Currently there is a tremendous amount of research interest in acute reperfusion therapy for patients suffering from acute ischemic stroke. However, other aspects of patient care in acute and subacute stroke are typically considered routine and thus have received less attention. The present guidelines emphasize medical management during the first 24–48 hours after infarction, but do little to address the management in the remainder of hospitalization. In this review article, we will discuss temperature management, blood pressure management, and glycemic control in patients with subacute ischemic stroke. Timely randomized controlled trials (RCTs) have attempted to address these topics, and in this review, we critically examine and summarize the evidence to date. We chose to focus on the management of temperature during the entire inpatient hospital stay. In regards to blood pressure, we focused on the inpatient management without discussing long-term outpatient management, and lastly for glycemic control, we focused on the acute to subacute management.
Temperature management in acute ischemic stroke
The issue of temperature management following acute ischemic stroke is complex and evolving. Hyperthermia is a frequent complication in up to 50% of patients with acute ischemic stroke.1 Recently, the European Stroke Organization (ESO) published evidence-based guidelines in 2015 for the management of temperature in patients with acute ischemic stroke.2 According to these guidelines, in patients with acute ischemic stroke and hyperthermia, no recommendations were made for treating hyperthermia as a means to improve functional outcome and/or survival.2 This conclusion was reached after finding low quality of evidence with only two RCTs with a total of 42 patients to analyze this question.
It is possible that therapeutic normothermia or the avoidance of hyperthermia provides the bulk of the benefit seen in prior studies of cardiac arrest survivors.3,4 However, the ESO guidelines state that in patients with acute ischemic stroke and normothermia, there is no recommended routine prevention of hyperthermia with antipyretics as a means to improve functional outcome and/or survival. The quality of evidence is moderate, and the strength of this recommendation is weak.2
Following two previous clinical trials3,4 showing a significant benefit of mild therapeutic hypothermia after out-of-hospital cardiac arrest, one can make a plausible argument that the benefit seen for cardiac arrest patients may also apply to acute ischemic stroke patients. In both scenarios there is ischemia to brain parenchyma secondary to hypoperfusion. However, one must be aware that controversy exists regarding the potential benefit of therapeutic hypothermia for cardiac arrest, especially given the results of the landmark targeted temperature management (TTM) trial.5 In this large multicenter, international trial including 939 patients there was no benefit conferred to patients treated with hypothermia at a targeted temperature of 33°C compared with a targeted temperature of 36°C.
Keeping this in mind, there are currently several human clinical trials attempting to answer the question of whether therapeutic hypothermia improves clinical outcome in acute ischemic stroke patients. One of these is EuroHYP-16, which is a phase III randomized open label trial to assess the effect of 24 hours of mild hypothermia (target body temperature 34–35°C) on 90 day modified Rankin Scale (mRS) score. The goal of the trial is to enroll 1500 patients. Another important trial is the ICTuS 2/3 study.7 In this randomized clinical trial, of which 200 patients out of 400 were enrolled, patients had endovascular cooling catheters placed after receiving intravenous thrombolysis with the goal of reaching a target temperature of 33°C within 6 hours of stroke onset, and maintaining that temperature for 24 hours. The trial was stopped early for unclear reasons, and the results are yet to be published. It remains to be seen if this new resurgence in research interest for the use of therapeutic hypothermia for neuroprotection in acute ischemic stroke patients will be fruitful. Presently, the ESO guidelines state that in patients with acute ischemic stroke, induction of hypothermia is not recommended as a means to improve functional outcome and/or survival with a very low quality of evidence and a weak recommendation.
The results of the previously mentioned clinical trials will surely provide us with guidance on therapeutic hypothermia for acute ischemic stroke patients and likely raise more questions as well. Clinical experience has clearly demonstrated that there are patients who have a clinical deterioration with fever and others that do not. Which specific factors determine the response to fever in ischemic stroke patients remains unknown. Perhaps the future will provide us with better knowledge of the specific factors involved which will allow us to provide more tailored therapies for these patients. Until there is convincing evidence for therapeutic hypothermia in ischemic stroke it is advisable to avoid this approach given the inherent risks of hypothermia without any proven benefit at this time. Finally, it appears reasonable to avoid hyperthermia and to aim for a goal of normothermia given that the risks of this approach are minimal and potentially beneficial.
Blood pressure management
The management of blood pressure in the setting of acute ischemic infarction is complicated by two opposing concepts: one maintains that acute hypertension has been associated with poor outcomes, the other states that rapid blood pressure reduction may limit the recovery of tissue penumbra.8–10 Current American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend treatment of blood pressure above 220 systolic and/or 120 diastolic.11 However, controversy lies in the management of more modest pressure elevations (i.e. 150-180s systolic), and this is especially true in the timeframe beyond 24–48 hours post-infarction.
The prospective COSSACS trial12 randomized 763 patients to either resume their outpatient anti-hypertensive regimen or stop for 2 weeks after ischemic or hemorrhagic infarction. At both 2- week and 6-month trial endpoints, there was no significant difference between groups in measures of dependency (characterized by mRS of >3), mortality, or additional cerebrovascular events.12
The COSSACs trial lacked sufficient statistical power to detect correlation between blood pressure reduction and improved patient outcomes. However, neutral results were also seen in the larger clinical trial CATIS, which included 4071 ischemic stroke patients.13 Eligible participants had initial systolic blood pressure between 140 and 220 mm Hg. The treatment group received antihypertensive therapy to reduce systolic blood pressure by 10% to 25% in the first 24 hours after group assignment, followed by a target blood pressure of <140/90, which was achieved at day five. Control subjects received no antihypertensive agents during hospitalization, with an average length of stay of 13 days. Outcome measures were death or major disability (mRS ≥3) at both 14 days (or hospital discharge) and at 3 months. Results indicated no significant differences between groups, with the exception of patients started on antihypertensive therapy greater than 24 hours after symptom onset, who demonstrated improved functional outcome at 3 months.13 This provides clinical evidence to support the concept of allowing permissive hypertension for the first 24 hours after infarction.
The strengths of CATIS include a large sample population, minimal loss to follow-up, categorization of ischemic stroke etiology, and exclusion of hemorrhagic strokes. Nevertheless, the selection criteria excluded all patients with atrial fibrillation and overrepresented thrombotic stroke. The average National Institutes of Health Stroke Scale (NIHSS) score of participants was only 4 (with an interquartile range of 2–7 in the treatment arm and 3–8 in the control), signifying a selection bias towards less severe strokes, which could account for the apparently blunted effects of aggressive blood pressure management due to a ceiling effect.