Induced hypertension for treatment of acute ischemic stroke

Introduction
Administering medications to raise blood pressure (i.e. vasopressors) to patients with acute ischemic stroke may help to enhance collateral flow, but also comes at risk of causing complications. Nonrandomized data over many decades showed that some patients responded to induced hypertension. A small but important randomized trial (SETIN-HYPERTENSION) has now shown benefit of induced hypertension for neurological improvement and functional outcome in patients not eligible for thrombolysis or endovascular intervention or who have progressively worsening symptoms. Phenylephrine is the most well-studied pressor and appears to be safe in properly-selected patients. Using inclusion/exclusion criteria for the SETIN-HYPERTENSION study to select patients for this treatment is probably reasonable.

Non-trial data
Shanbrom and Levy first described two patients with ischemic stroke (carotid occlusion and basilar occlusion) improved with epinephrine administration to raise the blood pressure to individual patient thresholds of 160 mmHg for one patient and 140 mmHg for the other. This was followed by several other reports in patients with vasospasm and cerebrovascular narrowing from tumors. In 1972, Wise et al. published a series of 13 patients who developed focal brain ischemia, and noted that in 5 patients their neurological dysfunction improved when blood pressure increased to higher levels. This idea persisted and was used commonly for treatment of vasospasm but not for ischemic stroke. The next time it was addressed in ischemic stroke was in 1991, when a group of researchers raised the SBP in 37 ischemic stroke patients to 210-220 mmHg for a period of 5 minutes on three occasions separated by one hour. They described less mortality, with improvements in consciousness and weakness after induced hypertension.

In 1997, Rordorf et al. published a retrospective series of 30 patients with acute ischemic stroke given phenylephrine, and compared them with 33 patients who did not receive phenylephrine. In 10 of the 30 patients given phenylephrine, a threshold was identified (mean 156 mmHg, range 120 to 190 mmHg) below which neurological deficits worsened and above which deficits improvement. There were no significant complications. In 2001, Hillis et al. published several reports of patients with aphasia who had improvement at higher blood pressures. This was followed by a 2001 pilot study in which Rordorf et al. prospectively administered phenylephrine to 13 acute ischemic stroke patients. The protocol was to place them on phenylephrine for 30 minutes to increase SBP to at least 160 mmHg or by 20% above the admission SBP, to a maximum of 200 mmHg. If the NIHSS improved by at least 2 points, they were considered a potential responder. 7 of 13 patients improved their neurological exam by ≥ 2 points on NIHSS, and a clear arterial pressure threshold was noted in 6 of these patients. There were no systemic complications. Schwab et al. used norepinephrine in patients with large MCA infarctions, some chronic. and showed improvements in CPP and MCA velocities on transcranial doppler.

In 2003 and 2004, Hillis et al. used MRI perfusion to select patients with diffusion-perfusion mismatch and showed that patients treated with phenylephrine had improvement in NIHSS and less hypoperfused tissue on follow-up imaging. Also in 2004, Marzan et al. retrospectively described 34 ischemic stroke patients in whom the BP was raised with norepinephrine. They only saw early neurological improvement in 5 of 25 patients not treated with thrombolytics (20%) which is far fewer than the 54% who had improvement in the 2001 study by Rordorf et al. But they also demonstrated safety of this treatment in 8 patients given norepinephrine after thrombolytics, although this conclusion is very limited by a low sample size.

In 2011, Lim et al. reported on 82 patients with lacunar infarction who had worsening NIHSS during hospitalization. 52 of these patients were given phenylephrine, and they were found to have lower NIHSS motor score after each treatment with more patients achieving mRS 0-2 at discharge (62% vs 50%, p=0.044), without serious side effects. . Similarly in a 2017 retrospective study of 66 patients, those who had induced hypertension had a lower NIHSS and better outcomes at discharge.

While all of these studies have suggested benefit, none were controlled trials and methods and analyses were quite variable.

Trial data
==== Safety and Efficacy of Therapeutic Induced Hypertension in Acute Non-Cardioembolic Ischemic Stroke (SETIN-HYPERTENSION) trial (2019) ==== This trial is a randomized, open-label, blinded endpoint trial run in South Korea.

Inclusion criteria: Exclusion criteria: Protocol: Results:
 * Acute ischemic stroke confirmed on MRI within 24 hours of symptom onset
 * Noncardioembolic etiology
 * NIHSS 4-18
 * Ineligible for recanalization therapy or had progressive stroke (defined as ≥2 point increase on NIHSS and presence of new lesions or infarct growth on MRI within 24 hours).
 * Received thrombolysis or thrombectomy
 * SBP >170 mmHg at baseline
 * History of intraparenchymal hemorrhage, subarachnoid hemorrhage, cerebral arterial dissection, or unruptured aneurysm
 * ≥3 cortical microbleeds
 * Infarction > 50% of the MCA territory
 * Cognitive impairment
 * Significant cardiac disease: arrhythmia, coronary artery disease, congestive heart failure, or hypertrophic cardiomyopathy.
 * Administered phenylephrine (starting at 20 mcg/min) until a 20% increase in baseline SBP was achieved, after which the dose was increased every 30-60 minutes up to a maximum dose of 320 mcg/min and a limit of SBP <200 mmHg. Phenylephrine was titrated up and then maintained at a level in which NIHSS had improved by ≥2 points, if possible.  Pressors were then maintained at that level, recommended for 24 hours, with subsequently slow tapering after 24 hours of stabilization in responders and after 60 minutes at the maximum dose or upper SBP limit in nonresponders.
 * Randomized a total of 160 patients.
 * 88% of intervention patients considered to be responders, with the upper threshold for neurological improvement being 179.7 ± 19.1 mmHg. Time interval from randomization and improvement was 1 day.
 * Primary outcome: Early neurological improvement (NIHSS improvement of ≥2 points) occurred more frequently in the intervention group (58% vs 31%, NNT ~4, aOR 2.49, 95% CI 1.25-4.96).
 * Secondary outcome: Functional independence (mRS 0-2) at 90-days was achieved more frequently in the intervention group (75% vs 63%, NNT ~8, aOR 2.97, 95% CI 1.32-6.68).
 * Safety: Eight patients had mild side effects (headache 6, palpitation 1, urticaria 1) in the intervention group. More patients in the intervention group had asymptomatic hemorrhagic transformation on follow-up MRI than controls (6.6% vs. 0%), but only one patient in the intervention group had symptomatic hemorrhage