The treatment of ischemic stroke is often divided between acute interventions (endovascular therapy, intravenous tissue plasminogen activator [IV tPA]) and long-term secondary prevention (modifying risk factors, antithrombotic therapy, etc.). There is great variability between practitioners in the medical management of stroke during hospitalization, in part because of confusing and contradictory results in the literature. Temperature management and therapeutic hypothermia is discussed in this review. In regards to blood pressure targets, while permissive hypertension is often recognized as a beneficial strategy in acute stroke, blood pressure reduction is essential for secondary stroke prevention. We review the literature regarding optimal timing of different blood pressure goals. Finally, the limited literature regarding glycemic control in ischemic stroke patients is discussed.
Ischemic stroke, hyperthermia, therapeutic hypothermia, hypertension, permissive hypertension, hyperglycemia, hypoglycemia
Shannon Hextrum, Barak Bar have nothing to disclose in relation to this article. No funding was received in the publication of this article.
Compliance with Ethics: This article involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
July 16, 2016 Accepted
August 31, 2016
Shannon Hextrum, Department of Neurology, Loyola University Chicago, Stritch School of Medicine, 2160 S. First Avenue, Maywood, Illinois, US, 60153. E: Shannon.email@example.com
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
1.Castillo J, Davalos A, Marrugat J, Noya M, Timing for feverrelated brain damage in acute ischemic stroke, Stroke, 1998;29:2455–60.
2. Ntaios G, Dziedzic T, Michel P, et al., European stroke organisation (ESO) guidelines for the management of temperature in patients with acute ischemic stroke, Int J Stroke, 2015;10:941–9.
3. Hypothermia after Cardiac Arrest Study Group, Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest, N Engl J Med, 2002;346:549–56.
4. Bernard SA, Gray TW, Buist MD, et al., Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia, N Engl J Med, 2002;346:557–63.
5. Nielsen N, Wetterslev J, Cronberg T, et al., Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest, N Engl J Med, 2013;369:2197–206.
6. van der Worp HB, Macleod MR, Bath PM, et al., EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke, Int J Stroke, 2014;9:642–5.
7. Lyden PD, Hemmen TM, Grotta J, et al., Endovascular therapeutic hypothermia for acute ischemic stroke: ICTuS 2/3 protocol, Int J Stroke, 2014;9:117–25.
8. Sharma VK, Elevated blood pressure in acute ischemic stroke - treat or leave?, Cerebrovasc Dis, 2016;41:101–2.
9. Willmot M, Leonardi-Bee J, Bath PM, High blood pressure in acute stroke and subsequent outcome: A systematic review, Hypertension, 2004;43:18–24.
10. Alqadri SL, Sreenivasan V, Qureshi AI, Acute hypertensive response management in patients with acute stroke, Curr Cardiol Rep, 2013;15:426.
11. Jauch EC, Saver JL, Adams HP,Jr, et al., Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the american heart association/american stroke association, Stroke, 2013;44:870–947.
12. Robinson TG, Potter JF, Ford GA, et al., Effects of antihypertensive treatment after acute stroke in the continue or stop post-stroke antihypertensives collaborative study (COSSACS): A prospective, randomised, open, blinded-endpoint trial, Lancet Neurol, 2010;9:767–75.
13. He J, Zhang Y, Xu T, et al., Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: The CATIS randomized clinical trial, JAMA, 2014;311:479–89.
14. ENOS Trial Investigators, Bath PM, Woodhouse L, et al., Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): A partial-factorial randomised controlled trial, Lancet, 2015;385:617–28.
15. Sandset EC, Bath PM, Boysen G, et al., The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): A randomised, placebo-controlled, double-blind trial, Lancet, 2011;377:741–50.
16. Schrader J, Luders S, Kulschewski A, et al., The ACCESS study: Evaluation of acute candesartan cilexetil therapy in stroke survivors, Stroke, 2003;34:1699–703.
17. Toyoda K, Okada Y, Fujimoto S, et al., Blood pressure changes during the initial week after different subtypes of ischemic stroke, Stroke, 2006;37:2637–9.
18. Fischer U, Rothwell PM, Blood pressure management in acute stroke: Does the scandinavian candesartan acute stroke trial (SCAST) resolve all of the unanswered questions?, Stroke, 2011;42:2995–8.
19. Wang Y, Xu J, Zhao X, et al., Association of hypertension with stroke recurrence depends on ischemic stroke subtype, Stroke, 2013;44:1232–7.
20. Saver JL, Fonarow GC, Smith EE, et al., Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke, JAMA, 2013;309:2480–8.
21. Bruno A, Liebeskind D, Hao Q, Raychev R, UCLA Stroke Investigators. Diabetes mellitus, acute hyperglycemia, and ischemic stroke, Curr Treat Options Neurol, 2010;12:492–503.
22. Kruyt ND, Biessels GJ, Devries JH, Ros YB, Hyperglycemia in acute ischemic stroke: Pathophysiology and clinical management, Nat Rev Neurol, 2010;6:145–55.
23. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al., Intensive versus conventional glucose control in critically ill patients, N Engl J Med, 2009;360:1283–97.
24. Gray CS, Hildreth AJ, Sandercock PA, et al., Glucosepotassium- insulin infusions in the management of post-stroke hyperglycaemia: The UK glucose insulin in stroke trial (GIST-UK), Lancet Neurol, 2007;6:397–406.
25. Johnston KC, Hall CE, Kissela BM, et al., GRASP Investigators. Glucose regulation in acute stroke patients (GRASP) trial: A randomized pilot trial, Stroke, 2009;40:3804–9.
26. Baird TA, Parsons MW, Phan T, et al., Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome, Stroke, 2003;34:2208–14.
27. Els T, Klisch J, Orszagh M, et al., Hyperglycemia in patients with focal cerebral ischemia after intravenous thrombolysis: Influence on clinical outcome and infarct size, Cerebrovasc Dis, 2002;13:89–94.
28. Parsons MW, Barber PA, Desmond PM, et al., Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study, Ann Neurol, 2002;52:20–8.
29. Rosso C, Corvol JC, Pires C, et al., Intensive versus subcutaneous insulin in patients with hyperacute stroke: Results from the randomized INSULINFARCT trial, Stroke, 2012;43:2343–9.
30. Connor JT, Broglio KR, Durkalski V, et al., The stroke hyperglycemia insulin network effort (SHINE) trial: An adaptive trial design case study, Trials, 2015;16:72.
Ischemic stroke, hyperthermia, therapeutic hypothermia, hypertension, permissive hypertension, hyperglycemia, hypoglycemia