Original Paper Received: May 13, 2013 Accepted: August 12, 2013 Published online: December 17, 2013
Eur Neurol 2014;71:132–139 DOI: 10.1159/000355020
Effects of Uric Acid Levels on Outcome in Severe Ischemic Stroke Patients Treated with Intravenous Recombinant Tissue Plasminogen Activator Sang-Hwa Lee a Sung Hyuk Heo a Jun-Hyun Kim a Dokyung Lee a Ji Sung Lee b Young Seo Kim c Hyun Young Kim c Seong-Ho Koh c Dae-Il Chang a
a Department of Neurology, College of Medicine, Kyung Hee University, b Department of Biostatistics, Korea University, and c Department of Neurology, College of Medicine, Han Yang University, Seoul, Korea
Key Words Uric acid · Thrombolysis · Neuroprotective antioxidant · Functional outcome
Abstract Uric acid (UA) has been known to be a neuroprotective antioxidant because of its free radical scavenger activity. We studied the influence of UA in patients with acute ischemic stroke after thrombolytic therapy. Two hundred eighteen consecutive patients treated with intravenous thrombolysis were included in this analysis. We analyzed the relationship between serum UA levels obtained at the emergency department and clinical outcomes. Early improvement and excellent functional outcomes were measured using the National Institutes of Health Stroke Scale (NIHSS) 24 h after onset and the modified Rankin scale after 3 months. There was no significant relationship between serum UA levels and early improvement or excellent functional outcome in the total patients (p = 0.583 and p = 0.082, respectively). However, in patients with severe baseline stroke deficits (NIHSS score ≥15), higher-tertile UA levels were significantly associated with excellent functional outcomes (p = 0.003). Excellent functional outcomes in patients with severe baseline disability might have a significant association with serum UA levels
© 2013 S. Karger AG, Basel 0014–3022/13/0714–0132$38.00/0 E-Mail [email protected] www.karger.com/ene
particularly in men but not in women (p = 0.007 in men and p = 0.621 in women). Increased serum UA levels might be associated with better outcomes in ischemic stroke patients treated with intravenous thrombolysis, but the effectiveness of UA can differ by initial stroke severity and gender. © 2013 S. Karger AG, Basel
Introduction
The only effective strategy for improving clinical outcomes after ischemic stroke is reperfusion therapy with thrombolysis. A number of neuroprotectants including antioxidants have been investigated in animal stroke models, but all clinical trials using these materials have failed [1, 2]. Uric acid (UA) is a final oxidative product of purine metabolism. It is thought to be the most important antioxidant and contributes to about two thirds of the antioxidant capacity in humans [3]. The increased generation of free radicals has been demonstrated in oxidative stress situations such as stroke. UA has been shown to be a neuroprotective antioxidant by virtue of its free radical scavenger activity, which has been demonstrated in an animal stroke model [4, 5]. Some studies have shown that UA Sung Hyuk Heo, MD, PhD Department of Neurology Kyung Hee University Hospital 23, Kyungheedae-ro, Dongdaemun-gu, Seoul 130-872 (Korea) E-Mail shheo73 @ khu.ac.kr
reduces oxidative stress and infarct volume. It has been suggested that the administration of UA increases the clinical benefits of recombinant tissue plasminogen activator (rtPA) after acute ischemic stroke [4–6]. Recently, increased serum UA was significantly associated with favorable outcomes in patients after ischemic stroke treated with thrombolysis [7, 8]. Standardization of the initial stroke severity is very important in the study of neuroprotectants such as UA, and there have been some reports demonstrating gender differences in functional recovery after acute ischemic stroke [1, 2, 9]. Therefore, in this study we aimed to confirm the positive association of admission serum UA levels with clinical outcomes in thrombolyzed patients stratified by stroke severity and gender.
Methods Subjects Two hundred forty-eight consecutive ischemic stroke patients from the prospective stroke registry of Kyung Hee University Hospital, Republic of Korea, were recruited for this study. All patients were treated with intravenous thrombolysis within 3 h after onset from November 2003 through December 2011. Patients who received mechanical embolectomy or intra-arterial thrombolysis were not included. Patients were excluded if they had undergone intravenous thrombolysis in another hospital (n = 13), had been recently discharged from the emergency room (n = 2), had suffered a stroke during hospitalization (n = 3), or did not have serum UA data in the emergency room (n = 12). A total of 218 patients were finally included. This study was approved by an independent ethics committee at Kyung Hee University Medical Center (KMC IRB 1101-02).
Symptomatic hemorrhage was defined as any form of intracerebral hemorrhage seen on the follow-up CT or MRI scan and an increase of 4 or more points on the NIHSS according to European Cooperative Acute Stroke Study (ECASS) 2 criteria [12]. Infarct volume was calculated by brain CT (n = 200) 12–48 h after intravenous thrombolysis using Medical Image Processing and Visualization software version 5.4.4 (FDA, USA). The 18 patients who had no brain CT data were assessed via diffusion-weighted imaging MRI. Vessel patency was evaluated in 178 patients who had a follow-up MR angiography after thrombolysis. This method using a second CT scan was similar to the methodology of a previous study by Amaro et al. [7]. Statistical Analyses Values are presented as means ± SD or medians (IQR) for continuous variables and as numbers of subjects (%) for categorical variables. Differences in baseline characteristic variables among serum UA tertile groups were examined using Pearson’s χ2 test, Fisher’s exact test, one-way analysis of variance, and the KruskalWallis test. The Cochran-Armitage linear trend test was performed to investigate the clinical outcome divided into early improvement and 3-month mRS score according to the serum UA concentration. For multivariable analysis, potential factors that were not significant (p > 0.2) were sequentially deleted from the full multivariable logistic regression model. The likelihood ratio test for trends was used to elucidate a relationship between the tertiles of serum UA and functional outcome. Data in this analysis are presented as adjusted ORs with 95% CIs. All statistical analyses were performed with SAS version 9.2 (SAS Institute Inc., Cary, N.C., USA). A 2-sided p value
Eur Neurol 2014;71:132–139 DOI: 10.1159/000355020
Effects of Uric Acid Levels on Outcome in Severe Ischemic Stroke Patients Treated with Intravenous Recombinant Tissue Plasminogen Activator Sang-Hwa Lee a Sung Hyuk Heo a Jun-Hyun Kim a Dokyung Lee a Ji Sung Lee b Young Seo Kim c Hyun Young Kim c Seong-Ho Koh c Dae-Il Chang a
a Department of Neurology, College of Medicine, Kyung Hee University, b Department of Biostatistics, Korea University, and c Department of Neurology, College of Medicine, Han Yang University, Seoul, Korea
Key Words Uric acid · Thrombolysis · Neuroprotective antioxidant · Functional outcome
Abstract Uric acid (UA) has been known to be a neuroprotective antioxidant because of its free radical scavenger activity. We studied the influence of UA in patients with acute ischemic stroke after thrombolytic therapy. Two hundred eighteen consecutive patients treated with intravenous thrombolysis were included in this analysis. We analyzed the relationship between serum UA levels obtained at the emergency department and clinical outcomes. Early improvement and excellent functional outcomes were measured using the National Institutes of Health Stroke Scale (NIHSS) 24 h after onset and the modified Rankin scale after 3 months. There was no significant relationship between serum UA levels and early improvement or excellent functional outcome in the total patients (p = 0.583 and p = 0.082, respectively). However, in patients with severe baseline stroke deficits (NIHSS score ≥15), higher-tertile UA levels were significantly associated with excellent functional outcomes (p = 0.003). Excellent functional outcomes in patients with severe baseline disability might have a significant association with serum UA levels
© 2013 S. Karger AG, Basel 0014–3022/13/0714–0132$38.00/0 E-Mail [email protected] www.karger.com/ene
particularly in men but not in women (p = 0.007 in men and p = 0.621 in women). Increased serum UA levels might be associated with better outcomes in ischemic stroke patients treated with intravenous thrombolysis, but the effectiveness of UA can differ by initial stroke severity and gender. © 2013 S. Karger AG, Basel
Introduction
The only effective strategy for improving clinical outcomes after ischemic stroke is reperfusion therapy with thrombolysis. A number of neuroprotectants including antioxidants have been investigated in animal stroke models, but all clinical trials using these materials have failed [1, 2]. Uric acid (UA) is a final oxidative product of purine metabolism. It is thought to be the most important antioxidant and contributes to about two thirds of the antioxidant capacity in humans [3]. The increased generation of free radicals has been demonstrated in oxidative stress situations such as stroke. UA has been shown to be a neuroprotective antioxidant by virtue of its free radical scavenger activity, which has been demonstrated in an animal stroke model [4, 5]. Some studies have shown that UA Sung Hyuk Heo, MD, PhD Department of Neurology Kyung Hee University Hospital 23, Kyungheedae-ro, Dongdaemun-gu, Seoul 130-872 (Korea) E-Mail shheo73 @ khu.ac.kr
reduces oxidative stress and infarct volume. It has been suggested that the administration of UA increases the clinical benefits of recombinant tissue plasminogen activator (rtPA) after acute ischemic stroke [4–6]. Recently, increased serum UA was significantly associated with favorable outcomes in patients after ischemic stroke treated with thrombolysis [7, 8]. Standardization of the initial stroke severity is very important in the study of neuroprotectants such as UA, and there have been some reports demonstrating gender differences in functional recovery after acute ischemic stroke [1, 2, 9]. Therefore, in this study we aimed to confirm the positive association of admission serum UA levels with clinical outcomes in thrombolyzed patients stratified by stroke severity and gender.
Methods Subjects Two hundred forty-eight consecutive ischemic stroke patients from the prospective stroke registry of Kyung Hee University Hospital, Republic of Korea, were recruited for this study. All patients were treated with intravenous thrombolysis within 3 h after onset from November 2003 through December 2011. Patients who received mechanical embolectomy or intra-arterial thrombolysis were not included. Patients were excluded if they had undergone intravenous thrombolysis in another hospital (n = 13), had been recently discharged from the emergency room (n = 2), had suffered a stroke during hospitalization (n = 3), or did not have serum UA data in the emergency room (n = 12). A total of 218 patients were finally included. This study was approved by an independent ethics committee at Kyung Hee University Medical Center (KMC IRB 1101-02).
Symptomatic hemorrhage was defined as any form of intracerebral hemorrhage seen on the follow-up CT or MRI scan and an increase of 4 or more points on the NIHSS according to European Cooperative Acute Stroke Study (ECASS) 2 criteria [12]. Infarct volume was calculated by brain CT (n = 200) 12–48 h after intravenous thrombolysis using Medical Image Processing and Visualization software version 5.4.4 (FDA, USA). The 18 patients who had no brain CT data were assessed via diffusion-weighted imaging MRI. Vessel patency was evaluated in 178 patients who had a follow-up MR angiography after thrombolysis. This method using a second CT scan was similar to the methodology of a previous study by Amaro et al. [7]. Statistical Analyses Values are presented as means ± SD or medians (IQR) for continuous variables and as numbers of subjects (%) for categorical variables. Differences in baseline characteristic variables among serum UA tertile groups were examined using Pearson’s χ2 test, Fisher’s exact test, one-way analysis of variance, and the KruskalWallis test. The Cochran-Armitage linear trend test was performed to investigate the clinical outcome divided into early improvement and 3-month mRS score according to the serum UA concentration. For multivariable analysis, potential factors that were not significant (p > 0.2) were sequentially deleted from the full multivariable logistic regression model. The likelihood ratio test for trends was used to elucidate a relationship between the tertiles of serum UA and functional outcome. Data in this analysis are presented as adjusted ORs with 95% CIs. All statistical analyses were performed with SAS version 9.2 (SAS Institute Inc., Cary, N.C., USA). A 2-sided p value
