, within the regions of ischemic brain, there is a linear increase in CBF with increase in MAP [35,37,38]. Similar loss of autoregulation in regions of brain ischemia has been demonstrated in human studies as well [39,40]. These studies led to the concept of using BP elevation (“induced hypertension”) as a means of cerebral reperfusion. Denny-Brown recognized that TIAs in patients with large vessel occlusion were often precipitated by a fall in blood pressure, particularly in patients with limited collateral supply [41]. Similar changes in cortical perfusion could be seen with BP manipulation in experimental monkey stroke model where cortical vessels were directly observed through a craniotomy window [42]. In a number of animal studies, elevation of BP correlated with elevation of CBF, and in some studies this also resulted in functional neuronal recovery as measured by neurophysiologic tests [35,37,38,42–48]. One group, however, reported adverse cardiac consequences of prolonged induced hypertension in a primate stroke model [49]. As discussed earlier, Astrup et al. [38] used the term “ischemic threshold” to describe the level of CBF where neuronal function was impaired but the neurons were still intact. In an MCA stroke model, Astrup demonstrated that raising MAP with the vasopressor agent aramine resulted in restitution of neuronal function as measured by evoked potentials (Fig. 4). In similar experiments, Hayashi et al. performed CBF studies in unanesthetized monkeys in a transient 4-hour middle cerebral artery (MCA) occlusion model using a removable ligature around the artery [37]. After closure of the ligature, the monkeys developed a range of measurable neurological deficits. MAP was elevated to 20 to 40% above baseline using IV phenylephrine, starting 30 min after MCA occlusion. Some degree of neurologic improvement was noted in all animals along with improvement of CBF in ischemic brain. Although there was a trend towards smaller infarct size measured by histology comparing induced hypertension versus control animals (10 monkeys each), the findings were not statistically significant. The authors also noted that the neurological deficits appeared to be MAPdependent in some monkeys, such that the exam improved with higher MAP and deteriorated when the MAP fell. In a series of experiments using a rat MCA occlusion model, Drummond et al. likewise found that induced hypertension during the period of MCA occlusion reduced the area of severe hypoperfusion as compared to control [45]. The presumption was that increased cerebral perfusion pressure improved blood flow via collaterals. The same group also suggested potential for benefit of a brief period of induced hypertension in a transient MCA occlusion model, when the induced hypertension was given during the period of reperfusion [50]. Worsening of cerebral edema or cerebral hemorrhage was not seen in these experiments.

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4. Induced hypertension — clinical studies

Fig. 4. Animal model of induced hypertension. Tracings of neuronal function (EP% — evoked potentials), extracellular potassium (Ke), extracellular pH (pHe), and mean arterial blood pressure (MABP). Shortly after the beginning of the tracing (point “A”), the middle cerebral artery is occluded, resulting in a substantial drop in evoked potentials and pH, and a modest release of potassium. At point “B”, an IV infusion of the pressor agent aramine results in elevation of MABP with concomitant return to normal of the evoked potential. However, when the MABP is lowered again and the animal made hypovolemic by bleeding (point “C”), the evoked potential is rapidly lost and marked release of potassium indicates cell death in the region of infarction. (Adapted with permission from [38].).

Smrcka et al. [47] studied the time course of the effect of induced hypertension in a rabbit MCA occlusion model using cortical laser Doppler perfusion imaging. With 1-hour MCA occlusion, induced hypertension resulted in an improvement of CBF to almost half of baseline values, with a significantly smaller infarct volume as compared to controls (Fig. 5). However, with a 2-hour MCA occlusion, CBF gradually deteriorated despite continued MAP elevation into the second hour, where it approached CBF values of the control group. Despite this, the infarct volume appeared smaller with treatment, although not statistically significant. Of concern was that in the induced hypertension animals, 3/7 animals had intracerebral hemorrhage as compared to 0/7 controls. Of note, in this study, the treated animals had a target MAP elevation of 60 mm Hg or more over baseline. Using a different animal model, Hosomi et al. [48] suggested that induced hypertension using phenylephrine was beneficial if the MAP was elevated to 21+/−4 mm Hg (mean+/− S.D.) above baseline, but elevation to 42+/−8 mm Hg resulted in increased cerebral edema and adverse events with poor outcome.

Anecdotal clinical reports of the use of induced hypertension to treat acute ischemic stroke date back to the 1950's. Shanbrom and Levy [51] reported two patients (one with an internal carotid artery occlusion and one with basilar artery thrombosis) who had fluctuating neurologic deficits followed by persistent neurologic deterioration. Both showed transient improvement in neurologic function after systemic blood pressure was elevated using intravenous norepinephrine. Farhat and Schneider [52] reported clinical improvement in 4 patients using induced hypertension. Cerebral ischemia was caused by large vessel occlusion from various causes (e.g. tumor compression of the internal carotid artery, occlusion of the internal carotid artery for treatment of an intracranial aneurysm). Patients appeared to have a blood pressure threshold below which neurologic deficits returned. Wise [53] reported use of vasopressor-induced hypertension in two patients with acute ischemic stroke as a consequence of arteriography. In the first patient, induced hypertension could be discontinued after 5 h without recurrence of neurological deficit. In the second patient, treatment was continued for 2 days, until the patient underwent a carotid endarterectomy. Wise [54] then went on to report a series of 13 patients with acute ischemic stroke who were treated with IV levarterenol as a vasopressor agent. Treatment was generally initiated within several hours of onset of symptoms. Fairly rapid clinical improvement (e.g. within an hour of induced hypertension) was noted in 5/13 patients, and improvement was maintained in 3/5 patients when assessed 24 h later. In many of these patients, neurologic deficits appeared to be BPdependent and returned when hypertensive treatment was stopped. In these cases, deficits improved again with reinstitution of induced hypertension. Baseline MAP was between 65 and 100 mm Hg in the five responders and a

Fig. 5. Animal model of middle cerebral artery occlusion. Infarct volume after 1 hour of ischemia is significantly reduced in animals treated with induced hypertension. After 2 h of ischemia, there is a suggestion of reduction in infarct size with induced hypertension, but this is not statistically significant (Adapted with permission from [47].).

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threshold response was seen after a MAP elevation of between 13 and 30 mm Hg above baseline. No systemic complications were reported. Human studies by Olsen [39] and Agnoli [40], examined the effects of induced hypertension on CBF using intracarotid tracer injection methods. Areas of cerebral hypoperfusion showed partial reperfusion with elevation of systemic blood pressure, confirming the relative loss of autoregulation in ischemic brain (Fig. 6) [39,40]. Similar findings were described in a patient studied by positron emission tomography [55]. Despite these early positive reports, induced hypertension did not achieve widespread use because of the perception of a high risk of intracerebral hemorrhage (ICH) and worsening of brain edema. Olsen [56] recognized by CBF studies that some patients with acute stroke had persistent ischemia, while others had reperfusion of the infarct associated with hyperemia, presumably due to either dissolution or distal migration of an embolus. In the latter situation, induced hypertension would be expected to worsen brain edema or lead to hemorrhage. Although induced hypertension was never widely adopted by neurologists for ischemic stroke treatment, its use instead shifted into the Neurology/Neurosurgery Critical Care Unit (NCCU) as a temporary treatment for cerebral hypoperfusion, e.g. during aneurysm clipping or intentional large vessel occlusion. In addition, induced hypertension became part of the management of delayed cerebral ischemia after subarachnoid hemorrhage (SAH). Treatment of vasospasm after SAH is an analogous to treatment of ischemic stroke, except that it can be detected early and treated expectantly. Although never subjected to a rigorous clinical trial, hypervolemic/hypertensive therapy has become an accepted treatment in the NCCU for patients with delayed focal neurologic deficits after SAH [57,58]. Induced hypertension results in neurological improvement in a fairly short period of time with minimal systemic toxicity. Miller et al. [59] reported a series of 25 patients with SAH treated with

Fig. 6. Loss of cerebral autoregulation. In regions of cerebral ischemia in humans, regional cerebral blood flow (rCBF) appears to vary linearly with mean arterial blood pressure (MABP), suggesting loss of cerebral autoregulation (Adapted with permission from [39].).

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volume expansion and IV phenylephrine. Two-thirds of the patients had underlying cardiac disease, hypertension or peripheral vascular disease. MAP was elevated an average of 25% over baseline. Only one patient had an adverse event related to therapy – worsening of a pre-existing bradycardia – that resulted in discontinuation of phenylephrine. No other cardiac or cerebral complications occurred relative to the intervention. 5. Pharmacologic agents for induced hypertension The ideal agent for induced hypertension should be available for IV administration, have rapid onset and easy titration, be devoid of adverse effects, and raise BP without raising ICP. Phenylephrine is a selective α1 adrenergic receptor agonist that increases BP by peripheral vasoconstriction, without increasing cardiac output or heart rate. The primary safety concern is that it has the potential to reduce cardiac output due to increased afterload. Some patients experience a vagally-induced reflex bradycardia on initiation of the drug. Other major adverse effects include ischemic bowel and digital necrosis, particularly in patients who are hypovolemic. Therefore, patients should be adequately hydrated prior to initiation of IV phenylephrine and monitored by cardiac telemetry and clinical evaluations for congestive heart failure, renal failure and digital ischemia. In theory, phenylephrine should have minimal effects on the cerebral vasculature, as there are relatively few á1 receptors in the brain [60]. Norepinephrine is a potent á1 adrenergic receptor agonist with some β1 agonist activity. Similar to phenylephrine, it raises MAP by increasing systemic vascular resistance and is expected to have similar effects on cerebral hemodynamics. Dopamine produces dose-dependent effects, with cardiac inotropic and chronotropic effects at a moderate dose and arterial vasoconstriction at high doses. Compared to phenylephrine and norepinephrine, dopamine is more arrhythmogenic and has not been evaluated in ischemic stroke treatment. Human data concerning the effects of these drugs on cerebral hemodynamics is limited. Schwartz et al. studied 19 patients with large MCA territory strokes (N2/3 MCA territory) treated briefly with IV norepinephrine to raise MAP by at least 10 mm Hg [61]. All patients were intubated, anesthetized, and had ICP monitors. In some patients, bilateral TCD measurement of MCA peak mean flow veloc\ities were recorded before and during induced hypertension. With MAP elevation, there was parallel elevation of CPP, but no significant change in ICP. Ipsilateral to the stroke, MCA peak mean flow velocities rose with elevation of MAP. In the hemisphere contralateral to the stroke, however, MCA peak mean flow velocities showed some increase, but to a much lesser degree. There were no cardiac or cerebral complications associated with induced hypertension. These findings are consistent with the concept that autoregulation is relatively impaired in the ischemic hemisphere as compared to

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the intact hemisphere, and within the parameters of MAP elevation studied, there was no increase in ICP or deterioration of CPP. 6. Induced hypertension — recent clinical Studies Over the past few decades, patients with ischemic stroke have been occasionally treated with induced hypertension in the NCCU setting, and reported in retrospective or prospective case series (Table 1). Rordorf [62] reviewed 30 ischemic stroke patients treated in the NCCU with induced hypertension and compared them to 30 similar stroke patients admitted to the NCCU during the same time period treated with standard therapy. IV phenylephrine was used to increase BP until a threshold was found at which point neurologic deficits improved. Treatment was started within 24 h of stroke onset. Patients had no evidence of hemorrhage on admission head CT, and all were treated with concomitant IV heparin. Induced hypertension was continued for a mean of 110 h (range 7–576 h). A systolic blood pressure (SBP) threshold associated with neurologic improvement was found in 10/30 (33%) of the patients treated. The SBP threshold ranged from 130 to 180 mm Hg. Improvements in neurologic deficits typically occurred within 2 to 30 min of raising BP. At the time of last follow-up, 4/10 patients who responded had no neurologic deficit and no infarct on imaging studies, despite the fact that they had an average of 10 h of neurological deficit before improvement. There was no overall difference in terms of neurological or cardiac complications between the patients treated with induced hypertension and patients without blood pressure manipulation. There was a trend towards higher CPK values in the treated patients, and one treated patient developed transient atrial fibrillation. In contrast, the nontreatment group had higher rates of ICH and cerebral edema

on CT scan. Since this was a non-randomized, retrospective review, it is possible that the presence of certain CT features led to a selection bias of treatment. The same investigators subsequently went on to perform a prospective study of induced hypertension using IV phenylephrine in a defined protocol [63]. All subjects had acute ischemic stroke and were treated within 12 h of onset of symptoms. Exclusion criteria included recent cardiac ischemia, congestive heart failure, intracerebral hemorrhage or signs of cerebral edema on initial head CT scan. All patients had admission SBP of b200 mm Hg. The goal was to increase SBP to at least 160 mm Hg or to 20% above the admission SBP, with a maximum allowed SBP of 200 mm Hg. Neurological improvement was defined as a reduction by at least 2 points in the NIHSS performed by two independent examiners. To avoid misinterpretation of spontaneous improvement as treatment-related improvement, phenylephrine was discontinued in all responders. After SBP returned to baseline for 20 min, the patient was examined for neurological deterioration. A blood pressure threshold was defined as a SBP below which the patient deteriorated and above which the neurologic deficit was reversed. Of 18 patients screened, four did not meet the inclusion criteria (two with initial SBP N 200 and two with EKG changes consistent with cardiac ischemia) and one declined participation. All 13 enrolled subjects were outside the time window for IV thrombolysis. A beneficial neurologic response was seen in 7/13 patients with BP elevation. Induced hypertension therapy was continued for 1 to 6 days, and eventually successfully weaned in all patients. In the responders, the neurological deficit did not worsen between discontinuation of induced hypertension and time of discharge. At the time of discharge, the mean NIHSS was 7.4 (range 2 to 15) among responders, as compared to an NIHSS

Table 1 Recent induced hypertension studies Study

Number of patients

Rordorf 13 (all treated) [63] Hillis [69]

15 (9 treated, 6 controls)

Entry criteria b12 h from onset of symptoms

Intervention

increase systolic BP to 160 mm Hg or 20% above baseline b7 days from onset, Increase MAP until presence of diffusion– response or maximum perfusion MRI mismatch MAP of 140 mm Hg

Outcome

Results

Serious adverse events

2 point improvement in NIHSS

7/13 (54%) responders

None

Mean NIHSS of treated vs. controls

Greater improvement of mean NIHSS by day 3 in treated group 6/9 (67%) responders Marzan 34 (all treated but b24 h from onset, Increase systolic BP to z2 point improvement 9/34 (26%) responders; [71] 8 also treated with SBPV 140 mm Hg 10 to 20% above baseline in NIHSS 5/26 (19%) responders thrombolysis) excluding thrombolysis patients Koenig 100 (46 treated, b7 days from onset, with “Intention to treat” with Adverse events, median Median NIHSS improved [72] 54 controls) diffusion–perfusion MRI any type of blood NIHSS improvement by 3 in treated v. 2 in on admission pressure elevation by discharge standard therapy (N.S.)

None

1 cardiac arrhythmia, 1 ICH

Treated: 2 ICH, 1 CHF, 1 HTE standard: 2 CHF, 2 MI

Abbreviations: BP — blood pressure; NIHSS — National Institutes of Health Stroke Score; MRI — magnetic resonance imaging; MAP — mean arterial pressure; ICH — intracerebral hemorrhage; N.S. — not statistically significant; CHF — congestive heart failure; HTE — hypertensive encephalopathy; MI — myocardial infarction.

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of 10 (range 5 to 15) among non-responders. The etiology of stroke was classified using the TOAST classification [64]. There were 6 patients with cardio-embolism, 4 with cryptogenic or other causes of stroke, 2 with large artery atherosclerosis and 1 with a lacunar stroke. The number of subjects was too small to correlate response rate with stroke mechanism. Despite the presence of multiple cardiovascular risks factors in the patients enrolled, there were no systemic, cardiac or neurologic complications associated with treatment. At our institution, Hillis et al. began using DWI and PWI to study the topography of aphasia and cognitive function in acute stroke patients [65,66]. One patient studied in detail was a 55 year-old right-handed man with a left carotid artery occlusion who had a left MCA territory infarct primarily involving the frontal lobe [67]. Neurologic examination revealed a transcortical motor aphasia with telegraphic speech and frequent paraphasias. DWI revealed a large region in the frontal lobe of restricted diffusion, but PWI showed an even larger area of hypoperfusion also involving the anterior temporal lobe (Wernicke's area) (Fig. 7A). On serial testing, it was noted that his language ability fluctuated, and worsened with a relative drop in BP. He was treated with induced hypertension to increase his MAP from a baseline of 88 mm Hg to a maximum of 100 mm Hg. A PWI study with the

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MAP maintained at the higher level showed reperfusion of Wernicke's area (Fig. 7B). A concurrent language evaluation showed a marked improvement in word and sentence comprehension at the higher MAP, consistent with the expected language function of this region. The patient was eventually transitioned from IV phenylephrine to oral medications (fludrocortisone, salt tablets and midodrine) to maintain his elevated MAP. By two months after stroke onset, he could be tapered off of these oral medications without worsening of aphasia and with return to his normal BP. A repeat PWI at that time showed persistence of normal perfusion to Wernicke's area and no expansion of the infarct beyond the original DWI abnormality (Fig. 7). The remarkable feature of this case was that induced hypertension resulted in partial but objective neurologic improvement when started 7 days after onset of stroke. Similar findings were subsequently reported in 5 other patients treated with induced hypertension 1 to 9 days after ischemic stroke [68]. With this preliminary experience, Hillis et al. went on to perform a prospective, unblinded study of induced hypertension in 17 consecutive ischemic stroke patients [69]. Two patients refused consent, so a total of 15 subjects were randomized in a 2:1 ratio to induced hypertension or standard stroke care. Patients were included if they had acute ischemic stroke presenting within 1 and 7 days of onset of

Fig. 7. Reperfusion with induced hypertension. Diffusion-weighted (DWI) and perfusion-weighted (PWI) MRI images from a 55 year old man with a left middle cerebral artery territory infarct. Panel A shows the admission study with a moderately large infarct on DWI involving the left frontal lobe and part of the basal ganglia (white area). PWI on admission shows a more extensive region of hypoperfusion with extension into Wernicke's area (arrow on all images). In panel B, patient has had elevation of blood pressure while the MRI is obtained. The DWI lesion is maturing, but the PWI region of hypoperfusion has shrunk, particularly in Wernicke's area. Later, in panel C, the patient has had recanalization of the left middle cerebral artery with resolution of the PWI lesion. He has a persistent infarct in the left frontal lobe, but has spared Wernicke's area. (From [67].).

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symptoms, a quantifiable neurologic deficit, and a diffusion– perfusion mismatch of 20% or greater on baseline MRI scan. Exclusion criteria included recent cardiac ischemia, congestive heart failure, hemorrhage on CT scan, or contraindication to IV phenylephrine use. All patients had DWI-PWI, NIHSS and a cognitive battery of tests at baseline and at day 3 of induced hypertension. The treatment protocol was similar to the IV phenylephrine use described by Rordorf et al. [63] MAP was increased initially with withdrawal of antihypertensive medications, then with infusion of IV normal saline infusion, and then finally with IV phenylephrine. MAP was increased in increments of 10–20% above baseline with a goal to improve NIHSS by N 2 points. The maximum allowed MAP was 140 mm Hg. All patients treated with induced hypertension were admitted to the NCCU for continuous BP and EKG monitoring. Most patients showed improvement in the neurologic deficit over the first 3 days after randomization, with a mean NIHSS of 11.5 at baseline and a mean NIHSS of 8.3 at day 3. Nine patients were randomized to induced hypertension and six to standard care. The two groups were similar in terms of age, baseline NIHSS and volume of DWI and PWI lesions on baseline MRI scan. By day 3, patients in the induced hypertension treatment arm had a significantly better mean NIHSS (5.6 vs. 12.3, p b 0.02) as compared to the standard treatment group, and this difference persisted until the time of last follow-up at 6 to 8 weeks (mean NIHSS 2.8 vs. 9.7, p b 0.04) (Fig. 8). No patient in the study experienced a serious adverse event. Using the definition of reduction of 2 points in the NIHSS to indicate a “responder,” 6/9 patients treated with induced hypertension were responders. The percent change in MAP from baseline to day 3 in these 6 responders ranged from 13% to 30%, with an absolute increase in MAP between 14 and 27 mm Hg. Analysis of the MRI studies from baseline to day 3 showed no significant difference in either treatment group in the volume of DWI lesion. In terms of the area of hypo-

Fig. 8. Results of a trial of induced hypertension. Control patients (light grey bars) are compared to patients treated with induced hypertension (dark grey bars), showing NIH stroke score at baseline, on day 3 of treatment and at 6 to 8-week follow-up visit. (From [69].).

perfusion determined by the PWI study, patients treated with induced hypertension had a significant reduction in PWI lesion volume (from mean 132 ml to 58 ml, p b 0.02) and a significant reduction in the volume of diffusion–perfusion mismatch (from mean 83 ml to 53 ml, p b 0.005) (Fig. 9). Among patients treated with conventional therapy, there also was a reduction of PWI volume and diffusion–perfusion mismatch from baseline to day 3, but these changes were not statistically significant. However, given the small number of patients in this group (n = 6), the lack of significance may be due to a lack of statistical power. Independent of treatment, a significant improvement in NIHSS appeared to correlate with a significant reduction in PWI volume on serial scans [70]. Marzan et al. reported their experience using IV norepinephrine for induced hypertension in 34 ischemic stroke patients [71]. The protocol used by the investigators allowed treatment of patients who would have been excluded from most of the other studies reported to date. For example, among the 34 subjects, 14 had infarcts on baseline CT of N 1/3 the MCA territory and 8 were concomitantly treated with thrombolytic agents. Intravenous heparin was used in 17 patients. Response was considered improvement in the NIHSS by N 2 points. Among all patients, 9/34 (26%) were responders; however, among patients not treated with thrombolytic therapy, 5/26 (19%) were responders. Serious complications potentially related to induced hypertension occurred in two patients: 1 with cardiac arrhythmia and 1 with a symptomatic intracerebral hemorrhage. (The patient with hemorrhage had also been on concomitant IV heparin.) The investigators felt this was an acceptable rate of complications, particularly given the severity of stroke and the relative aggressive nature of the interventions. At our institution, Koenig et al. reviewed the outcomes and adverse events associated with use of any form of blood pressure elevation in a database of patients with acute ischemic stroke who had baseline diffusion–perfusion MRI studies [72]. All were treated within 7 days of onset of symptoms. Using an “intention to treat” approach, 46 treated patients were compared to 54 patients from the same time period treated with “standard therapy.” Treated patients were more likely to have a larger volume of diffusion–perfusion MRI mismatch, the presence of large artery atherosclerosis and were more likely to be treated in the NCCU. Treated patients had a trend for a greater drop in median NIHSS by the time of discharge, but this was not statistically significant. Serious adverse events occurred in 4 patients in each group. Two treated patients had symptomatic hemorrhagic transformation of the infarct (one of whom was on IV heparin), one developed congestive heart failure and one had hypertensive encephalopathy. In comparison, the group treated with standard therapy had two patients with congestive heart failure and two patients with myocardial infarction. Several other approaches to BP manipulation in stroke patients have been reported. In a study of diaspirin cross-

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Fig. 9. MRI results from a trial of induced hypertension. Volumes of lesions on diffusion-weighted (DWI) and perfusion-weighted (PWI) MRI scans obtained at baseline and on day 3 of treatment. Controls are light grey bars and patients treated with induced hypertension are dark grey bars (From [69].).

linked hemoglobin (DCLHb — a hemoglobin-based oxygen carrier) in acute stroke patients, a dose-dependent elevation of MAP was noted in the DCLHb-treated subjects [73]. There was no excess of hemorrhagic transformation, cerebral edema or hypertensive encephalopathy in the treated group. The overall clinical outcome, however, was not improved in the treated patients. Finally, Campbell et al. reported the use of controlled aortic obstruction as a means to improve cerebral perfusion in acute stroke patients [74]. Intra-aortic balloons (NeuroFlo device, manufactured by CoAxia, Inc.) were placed above and below the renal arteries, causing partial aortic obstruction and resulting in increased cerebral perfusion, sometimes with no systemic BP elevation. CBF as assessed by transcranial Doppler (TCD) or angiography or PET/SPECT improved in 12/16 patients. 7. Future of induced hypertension In the absence of large, randomized, blinded clinical trials of induced hypertension, the use of this technique in acute stroke patients must be considered preliminary. Further studies are needed to determine the optimal target blood pressure to achieve, the proper selection of patients, and the length of time induced hypertension can be safely used. Induced hypertension could be considered a primary stroke treatment, maintaining cerebral perfusion until development of collateral circulation or spontaneous recanalization of the occluded vessel [75]. Alternatively, induced hypertension might be considered a “bridging therapy” which could prolong the time-window for more aggressive surgical or neuroradiological intervention to open occluded arteries. In the clinical studies reviewed, response to induced hypertension was often associated with the following clinical factors: 1. preceding TIA with similar symptoms to the acute stroke, 2. atherothrombotic mechanism of stroke, 3. the presence of large vessel occlusive disease, and 4. fluctuating neurological deficits prior to treatment [62]. Induced hypertension,

therefore, may be most useful in patients with instability of collateral circulation, manifesting as TIA, fluctuating or progressive stroke [76,77]. Several important studies are currently underway. In COSSACS (Continue Or Stop Post-Stroke Antihypertensives Collaborative Study), a simple trial design is used to randomize stroke patients who are on antihypertensive medication at the time of hospital admission to either continuing current antihypertensive therapy or discontinuing them using a pre-defined protocol. (http://www.le.ac.uk/COSSACS/ COSSACShome.html) In CHHIPS (Controlling Hypertension and Hypotension Immediately Post-Stroke Trial), patients with acute stroke presenting within 24 h of onset are enrolled [78]. Patients with SBP N 160 mm Hg are treated to lower BP using labetolol, lisinopril, or placebo for 14 days. Patients with SBP b 140 mm Hg are treated with IV phenylephrine to elevate BP versus placebo for 24 h. (http://www. le.ac.uk/CHHIPS/HomePage.html). The Pilot Clinical Trial of Induced Hypertension funded by the National Institutes of Health is currently studying patients treated with induced hypertension in the NCCU monitoring results and adverse events with MRI and intensive safety monitoring. This study aims to assess the feasibility of using this therapy in acute ischemic stroke patients presenting within 12 h of onset of symptoms; to assess the neurologic, cardiac and systemic toxicities of induced hypertension; and to assess the value of baseline DWI-PWI MRI studies in predicting potential responders to BP elevation. 8. Conclusion Induced hypertension was an early consideration in the treatment of acute ischemic stroke, but was not widely adopted given the concern for worsening cerebral edema and the risk of ICH. Nevertheless, the technique continues to have a role in the management of delayed neurologic deficits after subarachnoid hemorrhage and in selected neurosurgical

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