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(Stroke. 1997;28:2133-2138.)
© 1997 American Heart Association, Inc.

Articles

Pharmacological Elevation of Blood Pressure in Acute Stroke

Clinical Effects and Safety

Guy Rordorf, MD; Steven C. Cramer, MD; James T. Efird, MS, RC, CSP; Lee H. Schwamm, MD; Ferdinando Buonanno, MD; Walter J. Koroshetz, MD

From the Department of Neurology and Stroke Service (G.R., S.C.C., L.H.S., F.B., W.J.K.) and Department of Radiation Oncology (J.T.E.), Massachusetts General Hospital, and The Clinical Investigator Training Program, Harvard-MIT Division of Health Sciences and Technology and the Beth Israel Deaconess Medical Center, Boston, Mass, in collaboration with Pfizer Inc (S.C.C.).

Correspondence to Guy Rordorf, MD, Department of Neurology, GRB 1256, Massachusetts General Hospital, Fruit St, Boston, MA 02114. E-mail Rordorf{at}helix.mgh.harvard.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Lowering of blood pressure can adversely affect ischemic symptoms in acute stroke. The aim of our study was to determine whether induced hypertension in stroke is safe and to examine its effects on neurological deficits in patients presenting with acute cerebral ischemia.

Methods We retrospectively reviewed all patients admitted to our neurological intensive care unit with the diagnosis of ischemic stroke over a 2.5-year period. Thirty-three patients were not given a pressor agent (Ph- group), while 30 were treated with phenylephrine (Ph+ group) in an attempt to improve cerebral perfusion.

Results Baseline characteristics showed few differences between the Ph+ and Ph- groups. Intracerebral hemorrhage, brain edema, cardiac morbidity, and mortality were not increased in the Ph+ group. In 10 of 30 Ph+ patients, a systolic blood pressure threshold was identified below which ischemic deficits worsened and above which deficits improved. The mean threshold was 156 mm Hg (range, 120 to 190 mm Hg). The mean number of stenotic/occluded cerebral arteries was greater in those Ph+ patients with an identified clinical blood pressure threshold (mean, 2.1 per patient) than in Ph+ patients without a threshold (mean, 1.2 per patient; P<.05).

Conclusions The results suggest that careful use of phenylephrine-induced hypertension is not associated with an increase in morbidity or mortality in acute stroke. Although based on a retrospective analysis of clinical practice, this report suggests that a subset of patients, particularly those with multiple stenosis of cerebral arteries, may improve neurologically upon elevation of the blood pressure.

Key Words: hypertension • phenylephrine • stenosis • stroke management

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A spontaneous increase in BP is common in the setting of acute ischemic stroke in humans.^{1 2 3 4} The optimal management of elevated BP, which may be labile,⁵ is still a common clinical concern in a patient presenting with cerebral infarction. Neurological deterioration has been frequently associated with the use of antihypertensive agents.^{6 7 8 9 10 11 12 13}

Despite early reports of improved outcome in patients with ischemic stroke treated with induced hypertension,^{14 15 16} this practice has been confined to a handful of stroke units, and results have been rarely reported. Induced hypertension in acute stroke may be associated with adverse effects such as hemorrhage into the infarct, cerebral edema, and myocardial ischemia in the patient with concomitant atherosclerotic coronary artery disease. Despite these same concerns, induced hypertension is now recommended to improve cerebral perfusion in the treatment of cerebral ischemia due to vasospasm after SAH¹⁷ and in maintaining perfusion pressure in patients with posttraumatic brain edema.

After SAH, hypertension can produce clinical improvement with minimal and acceptable systemic toxicity.¹⁸ In such patients induced arterial hypertension increases CBF^{19 20} and can improve vasospasm-related ischemic neurological deficits. Recent data from PET²¹ and MRI²² studies in patients with ischemic stroke combined with clinical observations suggest that a parallel situation may exist in some acute stroke patients.

This report reviews the safety and clinical effects of the use of phenylephrine in stroke patients admitted to our NICU over a 2.5-year period.

	Subjects and Methods

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Medical records of patients admitted to the NICU of Massachusetts General Hospital with the primary diagnosis of cerebral ischemia between October 1992 and March 1995 were reviewed. Sixty-four patients were identified and divided into two groups. Thirty-three patients (group II) did not receive phenylephrine, while 30 patients (group I) did receive phenylephrine to elevate BP within 24 hours from the onset of symptoms. The decision to introduce phenylephrine was based on the clinical judgment of the treating physician and was not part of a study. The rationale for initiating treatment with phenylephrine was stated in the record in 26 cases: observation of a worsening neurological deficit associated with a drop in BP in 10; attempt to increase collateral flow in patients with known large-artery stenosis or occlusion in 8; history of recent transient neurological deficit potentially related to low CBF in 4; spontaneous fluctuations of symptoms early in the course of the stroke in 2; and sepsis associated stroke in 2 patients. One patient was excluded because he was admitted on paralyzing agents and died before neurological examination. All received an acute brain imaging study and were treated with heparin. Charts were reviewed for demographic information, past medical history, and delay between the onset of symptoms and emergency department presentation.

The first complete set of data available, before the introduction of phenylephrine, was used to retrospectively compute an APACHE II score.²³ The occurrence of an improvement or a decline in neurological status was determined from the records. Six neurological domains were examined for such a change: level of consciousness, motor function, sensory function, language, dysarthria, and extraocular movements. In each instance, the relationship between a clinical change, the SBP, and the use of phenylephrine were recorded. Death related to a cerebral event was included as a decline.

A BP threshold was defined as an SBP below which a sustained, consistent, neurological decline (ie, new or worsened hemiparesis, new or worsened aphasia or dysarthria, new gaze deviation, new or worsened sensory loss, decreased level of alertness) occurred at least twice, and above which the decline (lasting more than 5 minutes) was rapidly reversed after the BP was elevated with phenylephrine. Group I patients were then subdivided into Ia (BP threshold identified) and group Ib (no BP threshold identified). The BP at the time of surgery or discharge from the NICU (clinically stable and off phenylephrine) was determined.

Radiological data were reviewed for early signs of infarction on admission CT. Eventual stroke size was rated as large if it involved an entire ICA or MCA territory or, in the posterior circulation, two or more segments of brain stem, thalamus, or PCA territory. A medium-sized stroke was defined as an infarct in an ACA territory, in one of the MCA division territories, or, in the posterior circulation, as a single PCA territory infarct or a brain stem infarct larger than 10 mm in any one plane of the neuroimaging study. A small stroke was defined as a PCA, ACA, or MCA branch infarct or a lacunar stroke or, in the brain stem, an infarct smaller than 10 mm. The pathophysiology of stroke was assessed according to the Harvard Cooperative Stroke Registry criteria²⁴ based on all the data available at the time of discharge.

Carotid noninvasive studies, transcranial Doppler studies, MR angiography, and conventional angiography data were used to determine the incidence and presence of the cerebral artery stenosis or occlusion. Direct angiography results were considered conclusive; if not performed, then the more severe reading between carotid noninvasive studies, transcranial Doppler studies, and MR angiography was used to determine the presence of the arterial stenosis. Stenosis was diagnosed by angiography if there was a residual lumen of less than 1.5 mm. Signal dropout or a thin flow signal on MR angiography was recorded as showing a stenosis. On carotid noninvasive studies stenosis was characterized by increased peak systolic velocities above 125 cm/s, end-diastolic velocities above 100 cm/s, and ICA/CCA index greater than 2. Stenosis was diagnosed by transcranial Doppler studies if there was evidence of turbulence and increase in peak velocities of at least 30% above the opposite side.

Clinical data were also reviewed for possible systemic complications of phenylephrine use, including digital ischemia, increase of creatinine level of 0.6 mg/dL above baseline, and chest x-ray evidence of pulmonary edema. NICU records were reviewed for reports of cardiac arrhythmias. The electrocardiogram and CPK-MB fraction level were reviewed for evidence of cardiac ischemia. Brain imaging studies (CT and MRI) were reviewed for the appearance of radiological complications, including hematoma, petechial hemorrhage, midline shift, herniation, and edema.

SAS software (JMP-IN version 3.1.5, SAS Institute) was used in all the statistical analyses. Comparisons were made between group I versus group II, as well as group Ia versus group Ib. Comparisons were made with the use of Fisher's exact test in the case of categorical data and ANOVA in the case of continuous data.

	Results

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Phenylephrine (Group I) Versus No Phenylephrine (Group II)
In the study group of 63 patients with acute cerebral ischemia admitted to the NICU, 30 had induced hypertension with phenylephrine (group I), while 33 were not treated with phenylephrine or any other hypertensive agent (group II). The mean dose of phenylephrine used was 110 µg/min (range, 20 to 300 µg/min), and the mean duration of treatment was 110 hours (range, 7 to 576 hours).

Most baseline characteristics were similar between groups I and II. There was no significant difference in mean age (63.1 versus 65.5 years; P>.4) or sex (13 men and 20 women versus 18 men and 12 women; P>.1). There was no difference in the prior diagnosis of coronary artery disease, atrial fibrillation, prior strokes, transient ischemic attacks, peripheral vascular disease, hypertension, diabetes mellitus, or cigarette use. Increased cholesterol level was more common in group I (12 patients) than group II (5 patients) (P<.05). The APACHE II score was not different between the two groups (8.7 versus 9.2; P>.7). There was no difference between the two groups in the time between the onset of symptoms and time to presentation: 21 group II patients presented within 12 hours versus 20 in group I. There was no difference in the distribution of stroke size (P>.5).

There was no significant difference in morbidity or mortality between the two groups of patients. There were 4 deaths in group I and 9 deaths in group II (P>.2). No statistically significant difference between the two groups was seen in the incidence of any clinical or radiological complication. There was a trend toward increased frequency of CPK elevation (1.5 times normal) in group I (3 patients versus 0 in group II; P>.1) without concomitant electrocardiographic abnormalities. Arrhythmia was documented in one case; a patient in group I had a brief run of atrial fibrillation. Radiological abnormalities were seen in 8 group I and 12 group II patients. A trend toward increased radiological complications was seen among group II subjects for hematoma (2 patients versus 0 in group I) and cerebral edema (6 patients versus 2 in group I).

Phenylephrine-Treated Patients With (Group Ia) and Without (Group Ib) a Clinical BP Threshold
Ten of 30 patients receiving phenylephrine fit criteria for a BP threshold. The range of clinical SBP thresholds was 120 to 190 mm Hg, with a mean of 156 mm Hg. Group Ia patients improved neurologically when first treated with phenylephrine; generally within 2 to 30 minutes of elevation of BP. In most cases, attempts were made to maintain excellent intravascular volume with normal saline or albumin and to wean patients from phenylephrine on daily basis. Many patients experienced a repeated worsening during phenylephrine weaning that was reversible when BP increased. In group Ia patients, appearance and resolution of identical neurological deficits around a specific BP often occurred repeatedly in this controlled situation. Phenylephrine was eventually stopped when the patient's neurological examination no longer worsened during the course of weaning from phenylephrine (range, 1 to 24 days). At the time of the patient's discharge from the NICU in a stable neurological condition and off antihypertensive medications, the SBP in each patient in this group was always lower than the identified threshold; mean discharge SBP was 140 mm Hg.

The characteristics of the group Ia patients are summarized in the Table. The neurological signs that tended to change most commonly with changes in BP were level of consciousness, speech, and motor skills. The mean age in group Ia was not significantly different from that in group Ib (65.6 versus 61.8 years; P>.4). There was a trend for lower mean APACHE II score in group Ia patients (6.6 versus 9.8 in group Ib; P<.06). The only significant difference in past medical history was an increased incidence of transient ischemic attack in group Ia (6/10 in group Ia versus 2/20 in group Ib; P<.01). There was no statistically significant in the incidence of hypertension, diabetes mellitus, hypercholesterolemia, cigarette use, and cardiac history. There was no significant difference in the distribution of stroke size between those with and without a BP threshold (P>.1), but 40% of group Ia patients were discharged without a new stroke on follow-up imaging compared with 5% of group Ib and 16% of group II patients. The mean duration of neurological deficits of the 4 patients in group Ia who were discharged without stroke was 10 hours. Group Ia had a higher incidence of thrombotic strokes (8/10) compared with group Ib (7/20) (P<.05). When bilateral ICA, MCA, vertebral artery, and basilar artery were examined, group Ia patients had nearly twice as many stenotic/occluded arteries (mean, 2.1 per patient) than did group Ib (mean, 1.2 per patient) (P<.05).

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Subjects With BP Threshold for Neurological Deficits (Group Ia)

There were no significant differences in morbidity and mortality between groups Ia and group Ib. However, there was a trend toward fewer deaths (0/10 in Ia versus 4/20 in Ib; P>.2) and a lower incidence of CT/MRI complications (1/10 in Ia versus 4/20 in Ib; P>.5) in those demonstrating a BP threshold. Group Ia patients were more neurologically unstable, with the mean number of fluctuations in neurological status averaging 3.8 per patient compared with 1.2 per patient in group Ib (P<.001). During phenylephrine treatment the number of clinical improvements minus the number of clinical declines was greater in group Ia than in group Ib (1.4 versus 0.5; P<.05). Off phenylephrine, however, group Ia did worse; improvements minus declines averaged -0.9 in group Ia versus -0.25 in group Ib (P<.05).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This report suggests that induction of hypertension with phenylephrine can be performed without undue morbidity or mortality in acute stroke patients. Furthermore, in selected patients raising the BP was consistently associated with rapid improvement in neurological deficits.

In 10 of 30 acute stroke patients treated with phenylephrine, we repeatedly observed that neurological deficits improved above a specific BP and worsened below it. This BP threshold (mean, 156 mm Hg; range, 120 to 190 mm Hg), as well as the dependence on phenylephrine, was found to persist for a finite but variable period after the onset of stroke symptoms (1 to 24 days). These 10 patients with a clinically apparent BP threshold eventually were able to tolerate BPs below the acute clinical threshold without incurring deficits.

Patients whose neurological function depended on a pharmacologically raised systolic BP (group Ia) were more likely to have a thrombotic stroke and were more likely to have a history of transient ischemic attack than those without a clear threshold (group Ib or group II). Analysis of their vascular anatomy demonstrated that group Ia patients had nearly twice the number of stenotic/thrombosed arteries as group Ib patients. These associations suggest that patients requiring pressor agents to preserve neurological function might have more extensive brain regions with maximally dilated vascular beds in which local CBF is sensitive to BP.

The length of time during which group Ia patients depended on hypertensive therapy to maintain their level of neurological function varied considerably. Natural thrombolysis or improved collateral flow may have occurred to eventually obviate the need for increased BP. Such patients were more likely to leave the NICU without a stroke on their imaging study and with an improved neurological examination. Whether hypertensive therapy prevented stroke or improved final neurological outcome cannot be deduced from this nonblinded, retrospective study. Hypertensive therapy at times served as a temporizing measure until an emergent carotid endarterectomy or vessel angioplasty could be performed.

Parallel clinical observations have been reported in patients with vasospasm after SAH. In vasospasm after SAH, induced hypertension is thought to improve leptomeningeal collateral flow and improve CBF in the maximally dilated vascular bed.²⁰ Although this treatment has not been evaluated with a prospective randomized clinical trial, broad experience in recent years at a number of different centers supports its use.^{25 26 27 28 29 30}

Patients with focal brain ischemia treated with vasopressor drugs have been described.^{14 15 16 31} The largest cohort of patients treated with hypertensive therapy was reported by Wise et al¹⁶ in 1972. Of 13 patients treated with pressors, 5 showed improved neurological status immediately after increased BP. In 3 of the 5, significant recovery was maintained after the immediate postischemic period. Other series reported improved neurological function after BP was raised in association with volume expansion with low-molecular-weight dextran.^{32 33}

During experimental focal cerebral ischemia, induced hypertension has been shown to augment CBF, decrease brain injury, and improve neurological status.^{34 35 36 37 38 39 40} These effects may be mediated by several different mechanisms. In contrast to the normal condition, CBF is pressure dependent in regions of maximal dilation; such dilation has been shown in some patients with cerebrovascular lesions.⁴¹ Induced hypertension may also act by opening collateral channels, thereby improving perfusion to ischemic tissue.^{35 36 42} Recent data from PET and MRI in acute human stroke have demonstrated that there is frequently brain tissue with lowered CBF but sufficient energy stores for preservation of tissue viability for many hours.²² Hypertensive therapy may improve collateral blood flow in these regions. Indeed, phenylephrine-induced hypertension has been reported to improve oxygen metabolism on PET in a stroke patient⁴³ and CBF in patients with vasospasm after SAH.²⁰ Hypertensive therapy may also act by preventing postischemic hypoperfusion.^{44 45 46 47 48 49 50 51}

The paucity of differences in baseline and in morbidity/mortality between groups I and II suggests that phenylephrine use is safe in the setting of acute stroke. However, deleterious effects have been observed in some instances,^{26 52 53} including increased blood-brain barrier permeability⁵⁴ and vasogenic edema.⁵² In contrast with these studies, Patel et al⁵⁵ showed that during reperfusion after 2 hours of focal ischemia, induced hypertension reduced neuronal injury and did not lead to an exacerbation of edema formation. In a subsequent study, edema in the periphery of the ischemic territory was improved in association with hypertensive therapy.⁵⁶ In our study there was no increased risk for development of neurological or radiological complications due to the use of systemic hypertensive therapy, including hemorrhagic transformation and worsened cerebral edema.

Phenylephrine was selected as vasopressor agent of choice in our patient population because (1) cerebral vessels have a low density of ₁ receptors so that phenylephrine does not produce significant direct cerebral vasoconstriction,^{57 58} and (2) as a pure ₁-adrenergic receptor agonist, phenylephrine does not cause tachycardia or tachyarrhythmias, as ß-adrenergic receptor agonists do. However, phenylephrine can cause direct vasoconstriction in the coronary artery circulation and increased afterload and may contribute to congestive heart failure, cardiac ischemia, renal insufficiency, and gastrointestinal ischemia.⁵⁹ Use of vasopressors in a nonseptic cohort of patients with SAH has been reported not to increase the incidence of pulmonary edema, myocardial infarction, or systemic complications.²¹ CPK elevation was seen more commonly in phenylephrine-treated patients. Many of our patients (roughly 75%) had past history of cardiac or vascular disease or had one or more cardiovascular risk factors. Only a few patients developed clinically silent cardiac complications. No patient had phenylephrine discontinued because of systemic or neurological complications.

In conclusion, we find that hypertension induced with phenylephrine can be performed relatively safely and is not associated with adverse neurological or systemic complications. Some forms of morbidity are uncommon, however, and intergroup differences could be more apparent in a larger study with greater power. In the present study a distinct subpopulation was identified. Patients in this group were more likely to have had previous transient ischemic attacks characterized by symptoms similar to those on acute stroke presentation. They were also more likely to have thrombotic stroke, multiple stenotic/occluded large cerebral arteries, and fluctuating neurological deficits. We propose that patients with these features may benefit from a short test trial of phenylephrine-induced hypertension in the acute stroke setting. In group Ia patients, improvements in neurological deficits associated with phenylephrine use were commonly observed to occur within minutes of elevation of BP. Of interest, we noted the absence of eventual stroke (clinically and radiologically) in 4 of 10 patients in the group with a BP threshold. This raises the possibility that the acute use of induced hypertension to improve the neurological deficit of a stroke patient may prevent the threatened permanent neurological deficit and limit stroke size in some cases. A randomized, prospective study in acute stroke patients with specific vascular lesions is needed to evaluate the potential of phenylephrine-induced hypertension to improve functional outcome.

	Selected Abbreviations and Acronyms

 

ACA = anterior cerebral artery BP = blood pressure CBF = cerebral blood flow CPK = creatine phosphokinase ICA = internal carotid artery MCA = middle cerebral artery NICU = neurology-neurosurgery intensive care unit PCA = posterior cerebral artery PET = positron emission tomography SAH = subarachnoid hemorrhage SBP = systolic blood pressure

	Acknowledgments

 
This study was supported by a grant from the National Stroke Association (Dr Cramer).

Received May 9, 1997; revision received August 11, 1997; accepted August 11, 1997.

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