Neurosonology and Cerebral Hemodynamics 13, 2017:22–34.

M. Mijajlovic ^1*,V. Aleksic ^2*, N. Sternic ¹, N. Bornstein ^3,4 
1 Neurology Clinic, Clinical Center of Serbia and School of Medicine University of Belgrade – Serbia
² Department of Neurosurgery, Clinical Hospital Center Zemun – Belgrade, Serbia
³ Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv University – Tel-Aviv, Israel 
⁴ Shaare Zedek Medical Center – Jerusalem, Israel 
*M. Mijajlovic and V. Aleksic equally contributed to this work

Abstract

Significant number of patients with acute ischemic stroke suffers from hypertension, hyperglycemia or hyperthermia, particularly in hyper acute stage of ischemic stroke. These conditions dramatically influence early and late outcome of acute ischemic stroke. That is why early recognition and adequate treatment of hypertension, hyperglycemia and hyperthermia are very important. This review paper summarizes recent knowledge on association between acute ischemic stroke and hypertension, hyperglycemia and hyperthermia as well as emphasizes current treatment recommendations.

About two thirds of acute stroke patients arrive at the emergency room with systolic blood pressure greater than 140 mmHg and in 58% of patients diastolic blood pressure is higher than 80 mmHg. About 32% of acute stroke patients have blood glucose level above 150 mg/dL (~ 7mmol/L). Also, 17% of patients have body temperature above 37 °C on admission.

Hypertension

Within the first 24−48 h after stroke onset, up to 84% of patients have spontaneous elevation of blood pressure. Blood pressure elevation typically resolves within a few days or weeks [1]. A significant decline in blood pressure occurs in a third of patients in the first few days after stroke onset [2]. Explanations for high blood pressure are numerous: pre-existing hypertension, stress of hospitalization, neuroendocrine activation, Cushing reflex, and pain due to for example urinary retention [3]. There are two opposing opinions regarding the treatment of high blood pressure in acute ischemic stroke (AIS) [4]. Despite the prevalence of arterial hypertension following stroke, its optimal management has not been established [5]. However, it should be mentioned that there are a lot of deleterious effects of high blood pressure. There is an increased risk of hemorrhage into the infarcted area, malignant cerebral edema, recurrent stroke and hypertensive encephalopathy. On the other hand, low blood pressure can lead to shift of the cerebral auto regulation curve in chronically hypertensive patients, loss of normal cerebral auto regulation in ischemic brain, and extension of ischemic damage by hypoperfusion [5]. Leonardi-Bee et al. showed that both high blood pressure and low blood pressure were independent prognostic factors for poor outcome of AIS, relationships that appear to be mediated in part by increased rates of early recurrence and death resulting from presumed cerebral edema in patients with high blood pressure and increased coronary heart disease events in those with low blood pressure. This study was performed on 17 398 patients from the International Stroke Trial with confirmed ischemic stroke [6]. So, the question still remains, what is good for the patient? On the one side, the study of Oliveira-Filho et al. showed that blood pressure reduction in the first 24 h after stroke onset is independently associated with poor outcome after 3 months [7], and some studies suggest that induced hypertension is a treatment option in acute stroke. Denny-Brown was probably the first to note that improvement of neurological function following a brain ischemic episode is often associated with a rise in blood pressure [8]. In one study, Wise et al. administered vasopressor drugs (antihypotensive agents) to 13 patients soon after the development of focal brain ischemia even though there was no significant decrease in their blood pressure. The neurological function of five patients improved following an increase in their blood pressure. After this treatment was discontinued, significant recovery was maintained in three patients. Knowing the deleterious effects of high blood pressure one should always keep in mind that vasopressor agents may cause edema or hemorrhage if they are administered after the stroke has already occurred. That is why Wise et al. suggest that it is probably better to discontinue vasopressor therapy in patients who do not have any clinical improvement after several hours of treatment [9]. Nowadays, induced hypertension has been abandoned as a treatment for ischemic stroke due to the perceived risk of hemorrhage and edema, but interestingly similar therapy has become the gold standard for management of cerebral vasospasm after subarachnoid hemorrhage (triple H therapy) [10]. Rordorf and colleagues have conducted a retrospective study on 63 patients admitted to the neurological intensive care unit with a diagnosis of ischemic stroke. Thirty-three were not given a pressor agent, while 30 were treated with phenylephrine in an attempt to improve cerebral perfusion. The results of this study suggest that careful use of phenylephrine-induced hypertension is not associated with an increase in morbidity or mortality in AIS and that a subset of patients, particularly those with multiple stenoses of cerebral arteries, may improve neurologically upon elevation of the blood pressure [11]. A few years later the same author and his colleagues conducted a pilot study of drug-induced hypertension for the treatment of acute stroke. They concluded that induced hypertension in acute stroke is feasible and probably safe, and can improve the neurological examination in some patients [12]. Data about the safety of induced arterial hypertension therapy also came from the retrospective study by Marzan et al. These authors concluded that induced arterial hypertension is feasible and safe in patients with acute stroke [13]. In a randomized double-blind, placebo-controlled trial with 16 hypertensive patients, Lisk et al. found that hypertensive ischemic stroke patients with a moderate elevation of blood pressure in the first few days may not require antihypertensive therapy and that nicardipine and possibly other calcium channel blockers may cause an excessive fall in blood pressure and impair cerebral blood flow in these patients and should therefore be used with caution [14].
Based on the current data it is still unclear what should be the best management of blood pressure in AIS.
In 2003, Schrader et al. published the results of a prospective, double-blind; placebo-controlled, randomized, multicentre phase II study with 500 recruited patients. This study, called ACCESS (Acute Candesartan Cilexetil Therapy in Stroke Survivors), was designed to assess the safety of modest blood pressure reduction by candesartan cilexetil in the early treatment of stroke. Although this safety trial was stopped prematurely when 342 patients (339 valid) had been randomized because of an imbalance in endpoints, the cumulative 12-month mortality and the number of vascular events differed significantly in favor of the candesartan cilexetil group. In conclusion, the authors suggested that candesartan cilexetil (angiotensin type 1 receptor antagonist) is a safe therapeutic option when there is need for or no contraindication against early antihypertensive therapy in AIS [15].
However, a larger efficacy trial on candesartan therapy conducted on 2004 in randomly allocated AIS patients with a similar study design showed a mean systolic blood pressure reduction of 7 mmHg and mean dyastolic blood pressure of 5 mmHg at day 7 and no improvement in functional outcome. Favorable outcomes after 6 months, however, were less likely with candesartan than with placebo [16].
A few years later, Potter et al. evaluated the feasibility, safety and effects of two regimens for lowering blood pressure in patients who have had a stroke. Patients who had AIS or cerebral hemorrhage and were hypertensive (systolic blood pressure over 160 mmHg) were randomized to receive labetalol, lisinopril or placebo within 36 h of symptom onset in this double-blind pilot trial (called CHHIPS). The doses were titrated up if the target blood pressure was not reached. Of 179 patients, 58 received labetalol, 58 received lisinopril and the other 63 patients were the placebo group. There was no evidence of early neurological deterioration with active treatment, despite the significantly greater fall in systolic blood pressure within the first 24 h in this group compared with placebo. No increase in serious adverse events was reported with active treatment but 3-month mortality was halved, so the authors believe that early lowering of blood pressure with lisinopril and labetalol after acute stroke seems to be a promising approach to reduce mortality and potential disability. However, because of the small sample size, further evaluation in larger trials is needed [17].
Taking into account that about 50% of patients with acute stroke are taking antihypertensive drugs on hospital admission, Robinson et al. conducted a multicentre, prospective, randomized, open, blinded-endpoint trial on 763 patients to determine the efficacy and safety of continuing or stopping pre-existing antihypertensive drugs (COSSACS study) in patients who had recently had a stroke. In 379 patients antihypertensive therapy was continued, and in 384 it was stopped. Continuation of antihypertensive drugs did not reduce 2-week death or dependence, cardiovascular event rate or mortality at 6 months. Lower blood pressure levels in those who continued antihypertensive treatment after acute mild stroke were not associated with an increase in adverse events. These neutral results might be because COSSACS was underpowered owing to early termination of the trial, and support the continuation of ongoing research trials [18]. Anderson and other INTERACT2 investigators randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 h and elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mmHg within 1 h) or guideline-recommended treatment (with a target systolic level of <180 mmHg) with the use of agents of the physician’s choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability and a score of 6 indicates death) at 90 days. A pre-specified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups. Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52%) receiving intensive treatment, compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event. The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment. Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Non-fatal serious adverse events occurred in 23.3% and 23.6% respectively of the patients in the two groups. So, in patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure [19]. New guidelines of the American Heart Association/American Stroke Association (AHA/ASA) on blood pressure management in acute stroke patients were issued in 2013, with only minor changes from the previous ones. Revised recommendations are given in Table 1 [20].

The optimal time after the onset of AIS to restart or start a long-term antihypertensive therapy has not been established. It may depend on various patient and stroke characteristics. Nonetheless, it is reasonable to initiate a long-term antihypertensive therapy after the initial 24 h from stroke onset in most patients [20].
Despite the many trials referred to, the management of high blood pressure in AIS still remains unclear. The results of an international multicentre prospective randomized single-blind blinded-endpoint parallel-group partial-factorial controlled trial of transdermal glyceryl trinitrate (a nitric oxide donor, given for 7 days) versus no glyceryl trinitrate and of continuing versus stopping (temporarily for 7 days) pre-stroke antihypertensive drugs if relevant, in patients with AIS and high systolic blood pressure (140−220 mmHg), are about to be issued by Bath and his collaborators in the ENOS (Efficacy of Nitric Oxide in Stroke) study. The data from the trial will improve the precision of estimating the results (efficacy and safety) from completed trials of blood pressure management in acute stroke and provide the first large-scale randomized evidence on transdermal glyceryl trinitrate and on continuing (versus stopping) pre-stroke antihypertensive medications in AIS [21].
Regardless of whether it is the acute phase or sometime after stroke onset, considering antihypertensive therapy, an individualized approach is probably the best.