eTable 1. CASCADE* classification of arterial ischemic stroke (N=98).
eTable 2. Associated medical conditions and possible contributing causes of persistent hypertension* at 3-month follow-up (n=24).
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Grelli KN, Gindville MC, Walker CH, Jordan LC. Association of Blood Pressure, Blood Glucose, and Temperature With Neurological Outcome After Childhood Stroke. JAMA Neurol. 2016;73(7):829–835. doi:10.1001/jamaneurol.2016.0992
To our knowledge, no evidence-based guidelines are available for the best medical management of blood pressure, blood glucose levels, and temperature in pediatric patients after arterial ischemic stroke.
To determine the prevalence of abnormal blood pressure, blood glucose levels, and temperature in pediatric patients with acute arterial ischemic stroke and to explore any association between these measures and neurological outcome.
Design, Setting, and Participants
We performed a retrospective review of children aged 29 days to 18 years with their first arterial ischemic stroke between January 2009 and December 2013 at a tertiary academic children’s hospital. Ninety-eight children with stroke were identified by an International Classification of Diseases, Ninth Revision, code search and medical record review. Blood pressure, blood glucose, and temperature data were collected for 5 days after the stroke. Hypertension was defined as systolic blood pressure at or above the 95th percentile for age, sex, and height for 2 consecutive recordings and 2 consecutive days. Hypotension was defined as systolic and/or diastolic blood pressure below the fifth percentile for age, sex, and height for 2 consecutive recordings. Hyperglycemia was defined as a blood glucose level of 200 mg/dL or greater. Morbidity and mortality at 3 months were documented. Data analyses were performed from July 1, 2014, to December 31, 2015.
Interventions or Exposures
Abnormal blood pressure, blood glucose levels, and fever in the setting of arterial ischemic stroke.
Main Outcomes and Measures
The a priori outcome measure was poor clinical outcome, defined as a Pediatric Stroke Outcome Measure score of 1 or greater, which represents a moderate neurological deficit.
The median (interquartile range) age of the 98 children was 6.0 (0.6-14.3) years, and 58 (59.2%) were male. Hypertension was present in 64 (65.3%), hypotension in 67 (68.4%), hyperglycemia in 17 (18.1%), and fever in 37 (37.8%). The strongest association with poor neurological outcome was an infarct size of 4% or greater of brain volume (odds ratio, 5.6; 95% CI, 2.0-15.4; P = .001). Hyperglycemia was also independently associated with poor neurological outcome (odds ratio, 3.9; 95% CI, 1.2-12.4; P = .02). Hypertension and fever were not significantly associated with infarct size, poor outcome, or death. Hypertension was not documented in 24 of 87 surviving children (27.6%) at 3-month follow-up and was not associated with poor neurological outcome.
Conclusions and Relevance
Abnormalities of blood pressure, blood glucose levels, and temperature are prevalent in children with arterial ischemic stroke. Infarct volume and hyperglycemia were associated with poor neurological outcome but hypertension and fever were not. Prospective studies that systematically record blood pressure, blood glucose, and temperature data are required to further assess the associations between these potentially modifiable physiological parameters and pediatric stroke outcome.
To our knowledge, no evidence-based guidelines are available for the management of blood pressure (BP), blood glucose levels, or temperature after pediatric patients experience acute arterial ischemic stroke (AIS). Elevated BP can be harmful because it increases the risk of cerebral edema and hemorrhagic transformation and is associated with poor short-term and long-term outcomes in adults with ischemic stroke (IS).1,2 Low BP following an acute stroke is also associated with a poor prognosis because it threatens the viability of the ischemic penumbra.1 In adults with IS, a U-shaped relationship between BP and outcome exists; both high and low BP are associated with worse outcome.3 Brush et al4 demonstrated an association between hypertension and 12-month mortality but not neurological outcome in 84 children with IS (arterial and venous infarcts). Unfortunately, BP measurements were not standardized, and convalescent BPs and infarct volumes were not available in this study. To our knowledge, no studies have examined the role of hypotension in children with IS. Similarly, although adult studies have shown that hyperglycemia and hyperpyrexia are important risk factors for poor outcome after IS, no studies have investigated the role of blood glucose levels and temperature after a stroke in nonneonate children.5-9 A significant knowledge gap exists regarding the effect of these potentially modifiable factors on outcome in children after a stroke.
Our objectives were to investigate (1) the prevalence of hypertension, hypotension, hyperglycemia, and fever in children in the acute period after AIS, (2) if hypertension persisted at follow-up, and (3) if there was any association between these factors and outcome. We hypothesized that high and low BP, hyperglycemia, and fever after AIS were all associated with poor neurologic outcome in children.
Question Do alterations in blood pressure, blood glucose levels, or temperature influence neurologic outcome in pediatric patients with acute arterial ischemic stroke?
Findings In this cohort study of 98 children, poor outcome was significantly associated with infarct volume and hyperglycemia. Alterations in blood pressure and fever were not associated with worsened outcome.
Meaning In pediatric patients with acute arterial ischemic stroke, achieving euglycemia may be important.
We conducted a retrospective medical record review of children with acute AIS aged 29 days to 18 years admitted to Vanderbilt Children’s Hospital from January 2009 to December 2013. Inclusion criteria for our study were a clinical presentation consistent with acute AIS, neuroimaging consistent with clinical neurological findings,10 and arrival at Vanderbilt Children’s Hospital within 48 hours after symptom onset. After conducting an International Classification of Diseases, Ninth Revision (ICD-9), code search involving vascular codes 433 through 438, 99 patients were selected from 668 entries. Thirty of these children had previously been enrolled in the Vanderbilt Children’s Hospital International Pediatric Stroke Study database between 2011 and 2013. Children with perinatal stroke, global hypoxic ischemic injury, and infarcts from nonaccidental trauma were excluded from this study. Demographic information and pertinent medical history were obtained. We collected data on BP, blood glucose levels, and temperature from admission through hospital day 5. The study was approved by the Vanderbilt University Institutional Review Board, and informed consent was waived because the data recorded in the study database were deidentified. Study data were collected and managed using REDCap (Vanderbilt).11
Hypertension was classified per the Working Group on High Blood Pressure in Children and Adolescents12 as systolic BP (SBP) and/or diastolic BP (DBP) at or above the 95th percentile for age, sex, and height. Given the possibility of a spurious BP reading owing to an upset child or pain, 2 definitions for hypertension from admission through hospital day 5 were used. The first definition of hypertension (HTN1) required SBP and/or DBP at or above the 95th percentile for age, sex, and height for 2 consecutive recordings within the same day during the first 5 days after the stroke (the definition used by Brush et al4). More stringently, the other definition of hypertension (HTN2) required SBP and/or DBP at or above the 95th percentile for age, sex, and height for 2 consecutive recordings and 2 consecutive days within the first 5 days after the stroke. While many children had an accurate height recorded, 35 of 98 patients without height documented were placed in the 50th percentile for height. Similarly, hypotension was classified as SBP and/or DBP below the fifth percentile for age, sex, and height for 2 consecutive recordings and was collected from admission through hospital day 5. The treatment of hypertension and hypotension was recorded.
Blood glucose levels were collected from admission through hospital day 5. Hyperglycemia was defined as a blood glucose level of 200 mg/dL (to convert to millimoles per liter, multiply by 0.0555) or greater,13,14 the typical value for postprandial hyperglycemia, because it was difficult to determine if children were fasting at the time of glucose monitoring. Hypoglycemia was defined as a blood glucose level less than 60 mg/dL.13,15 Treatment and number of days of hyperglycemia and hypoglycemia were also recorded.
Temperature data were collected from admission through hospital day 5. Hyperpyrexia was defined as an axillary temperature of 37.8°C or higher9 or a rectal temperature of 38.0°C or higher.16 Treatment and number of days of hyperpyrexia were recorded.
Magnetic resonance images (MRIs) were preferentially used to establish the radiologic diagnosis of AIS, but computed tomography (CT) images were used when MRIs were unavailable. Imaging was subclassified with regard to arterial distribution and patients with AIS with and without hemorrhagic transformation. Volumetric analysis was performed using the ABC/2 method previously modeled to be an accurate reflection of infarct size in IS.17,18 This method was applied preferentially to diffusion-weighted images but was also used for T2-weighted fluid-attenuated inversion recovery images and CT images when diffusion-weighted images were unavailable. Prior literature19-21 suggests that infarct volume is a strong predictor of neurological outcome. Infarct volumes were categorized as 2% or more of brain volume22 and 4% or more of brain volume23 for analysis.
At the 3-month follow-up, neurological impairment was assessed by medical record review via the retrospectively scored Pediatric Stroke Outcome Measure (PSOM), a well-established index to assess neurological disability in infants and children with stroke24,25; PSOM scores include 5 subscales, including sensorimotor function, expressive and receptive language, and cognition/behavior, scored from 0 (normal) to 2 (major disability with missing function). Total scores range from 0 (normal) to 10 (major disability). At the follow-up, weight, height, BP, and medication data were recorded. Poor neurological outcome was defined as a PSOM score of 1 or greater (moderate disability).
Parametric and nonparametric statistics were used, as appropriate. χ2and Fisher exact test (when any cell value was less than 10) were used for binomial and categorical variables. Backward stepwise multivariable logistic regression was used to assess the association of hypertension or hypotension, hyperglycemia or hypoglycemia, and fever with poor neurological outcome or death. Statistical significance was set at P < .05, and all P values were 2-sided. Data were analyzed using Stata version 13 (StataCorp). Missing data were not imputed and were reported as missing in tables and text.
Ninety-nine children with acute AIS met inclusion criteria; 1 child was excluded because data on BP and blood glucose levels were missing. Therefore, 98 children composed the study population. Demographic and stroke characteristics are described in Table 1. The median (interquartile range) age of study participants was 6.0 (0.6-14.3) years. Eleven of 98 children (11.2%) died—8 during the acute hospital stay and 3 between discharge and follow-up. Of these 11 children, 5 died of cardiac disease and 6 died of systemic illness. Stroke was not the primary cause of death in any child, although stroke contributed to a decision to withdraw care in several children with severe systemic illness. Multiple stroke risk factors were identified, including a high number of patients with cardiac disease (50 [51.0%]), hematologic and oncologic disorders (25 [25.5%]), and acute systemic illness (19 [19.4%]) (Table 2). Primary and secondary stroke subtypes were also classified by the standardized Childhood AIS Standardized Classification and Diagnostic Evaluation system26 (eTable 1 in the Supplement). Follow-up was available for the 87 surviving children at a median (interquartile range) of 2.9 (2-4.5) months. The median (range; interquartile range) PSOM score was 0.5 (0-3; 0-1). Four children had recurrent AIS. Of 90 children surviving to hospital discharge, 23 (25.6%) were not discharged while receiving antithrombotic therapy, presumably because their strokes were thought to be perioperative or related to a systemic medical illness without ongoing risk factors. Fifty-two children received aspirin at discharge, 21 received enoxaparin, and 5 received warfarin. Of the children receiving antithrombotic therapy, 9 were prescribed dual antithrombotic therapy (8 were prescribed aspirin and enoxaparin and 1 was prescribed aspirin and warfarin) and 2 were transitioning from enoxaparin to warfarin.
Hypertension was prevalent in our study population. At the time of stroke onset, 15 children were taking antihypertensive medications, including 12 children with cardiac disease and 3 children with hypertension unrelated to cardiac disease (2 with chronic renal failure and 1 with pheochromocytoma). Our more stringent definition of hypertension, HTN2, was present in 64 children (65.3%) during the first 5 days after stroke (Table 3) and was not associated with body mass index (calculated as weight in kilograms divided by height in meters squared). There were no clear temporal trends in BP values over the 5-day period. Of the children with hypertension, 18 of 64 (28.1%) were treated with antihypertensive medication during the acute period after stroke. At hospital discharge, 26 of 87 patients (29.9%) were receiving antihypertensive medication, and none of these children died prior to follow-up. Neither HTN2 nor HTN1 were significantly associated with infarct size, poor outcome, or death.
A subanalysis of 83 children, excluding the 15 children with hypertension or who used antihypertensive agents prior to stroke, found that HTN2 was present in 52 children (62.7%) during the first 5 days after stroke. Of the 83 children with hypertension, 12 (14.5%) were treated with antihypertensive agents in the period after stroke. At hospital discharge, 12 of 75 survivors (16.0%) without premorbid hypertension received antihypertensive medication. Neither HTN2 nor HTN1 was significantly associated with infarct size, poor outcome, or death.
At the 3-month follow-up, 69 of 87 survivors (79.3%) had BP recorded. Hypertension at follow-up, measured by SBP and/or DBP at or above the 95th percentile for age, sex, and height, was documented in 24 of 87 surviving children (27.6%) and in 24 of 69 (34.8%) with a documented BP (eTable 2 in the Supplement); only 6 of these were still taking antihypertensive medication. Excluding the 15 children receiving antihypertensive medications prior to stroke, hypertension at follow-up was documented in 17 of 75 surviving children (22.7%), with 4 (23.5%) with a documented follow-up BP. However, only 2 of 75 children (2.7%) were still taking antihypertensive medication.
Hypotension was present in 67 of 98 children (68.4%) during their hospital stay and was treated in 16 children (23.9%), and 13 of 16 (81.3%) had cardiac disease and 6 of 16 (37.5%) had serious infection. Of 98 children, 38 (38.8%) had both hypotension and hypertension, and only 5 children (5.1%) had neither condition. Hypotension requiring treatment was associated with poor outcome in univariable analysis but not multivariable analysis. The 38 children with both hypotension and hypertension were considered to have more labile BP; this BP variability was not associated with poor outcome or death.
One child had type I diabetes and was excluded. Blood glucose levels were documented in 94 of 97 children (96.9%), and a blood glucose level of 200 mg/dL or greater was present in 17 of 94 children (18.1%) (Table 3). Three of 94 children (3.2%) were treated with insulin for hyperglycemia during the first 5 days after stroke. Eight of 17 children (8.5%, or 47.1% of those with hyperglycemia) were taking steroids at the time of stroke for another medical condition; steroids were not a part of stroke treatment. Hyperglycemia was not associated with elevated body mass index. Hypoglycemia was present in 3 of 94 children (3.2%). Blood glucose level was not assessed at follow-up. No children were taking oral hypoglycemic medications or insulin at follow-up. A blood glucose level of 200 mg/dL or greater was associated with poor outcome (P = .01).
Fever was present in 37 of 98 children (37.8%) and treated in 35 children (35.7%, or 94.6% of children with fever). A temperature of 39°C or greater was present in 16 of 98 children (16.3%). Neither temperature at or above 38°C nor temperature at or above 39°C were associated with poor outcome in this sample.
Magnetic resonance imaging was completed in 76 of 98 children (77.6%); CT scans were performed in 71 children (72.4%). Of these, 25 children (25.5%) received MRI scans only and 21 (21.4%) received CT scans only. One child received a head ultrasound and therefore was not included in the volumetric analysis of stroke size. Many children had large infarct volumes (Table 1); 39 (40.2%) had infarct volumes that were 2% or greater of brain volume and 25 (25.8%) had infarct volumes that were 4% or greater of brain volume. Infarct volume, particularly 4% or greater of brain volume, was strongly associated with poor outcome (χ2 = 13.9; P < .001). Hypertension was not associated with large infarct volume, bilateral infarcts, or multiple infarcts.
Variables with P < .10 in univariable analysis were included in multivariable analysis, including infarct size 4% or greater of brain volume, hypotension requiring treatment, and blood glucose level of 200 mg/dL or greater. Given 2 prior studies that found that hypertension is associated with death,4,27 this variable was also included in the multivariable models owing to biological plausibility (Table 4). Only 2 covariates reached statistical significance; the strongest association with poor outcome was infarct size 4% or greater of brain volume (OR, 5.6; 95% CI, 2.0-15.4; P = .001). Blood glucose level of 200 mg/dL or greater was also independently associated with poor outcome (OR, 3.9; 95% CI, 1.2-12.4; P = .02).
Blood pressure appeared labile in children after stroke, with many children documented with both hypertension and hypotension. We used 2 definitions of hypertension. We applied the definition of HTN1 given by Brush et al4 so that our results could be comparable, but an upset or anxious child might have 2 consecutively elevated BP measurements.4 In fact, with this definition, 81 children (82.7%) with acute AIS in our study population had hypertension. Therefore, we also used a more stringent definition of hypertension (HTN2), yet 67 (68.4%) of children still met this definition. Neither definition of hypertension was associated with poor outcome or death. Only 24 of 87 surviving children (27.6%) had hypertension at follow-up, and nearly all of these children had secondary hypertension associated with another condition, such as cardiac disease or intracranial stenosis (eTable 2 in the Supplement).
There are 3 possible causes of the high prevalence of hypertension in children after acute AIS: (1) Elevated BP is a compensatory response driven by cerebral autoregulation to perfuse a marginally perfused brain. Of note, there was no association between large infarct size and the presence of hypertension. (2) Hypertension is present prior to stroke (and after stroke) in many children and may be underdiagnosed by health care professionals. (3) Blood pressure readings in acutely ill children are often high because of the distress of acute illness and may remain high at clinic because of the stress of vital sign measurements and do not reflect true hypertension.
Our study found no significant association between outcome and hypertension at 3 months after stroke, even with our more stringent definition of HTN2. This differs from Brush et al,4 who found that hypertension was associated with death but not poor outcome at 1 year. The Brush et al study4 did not include data on infarct volume or BP at follow-up. Infarct volume was very strongly associated with outcome in our study population, a finding similarly reported by Ganesan et al19 with pediatric large-vessel strokes and by Beslow et al28 when using MRI to estimate infarct volume. Our study population included 50 children (51.0%) with cardiac disease, presumably those at high risk for hypertension. Depending on cardiac anatomy, pediatric cardiac patients may have variations of preload and afterload that consequently affect BP unrelated to an acute AIS. However, excluding children with cardiac disease did not change our results, and Brush et al4 had a similar proportion of cardiac patients (31%). The differing results on the role of hypertension and outcome after pediatric stroke and the finding in our univariable analysis of an association between poor outcome and hypotension requiring treatment suggest that a larger, prospective study of BP in children after stroke is needed.
A blood glucose level of 200 mg/dL or greater was associated with poor outcome in our study, a finding reported extensively in the adult5-7 but not pediatric stroke literature. However, hyperglycemia in critically ill pediatric patients is a well-reported occurrence and is associated with increased mortality and hospital length of stay.29,30 Animal models suggest that hyperglycemia worsens both neuronal acidosis and the generation of free radicals, increasing damage within the ischemic penumbra.31,32 Proposed pathophysiological mechanisms in adults involve the activation of the hypothalamic-pituitary axis as well as an increased immune response, leading to increased insulin resistance33 and subsequent hyperglycemia. A recent randomized clinical trial34 of tight glucose control in critically ill children did not result in improved outcome. A clinical trial35 of tight glucose control after adult stroke is in progress.
Finally, a strong association was found between large infarct volume and poor outcome, as expected.19,28 We believe that future studies should consider infarct volume when assessing predictors associated with outcome.
Our study had limitations. One is a lack of information about intravenous fluid dextrose content in relation to blood glucose measurements. Other limitations include BP measurement technique, our tertiary care study population that included many children with cardiac disease and relatively fewer with cerebral arteriopathy, and the use of ICD-9 codes to identify study patients. This analysis did not allow for standardized BP measurements. The Chronic Kidney Disease of Children study36 required that BP be taken with a manual, aneroid sphygmomanometer with 3 averaged BP measurements, each taken at 30-second intervals. Otherwise, our definitions of hypertension are identical.12 Blood pressure assessment in our study reflects clinical practice, and the frequency of elevated BP in children with stroke is similar to that seen by Brush et al.4 Therefore, our results seem generalizable. Lastly, ICD-9 codes are known to have limitations in both sensitivity and specificity.37 The use of our local International Pediatric Stroke Study stroke registry in addition to the ICD-9 codes may have helped to properly identify children with stroke.
Future directions include a prospective analysis of the roles of hypertension, hypotension, blood glucose, and fever in children following acute AIS. Neurologists are asked how to manage these parameters as part of supportive care for every child with AIS. The adult literature supports the role of BP1,3 and glucose level control6,7 after stroke; it is critical to determine the role of this practice in children to help improve outcome. The only prior study of hypertension and outcome after stroke in children suggests that hypertension is a risk factor for poor outcome,4 while our study had negative findings for hypertension. A prospective analysis would allow for standardized BP, blood glucose, and temperature measurements, improve generalizability, and inform clinical practice.
Evidence to guide supportive care and medical management for children with acute AIS is lacking. In the present study, hyperglycemia and infarct size were both independently associated with increased disability after pediatric AIS. While hypotension was also weakly associated with poor outcome, no significant association was observed between hypertension and poor outcome or death as seen in the adult literature1,3 and 1 prior pediatric study.4 Future prospective studies are needed to clarify the associations between these potentially modifiable physiological parameters and pediatric stroke outcome.
Corresponding Author: Lori C. Jordan, MD, PhD, Division of Pediatric Neurology, Department of Pediatrics, Vanderbilt University Medical Center, 2200 Children’s Way, DOT 11212, Nashville, TN 37232-9559 (firstname.lastname@example.org).
Accepted for Publication: March 11, 2016.
Published Online: May 23, 2016. doi:10.1001/jamaneurol.2016.0992.
Author Contributions: Dr Jordan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Jordan.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Grelli, Jordan.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Jordan.
Administrative, technical, or material support: Grelli, Gindville, Walker.
Study supervision: Jordan.
Conflict of Interest Disclosures: None reported.
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