Acute Hypertensive Response in Patients With Stroke
2008; Lippincott Williams & Wilkins; Volume: 118; Issue: 2 Linguagem: Inglês
10.1161/circulationaha.107.723874
ISSN1524-4539
Autores Tópico(s)Traumatic Brain Injury and Neurovascular Disturbances
ResumoHomeCirculationVol. 118, No. 2Acute Hypertensive Response in Patients With Stroke Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBAcute Hypertensive Response in Patients With StrokePathophysiology and Management Adnan I. Qureshi Adnan I. QureshiAdnan I. Qureshi From the Zeenat Qureshi Stroke Research Center, University of Minnesota, Minneapolis. Originally published8 Jul 2008https://doi.org/10.1161/CIRCULATIONAHA.107.723874Circulation. 2008;118:176–187Acute hypertensive response is the elevation of blood pressure (BP) above normal and premorbid values that initially occurs within the first 24 hours of symptom onset in patients with stroke. This phenomenon was reported in >60% of patients presenting with stroke in a nationally representative study from the United States.1 With ≈980 000 patients2 admitted with stroke each year in the United States, the estimated annual prevalence of acute hypertensive response is more than half a million patients. With ≈15 million patients experiencing stroke worldwide each year,3 the acute hypertensive response may be expected in ≈10 million patients per year. The acute hypertensive response in stroke patients is managed by a diverse group of physicians, including emergency physicians, intensivists, internists, primary care physicians, neurologists, neurosurgeons, and cardiologists. Previous audits suggest that antihypertensive agents and management strategies vary considerably and are not always consistent with recommended guidelines.4 Data from 1181 acute ischemic stroke patients enrolled in the Project for Improvement of Stroke Care Management suggested that administration of antihypertensive medication within 24 hours in 56% of the patients was inconsistent with guidelines provided by the American Stroke Association (ASA).5 The present review article summarizes the current concepts pertaining to treatment of the acute hypertensive response derived from recent guidelines provided by professional organizations and "best available" evidence derived from experimental and clinical studies and discusses incorporation of these concepts into clinical practice. Randomized trials, nonrandomized controlled studies, and selected observational studies were identified with multiple searches on Medline from 1980 to 2007 by cross-referencing the key words of stroke, acute hypertension, antihypertensive agents, acute stroke, and hypertension. Pertinent articles identified from bibliographies of selected articles were also reviewed. Treatment targets and strategies were identified by review of existing guidelines from professional organizations.Definition of Acute Hypertensive ResponseThe 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement6 and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)7 define hypertension on the basis of the presence of consistent BP ≥140/90 mm Hg (multiple readings on separate days). This definition of hypertension is a threshold for the use of long-term antihypertensive treatment that is supported by evidence derived from randomized trials and clinic- or population-based data that demonstrate reduction in cardiovascular events with this threshold for treatment. The same definition cannot be applied in the case of acute hypertensive response, because the above-mentioned ascertainment criteria and rationale are not valid. The executive summary of the ISH statement8 on management of BP in acute stroke stated that high BP (>140/90 mm Hg) is very common early after ischemic stroke (occurring in ≈75% of cases) and intracerebral hemorrhage (ICH; >80%) and is independently associated with a poor functional outcome. To maintain consistency with the ISH statement, acute hypertensive response is defined as "systolic BP ≥140 mm Hg or diastolic BP of ≥90 mm Hg demonstrated on 2 recordings taken 5 minutes apart within 24 hours of symptom onset." This definition predominantly serves to provide a uniform standard for measuring prevalence and not for setting treatment thresholds for antihypertensive treatment, which may vary depending on stroke subtype and other considerations.Prevalence of Acute Hypertensive ResponseThe reported prevalence of the acute hypertensive response depends on patient selection, study design, referral patterns, and the definition used. In a systematic review of 18 studies,9 52% of patients with stroke were reported to have an acute hypertensive response at the time of admission. The criteria used to define high BP varied considerably: Systolic BP criteria ranged from 150 to 200 mm Hg and diastolic BP criteria from 90 to 115 mm Hg. In one of the largest studies in the United States using the National Hospital Ambulatory Medical Care Survey,1 systolic BP ≥140 mm Hg was observed in 63% of the 563 704 adult stroke patients, diastolic BP ≥90 mm Hg in 28%, and mean arterial pressure (MAP) ≥107 mm Hg in 38%. In the International Stroke Trial,10 17 398 patients were randomized within 48 hours of stroke onset (median time 20 hours) from 467 hospitals in 36 countries. Mean systolic BP at enrollment was 160.1 mm Hg, and 82% of patients had high BP based on the WHO definition of hypertension (systolic BP >140 mm Hg).Characteristics of Acute Hypertensive ResponseThe acute hypertensive response in stroke is characterized by its high prevalence, self-limiting nature, and prognostic significance. With the definition of hypertension provided by the WHO6 and JNC 7,7 the age-, sex-, and ethnicity-adjusted rates were 61% among stroke patients and 14% in the US population in 1999 to 2000.1,11 New-onset high BP in patients without a previous history of hypertension has been observed in 20% of patients with stroke12 and 8% of the general population.11 A crude comparison suggests that these proportions are higher than expected on the basis of premorbid hypertension among stroke patients. There is also spontaneous reduction of BP (by an average of 20/10 mm Hg) within 10 days after the acute event without any specific antihypertensive therapy.13 Among the 1455 patients from the Glycine Antagonist in Neuroprotection International Trial14 evaluated within 6 hours of symptom onset, MAP declined gradually over the next 60 hours regardless of initial MAP value, with a prominent reduction observed within 10 hours of the first measurement. The prognostic significance is highlighted in a systematic review of 18 studies9 that demonstrated that patients with stroke and high initial BP were at a 1.5- to 5.0-fold increased risk of death or dependency and clinical deterioration.Underlying Causes of Acute Hypertensive ResponseIn at least a portion of these patients, the acute hypertensive response is merely a reflection of inadequately treated or undetected chronic hypertension15; however, spontaneous reduction in the initial BP over the next few days in most patients13,14 supports the role of other transient and stroke-specific mechanisms. Spontaneous reduction of BP after vessel recanalization in patients with ischemic stroke also implies stroke-specific mechanisms.16 Stroke involves transient or permanent damage to the areas involved in the brain regulation of cardiovascular functioning, including BP. The parasympathetic and sympathetic nervous systems are lateralized to the left and right cerebral hemispheres, respectively.17 Prefrontal18 and insular19 cortices provide inhibitory and excitatory input, respectively, through pathways that connect to the nuclei in the brainstem, particularly in nucleus tractus solitarius and ventrolateral medulla.20 Further modulation is provided by cingulated cortex, amygdala, and hypothalamus. Because of the widespread distribution of these areas, most stroke lesions involve these areas to a varied extent.Increased sympathoadrenal tone21 with subsequent release of renin and vasoconstriction of arterioles results from (1) direct injury to inhibitory or modulatory brain regions or (2) indirect effects of reduced parasympathetic activity,22 which leads to impaired cardiac baroreceptor sensitivity in patients with stroke.23 Although direct injury is the most likely explanation, an indirect effect of muscle paralysis24 or the release of neurotransmitters such as nitric oxide25 during ischemia may be contributing factors to altered activity of these nuclei. Other stress responses to hospitalization, headache, urinary retention, or concomitant infection26 may lead to abnormal autonomic activity and raised levels of circulating catecholamines27 and inflammatory cytokines12 and subsequently may contribute to the hypertensive response. Presumably, these abnormal autonomic responses normalize over a few hours owing to spontaneous or therapeutic recanalization and resolution of the ischemia and perhaps because of other neural compensatory mechanisms.28An increase in systemic BP associated with increased intracranial pressure (ICP), particularly in the presence of brainstem compression,29–31 has particular relevance for patients with intracerebral and subarachnoid hemorrhages. Elevated ICP can result in a systemic BP increase32; however, the elevation in systemic BP does not appear to demonstrate a clear relationship to the presence of cerebral ischemia,32,33 ICP values, transtentorial herniation,32,33 or response to hyperosmotic treatment.32,33 This suggests that the primary cause of the acute hypertensive response is damage or compression of specific regions in the brain that mediate autonomic control. Hypertensive responses to other factors mentioned above are exaggerated and additive because of impaired parasympathetic activity and baroreceptor sensitivity.Cerebrovascular Physiology and Implications for TreatmentUnder normal circumstances, changes in precapillary arteriolar diameter ( 60 mm Hg may not be adequate to maintain constant cerebral blood flow in the capillary bed. Ascertainment of the difference between MAP and ICP is recommended as an index of cerebral perfusion pressure. The standard, global measure of cerebral perfusion pressure can underestimate the localized pressure and perfusion changes in focal stroke lesions but is still useful in the absence of another, more sensitive measure. The Brain Trauma Foundation41 recommends maintenance of a cerebral perfusion pressure >70 mm Hg to enhance perfusion to ischemic regions of the brain after severe traumatic injury. In stroke, such treatment thresholds have been extrapolated from global cerebral perfusion data derived from traumatic brain injury patients in the absence of any other pertinent data.Management of Acute Hypertensive Response in Stroke SubtypesDespite the high prevalence of acute hypertensive responses observed in all stroke subtypes, differences in underlying pathophysiology mandate different management strategies (Figure).7,42–47 BP responses can be categorized as (1) spontaneous decline without medication; (2) no clear decline, or even an elevation, despite administration of antihypertensive medication; (3) modest decline with antihypertensive medication (≈10% to 15% from baseline value); and (4) intense decline with antihypertensive medication (≥20% from baseline value). The studies presented below are confounded by overlap of the 4 categories of responses in varying proportions and require interpretation with this understanding. Another important issue in management is the identification of intravascular volume depletion (dehydration)48 in these patients, which may result in a natural hypertensive or hypotensive response or an exaggerated hypotensive response to antihypertensive medication.49,50 Early identification and appropriate fluid repletion before pharmacological intervention ensures a controlled response to treatment. Download figureDownload PowerPointFigure. Algorithm for treatment of acute hypertensive response among patients with stroke and stroke subtypes. IV indicates intravenous; SBP, systolic BP; DBP, diastolic BP; and CPP, cerebral perfusion pressure. *Based on the NINDS rtPA prethrombolytic protocol42 for patients with acute ischemic stroke, for short-term BP management by Emergency Medical Services without delaying early diagnosis and differentiation. The Emergency Medical Services BP management practices vary considerably in the absence of distinction between ischemic stroke and ICH.43 αBased on recommendations of the ASA, Stroke Council,44,46 and/or European Stroke Initiative.45 βThe recommended BP treatment threshold is similar to the existing ASA and European Stroke Initiative recommendations for patients with ICH.44,45 γBased on recommendations of JNC 77 and the ACCESS protocol.47Patients With Acute Ischemic StrokeIschemic stroke results from occlusion of an artery with subsequent reduction in regional cerebral blood flow, demarcated into regions of severe reduction (core) and moderate reduction (penumbra).51 The penumbra remains viable for hours because some degree of blood flow is sustained through collateral supply; however, it is theoretically vulnerable to further ischemic injury with systemic BP reduction52 because of impaired regional autoregulation,38 particularly during rapid BP reduction. Conversely, in an experimental model of focal cerebral ischemia and reperfusion, BP reduction reduced infarct size and deficits.53 Therefore, a period of vulnerability to progression of ischemic deficits may exist after which there may be benefit from BP reduction. A higher rate of death or dependency was observed in patients with initially high or low systolic BP (U-shaped relationship) among 17 398 ischemic stroke patients randomized in the International Stroke Trial.10 The relationship appeared to be mediated in part by increased rates of early recurrence and death that resulted from presumed cerebral edema in patients with high BP and increased coronary heart disease events in those with low BP. Recent data suggest that wide fluctuations (not initial values) of BP in the first few hours in patients with acute ischemic stroke may be associated with an increased risk of death at 90 days.14,54The Low Dose Beta Blockade in Acute Stroke (BEST) study55 (Table 142,47,55–60) revealed greater mortality among patients in whom β-blocker therapy was begun within 48 hours of symptom onset. An analysis of data from the Intravenous Nimodipine West European Stroke Trial (INWEST) found a significant correlation between diastolic BP reduction with nimodipine and worsening of neurological status (within 24 hours of symptom onset).61 Patients with a diastolic BP reduction ≥20% or a diastolic BP drop to ≤60 mm Hg had a significantly higher risk of death or dependency at 21 days. A subsequent meta-analysis58 evaluating the use of oral or intravenous calcium channel blockers initiated at 6 hours to 5 days after symptom onset in acute ischemic stroke patients found that intravenous administration, higher doses, and administration within 12 hours of symptom onset were associated with an increased risk of poor outcomes. The effect may be mediated in part by alterations of regional cerebral blood flow.62 This susceptibility varies with stroke subtype and evolution stage, showing higher tolerance to BP lowering in patients with total anterior circulation infarction63 and in those treated after 12 hours of symptom onset.58Table 1. Summary of Completed and Ongoing Prospective Clinical Trials That Evaluated or Are Evaluating Various Aspects of Antihypertensive Treatment in the Acute Period of StrokeTrial(s)DesignPatients IncludedInterventionPrimary OutcomeNo. of PatientsCommentsInterventions for deliberately altering BP in acute stroke56Meta-analysis (5 trials)Any stroke within 2 wk of symptom onsetNimodipine (n=66), nicardipine (n=5), captopril (n=3), clonidine (n=2), nitroglycerin (n=16), perindopril (n=14), and placebo/control (n=92)BP reduction and case fatality218Oral calcium channel blockers reduced SBP (weighted mean difference 10.9 mm Hg) at 48 h, ACEI reduced SBP (weighted mean difference 15.0 mm Hg) at 24 h; Nitroglycerin showed a nonsignificant reduction in BP at 24 hLow Dose Beta Blockade in Acute Stroke (BEST)55Randomized trialHemispheric stroke presenting within 48 h of symptom onsetAtenolol (50 mg/d), slow-release propranolol (80 mg/d), or matching placebo capsules for 3 wk or until dischargeNeurological assessment at entry, day 8, and 1 and 6 mo302Deaths more common among patients taking β-blockers. Neurological recovery and functional outcome at 6 mo did not differAcute Candesartan Cilexetil Evaluation in Stroke Survivors (ACCESS)47Double-blind, randomized multicenter trialInitial BP >200/110 mm Hg, acute cerebral ischemia and motor paresisCandesartan or placebo for 7 d initiated over a mean period of 30 h after symptom onsetFunctional status assessed by mRS and Barthel Index and mortality rates after 3 mo339Total mortality, cerebral complications, and cardiovascular complications reduced by 47.5% with candesartan initiated within 24 h of admissionNitroglycerin for acute stroke57Meta-analysis (2 studies)Any stroke within 4 d of symptom onsetNitroglycerin (5–10 mg/d) by transdermal patchBP change on day 1127No clear effect on end-of-treatment death, combined death or deterioration, or end-of-trial death, combined death, or dependencyCalcium antagonists for acute ischemic stroke58Meta-analysis (28 trials)Any stroke 6 h to 5 d after symptom onset (ischemic stroke only in 23 trials)IV isradipine (1 trial); oral nimodipine (16 trials); IV nimodipine (5 trials); IV flunarizine (3 trials); oral PY108-608 (1 trial); and IV and oral nimodipine (2 trials)Poor outcome, defined as death or dependency in activities of daily living7521No overall effect on outcome at the end of follow-up. IV administration, higher doses, and administration within 12 h of symptom onset were associated with an increased rate of poor outcomeNINDS rt-PA Stroke Trial42Post hoc analysis of randomized trialIschemic stroke within 3 h of symptom onset and BP >180/105 mm Hg after receiving IV rt-PA or placeboIV labetalol or nitroprusside infusion if DBP >140 mm Hg or inadequate response to labetalol; treatment for 24 h; 80/195 placebo-treated patients and 65/177 rtPA-treated patients received antihypertensive treatmentNeurological deterioration, ICH, and good outcome (multiple scales at 3 mo)372All outcome measures similar for those patients who received postrandomization antihypertensive therapy and those who did not among placebo-treated patients; among rtPA patients, those who received antihypertensive therapy had worse outcomes than those who did notControlling Hypertension and Hypotension Immediately Post-Stroke Trial (CHHIPS)59Prospective, multicenter, randomized, double-blind, titrated-dose trial(1) Hypotensive (SBP 160 mm Hg), nondysphagic within 36 h of stroke onset; (3) Hypertensive, dysphagic within 36 h of stroke onset(1) IV phenylephrine at 80 μg/min titrated to target SBP 150 mm Hg or 15 mm Hg increase above baseline; (2) oral lisinopril 5 mg or labetalol 50 mg to target SBP 150 mm Hg or 15 mm Hg reduction from baseline; (3) sublingual lisinopril 5 mg and/or IV labetalol 50 mg to target SBP 150 mm Hg or 15 mm Hg reduction from baselineDeath or dependency (mRS >3) at 14 d2050Ongoing(Continued)Table 1. ContinuedTrial(s)DesignPatients IncludedInterventionPrimary OutcomeNo. of PatientsCommentsSBP indicates systolic BP; ACEI, ACE inhibitor; mRS, modified Rankin scale; DBP, diastolic BP; ASA, American Stroke Association; rCBF, regional cerebral blood flow; and SAH, subarachnoid hemorrhage.Efficacy of Nitric Oxide in Stroke Trial (ENOS)59Prospective, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled trialAny stroke treated within 48 hTransdermal nitroglycerin or placebo for 7 d. Patients taking antihypertensive drugs will be randomized to continue or discontinue their medication for 7 dMortality rate and mRS at 3 mo5000OngoingScandinavian Candesartan Acute Stroke Trial (SCAST)59Randomized, controlled multicenter trialAcute stroke within 30 h and SBP ≥140 mm HgCandesartan (dose increasing from 4 to 16 mg/d) or placebo for 7 dDeath or disability at 6 mo; combination of vascular death, myocardial infarction, or stroke during first 6 mo2500OngoingContinue Or Stop post-Stroke Antihypertensives Collaborative Study (COSSACS)59Multicenter, prospective, randomized, open, blinded end-point ascertainment studyAny stroke within 24 h of symptom onsetPatients will receive antihypertensive therapy for a 2-wk periodDeath or disability (mRS >2) at 14 d after stroke2900OngoingAntihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH)60Prospective, open-label, multicenter safety and tolerability studySupratentorial ICH within 6 h of symptom onset and SBP ≥200 mm HgStepwise, interventional design to test 3 tiers of SBP reduction: 170–200 mm Hg, 140–170 mm Hg and 110–140 mm Hg with IV nicardipineAbility to achieve and maintain treatment goals (SBP range for the 18–24-h period) and any neurological deterioration60Recruitment complete; no safety concernsIntensive Blood Pressure Reduction in Acute Cerebral Hemorrhage – (INTERACT) Pilot Study59Randomized, open-label, active-control, parallel-assignment, safety/efficacy studyICH within 6 h of symptom onset and SBP ≥150 mm Hg and ≤200 mm HgIntensive SBP lowering; control group receives ASA guideline-based BP managementMortality and dependency (mRS of 3 to 5) at 3 mo400Recruitment complete; no safety concernsIntracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT)59Multicenter, randomized, open-label, blinded-point trialPrimary ICH and SBP ≥150 mm HgIV labetalol to reduce SBP to 135/85 mm Hg), candesartan was increased or an additional antihypertensive drug was added. In placebo-treated patients with a hypertensive profile on day 7, candesartan was begun. Both the cumulative 12-month mortality rate (2.9% versus 7.2%) and the incidence of vascular events (9.8% versus 18.7%) were lower in the candesartan-treated group; however, the primary outcome of disability measured by Barthel index at 3 months was not different between the 2 treatment groups.A post hoc analysis of hypertensive patients in the National Institutes of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen (rtPA) trial42 who received antihypertensive therapy (intravenous labetalol and/or nitroprusside in selected patients) but no rtPA therapy within 24 hours of randomization showed no difference in rates of deterioration or death at 24 hours or in rates of favorable outcome at 3 months compared with hypertensive patients who received neither antihypertensive medication nor rtPA. The results from various studies suggest somewhat contradictory consequences of antihypertensive treatment in acute ischemic stroke: INWEST showed a detrimental effect; ACCESS, a favorable effect; and post hoc analysis of NINDS rtPA study showed no effect. The mean systolic BP in the ACCESS trial was higher than in INWEST (196 versus 162 mm Hg), and the mean value during the first 2 days was also higher (>150 versus 110 mm Hg) also appear higher than those observed in INWEST. The difference in aggressiveness of BP reduction between the studies was also evident from the 60% incidence of diastolic BP values of ≤60 mm Hg during nimodipine treatment in INWEST. These differences stress the importance of BP thresholds and treatment targets in determining tolerability of antihypertensive treatment in acute ischemic stroke.Another aspect that requires further consideration is the potential for differential benefit or harm between classes of antihypertensive medication. The differences in results between trials such as the BEST, INWEST, ACCESS, and NINDS rtPA studies may be related to the properties of the antihypertensive medication used. A systematic review64 of 7 randomized, controlled trials involving patients with prior stroke or transient ischemic attack demonstrated heterogeneity in outcomes that were related in part to the class of antihypertensive drugs used. Angiotensin-converting enzyme inhibitors and diuretics, separately and in combination, but not β-blockers, reduced vascular events. Another estimate of stroke reduction with different antihypertensive medications (angiotensin-converting enzyme inhibitors, calcium antagonists, angiotensin receptor blockers, and diuretics or β-blockers) using data from 29 randomized trials65 directed toward primary prevention suggested that the greatest reduction was observed with angiotensin receptor blockers, with small (borderline significance) differences between the other different classes of antihypertensive medication. Conclusive evidence for differential effects of different antihypertensive medications in the acute period is not available.The management of high BP in acute ischemic stroke is highly controversial because of a lack of reliable evidence from randomized, controlled trials. The current recommendations regarding BP management in acute ischemic stroke46 are based on 2 observations. BP reduction is associated with an increased risk of neurological deterioration and worse outcome in patients with ischemic stroke in some studies,59,66 although a causal relationship has not been demonstrated conclusively. The benefit of acute BP lowering (unlike chronic treatment) in patients with ischemic stroke remains unclear.46 There may be a reduction of cardiovascular events with early institution of angiotensin receptor antagonists; however, the benefit is not conclusively related to BP reduction.47 Therefore, in the absence of definitive benefit, both the ASA and the European Stroke Initiative are consistent in not recommending routine lowering of BP unless it is repeatedly exceeds 200 to 220 mm Hg systolic or 120 mm Hg diastolic in the acute period.46,67,68 However, with the anticipated completion of several large clinical trials42,47,55–60 in the next 5 years (Table 1), these recommendations may be modified.Patients With Acute Ischemic Stroke Receiving ThrombolysisThe acute hypertensive response among patients with ischemic stroke receiving thrombolysis is frequently transient69 and resolves after recanalization70; however, elevated BP before receipt of thrombolysis has been associated with an increased risk of ICH. In the Australian Streptokinase Trial,71 baseline systolic BP >165 mm Hg resulted in a 25% increased risk of major ICHs among patients with ischemic stroke treated with streptokinase. In a multicenter retrospective and prospective investigation72 of individual data from
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