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Keywords:

  • acute stroke therapy;
  • cost factors;
  • CT scan;
  • ischemic stroke;
  • neuroworsening;
  • tPA

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aims/hypothesis
  5. Methods
  6. Results
  7. Discussion
  8. References

Background

International management of acute ischemic stroke patients treated with intravenous tissue plasminogen activator frequently includes 24-h head imaging. These recommendations stem from the National Institute of Neurological Disorders and Stroke (NINDS) clinical trial protocol regarding the risk of intracerebral hemorrhage post-tissue plasminogen activator administration. Follow-up computed tomography scans on select patients, however, may not effect clinical management, resulting in unnecessary radiation exposure and healthcare costs.

Aims

Our study questions the utility of routine 24-h computed tomography imaging and looks at the National Institute of Health Stroke Scale as a possible clinical screen for selecting candidates for 24-h imaging. Such a tool would result in decreased radiation exposure to the patient and decreased cost to the hospital.

Methods

Consecutive patients with acute ischemic stroke given intravenous tissue plasminogen activator between June 2008 and December 2011 were retrospectively identified and dichotomized based on change in 24-h National Institute of Health Stroke Scale from baseline. Initial analysis compared patients with National Institute of Health Stroke Scale worsening to those without worsening. Subsequent analysis was limited to patients with a baseline National Institute of Health Stroke Scale ≤10. Baseline demographics and medical history, baseline and 24-h computed tomography findings, medical and/or surgical orders within six-hours of imaging, and antithrombotic administration within 24–48-h postintravenous tissue plasminogen activator were compared between the two groups.

Results

Two-hundred patients met inclusion criteria: No 24-h National Institute of Health Stroke Scale worsening (n = 167) vs. 24-h National Institute of Health Stroke Scale worsening (n = 33). No baseline demographic or admission data differed significantly between the two groups. Patients without 24-h National Institute of Health Stroke Scale worsening had significantly lower incidence of hemorrhagic infarction (10·8% vs. 31·3%, P = 0·0014) on follow-up imaging. Less than 2% of all patients without 24-h National Institute of Health Stroke Scale worsening had a parenchymal hematoma. No patient with baseline National Institute of Health Stroke Scale ≤10 and without 24-h National Institute of Health Stroke Scale worsening had parenchymal hematoma. Patients with 24-h worsening were significantly less likely to receive timely antithrombotic therapy (60·6% vs. 77·8%, odds ratio 0·44, 95% confidence interval 0·20–0·96).

Conclusions

Our results demonstrate that routine 24-h computed tomography scan in patients without 24-h National Institute of Health Stroke Scale worsening (especially those with baseline National Institute of Health Stroke Scale ≤10) is less likely to yield information that results in a deviation from standard acute stroke care. No patient without worsening and baseline National Institute of Health Stroke Scale ≤10 had parenchymal hematoma on 24-h computed tomography. Application of the National Institute of Health Stroke Scale to distinguish patients who should have 24-h follow-up imaging from those who will not benefit is a potential avenue for improving utilization of resources and warrants further study.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aims/hypothesis
  5. Methods
  6. Results
  7. Discussion
  8. References

In the United States, guidelines for follow-up imaging after administration of intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke (AIS) recommend obtaining 24-h head imaging [1, 2]. This suggestion stems primarily from the NINDS recombinant tPA trial protocol and, secondarily, from the current recommendation to delay antithrombotic therapy until 24–48 h post-tPA treatment [1, 3]. Similar recommendations are evident internationally. Recommendations from Canada, Australia, and New Zealand clearly recommend 24-h head imaging [4, 5]. Elsewhere, guidelines are not as explicit, but 24-h head imaging before administration of antithrombotics appears to be standard practice. In both Europe and Asia, all the clinical trials from which guidelines are derived include safety monitoring for intracerebral hemorrhage (ICH) at 24 h [6-11]. As such, 24-h follow-up head computed tomography (CT) scans are routinely obtained and are driven by the increased risk for hemorrhagic conversion post-IV tPA therapy [12-14].

However, the benefit of repeat imaging is unclear [15, 16]. Evidence exists for the utility of a 24-h follow-up CT scan in treated patients with clinical signs of deterioration [15]. However, data supporting the repeat CT in the same patient population without neurological deterioration is sparse. To date, little to no prognostic information is gained from repeat imaging [15, 17, 18]. A 2012 Thai study challenges whether it is necessary for all patients treated with thrombolysis to receive 24-h follow-up CT. Dharmasaroja et al. showed that the majority of patients with early improvement on the National Institute of Health Stroke Scale (NIHSS) and 24-h NIHSS ≤10 had no change in management following 24-h CT [19].

Aims/hypothesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aims/hypothesis
  5. Methods
  6. Results
  7. Discussion
  8. References

In the present study, we similarly compare routine 24-h follow-up CT findings after IV tPA and subsequent changes in medical and/or surgical management between patients with and without clinical worsening on 24-h NIHSS. We hypothesized that patients without 24-h NIHSS worsening would have no significant findings on 24-h follow-up CT or significant medical and/or surgical deviations from standard care [1]. We attempted to define a sub-population of patients for which post-IV tPA brain imaging may not alter patient management per protocol. This knowledge would contribute to defining appropriate guidelines for post-IV tPA brain imaging in AIS patients.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aims/hypothesis
  5. Methods
  6. Results
  7. Discussion
  8. References

We conducted an Institutional Review Board-approved retrospective analysis of all AIS patients admitted to our center from July 2008 through December 2011 pooled from a prospective registry [20]. Patients were included if they were treated with IV tPA and received a head CT scan 12–36 h from administration of IV tPA. Patients treated with intra-arterial therapy or without documented 24-h NIHSS were excluded.

All repeat CT scan results were reviewed retrospectively by a vascular neurologist (SMS). The scans were interpreted prior to the development of this protocol, and interpretations were blinded to the baseline and 24-h NIHSS scores. New infarcts were categorized by location and degree of hemorrhagic transformation (HT), if present. HT was classified in accordance with the European Cooperative Acute Stroke Study: hemorrhagic infarction-type 1 (HI-1), hemorrhagic infarction-type 2 (HI-2), parenchymal hematoma-type 1 (PH-1), and parenchymal hematoma-type 2 (PH-2) [8]. Additionally, patient records were reviewed for medical and/or surgical management changes within six-hours of the follow-up CT scan. Management categories included new orders for blood products, the addition or discontinuation of medications, therapies suggestive of intracranial pressure management (e.g. osmotherapy), neurosurgical consultation, additional neuroimaging, and Do Not Resuscitate/Do Not Intubate (DNR/DNI) orders. Antithrombotic therapy was analyzed separately for administration between 24-h and 48-h post-IV tPA therapy, in accordance with current guidelines [1].

Patients were dichotomized based on 24-h NIHSS into those whose 24-h NIHSS score remained the same or improved from admission (‘no NIHSS worsening’) and those whose 24-h NIHSS worsened (‘NIHSS worsening’). The same criteria was applied to a sub-class of patients whose baseline NIHSS was ≤10 for further analysis. Categorical data were compared using Pearson Chi-squared or Fisher exact test where appropriate. Continuous data were compared using Wilcoxon Rank Sum test. Logistic regression was performed to determine the odds of dichotomous outcomes. All tests were performed at the alpha 0·05 level and were two sided. As this was an exploratory analysis, no adjustments were made for multiple comparisons [21].

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aims/hypothesis
  5. Methods
  6. Results
  7. Discussion
  8. References

Of the 200 patients who met criteria, 167 patients (83·5%) had no NIHSS worsening. No significant differences were found when patients with NIHSS worsening were compared with patients with no NIHSS worsening regarding baseline demographics, admission data, or stroke etiology (Table 1).

Table 1. Demographic and etiological data
 No 24-h NIHSS worsening (n = 167)24-h NIHSS worsening (n = 33)P-value
  1. NIHSS, NIH Stroke Scale, TOAST, Trial of Org 10172 in Acute Stroke Treatment.

Age, median years (range)62 (22–95)63 (29–87)0·8264
Race ethnicity (%)  0·6571
Caucasian47 (28·7)11 (33·3) 
Black114 (69·5)22 (66·7) 
Other3 (1·8)0 
Gender (% female)68 (41)11 (33·3)0·3988
Baseline glucose (mg/dl), median (range)113 (67–446)115 (75–270)0·7994
Baseline NIHSS, median (range)5 (0–34)11 (0–30)0·2531
TOAST classification (%)  0·8818
Cardioembolic34 (20·9)7 (21·2) 
Large vessel40 (24·5)9 (27·3) 
Small vessel44 (26·9)6 (18·2) 
Cryptogenic, 1 cause27 (16·6)6 (18·2) 
Cryptogenic, >1 cause6 (3·7)1 (3·0) 
History of stroke (%)76 (46·3)17 (53·1)0·4821
Ischemic74 (45·1)16 (50)0·6125
Hemorrhagic2 (1·2)1 (3·1)0·42

Findings of follow-up CT between patients with and without NIHSS worsening (Table 2) were significantly different for any new findings (P = 0·0012), cortical lesions (P = 0·0355), and cerebellar lesions (P = 0·0108). After logistic regression analysis (Table 3), patients with NIHSS worsening were five times more likely to have new findings on 24-h CT [unadjusted odds ratio (OR) 5·24, 95% confidence interval [CI] 1·76–15·63]. Furthermore, NIHSS worsening patients were two times more likely to have a cortical lesion (OR 2·24, 95% CI 1·04–4·81) and nearly four times more likely to have a cerebellar lesion than patients without NIHSS worsening (OR 3·90, 95% CI 1·29–11·85).

Table 2. Follow-up CT findings
 No NIHSS worsening (n = 167)NIHSS worsening (n = 33)P-value
  1. HI, hemorrhagic infarct; HT, hemorrhagic transformation; NIHSS, NIH Stroke Scale; PH, parenchymal hematoma; sICH, symptomatic intracerebral hemorrhage defined by NIHSS increase ≥4 points.

Normal or no change from baseline (%)70 (41·9)4 (12·1)0·0012
New infarct (%)97 (58·1)29 (87·9)0·0012
Cortical68 (40·7)20 (60·6)0·0355
Sub-cortical42 (25·1)9 (27·3)0·7982
Cerebellar9 (5·4)6 (18·2)0·0108
Brainstem3 (1·8)2 (6·1)0·1587
Midline shift5 (2·9)2 (6·1)0·2356
Herniation1 (0·6)00·8350
Hemorrhagic infarct (%)18 (10·8)10 (31·3)0·0014
Grade of HT (% of total)  <0·0001
HI-15 (2·9)0 
HI-210 (6·0)2 (6·1) 
PH-13 (1·8)2 (6·1) 
PH-206 (18·2) 
sICH05 (15·2)<0·0001
24-hour NIHSS, median (range)4 (0–42)7 (0–30)0·1408
Change in NIHSS (0–24 h), median (range)−3 (−24–0)3 (1–22)<0·0001
Table 3. Logistic regression results of 24-hour CT findings
 Unadjusted OR*95% Confidence intervalP-value
  1. *Unadjusted odds ratios (OR) reflect odds for patients with NIHSS worsening.

New infarct5·241·76–15·630·0029
Cortical lesion2·241·04–4·810·0384
Cerebellar lesion3·901·29–11·850·0163

Less than 2% of no NIHSS worsening patients had a PH-1 or PH-2 on their 24-h CT. The negative predictive value of no NIHSS worsening for the presence of HT, PH and symptomatic intracerebral hemorrhage (sICH) was 89%, 98%, and 100%, respectively. The sensitivity and specificity of NIHSS worsening was 37%/87% for HT, 73%/87% for PH, and 100%/86% for sICH. Evidence of brain edema on 24-h CT did not significantly differ between NIHSS worsening and no NIHSS worsening groups (6·1% vs. 3·0%, P = 0·3254). Of patients with baseline NIHSS ≤10 (Table 4), those without NIHSS worsening were less likely to have HI (9·6% vs. 33·3%, P = 0·0089) and none had PH. Also, patients with baseline NIHSS ≤10 were significantly less likely to have sICH (0 vs. 13·3%, P = 0·0127).

Table 4. Follow-up CT findings with baseline threshold
 No 24-h NIHSS worsening and baseline ≤10 (n = 114)24-h NIHSS worsening and baseline ≤10 (n = 15)P-value
  1. HI, hemorrhagic infarct; HT, hemorrhagic transformation; IHSS, NIH Stroke Scale; PH, parenchymal hematoma; sICH, symptomatic intracerebral hemorrhage defined by NIHSS increase ≥ 4 points.

Normal or no change from baseline (%)47 (41·2)3 (20)0·1127
New infarct (%)67 (58·8)12 (80)0·1127
Cortical49 (42·9)10 (66·7)0·0835
Sub-cortical32 (28·1)3 (20)0·5087
Cerebellar5 (4·4)1 (6·7)0·6934
Brainstem1 (0·9)1 (6·7)0·0880
Midline shift4 (3·5)2 (13·3)0·0894
Herniation00n/a
Hemorrhagic infarct (%)3 (3·0)5 (31·3)0·0011
Grade of HT (% of HI)  0·0979
HI-11 (33)0 
HI-22 (67)1 (20) 
PH-101 (20) 
PH-203 (60) 
sICH02 (13·3)0·0127
24-hour NIHSS, median (range)3 (0–9)3 (3–22)0·3821
Change in NIHSS (0–24 h), median (range)−3 (−6–0)3 (1–22)<0·0001

New management orders (Table 5) were placed less frequently for patients without NIHSS worsening (18·6% vs. 45·5%, P < 0·0008), including DNR/DNI orders (0·6% vs. 9·1%, P = 0·014). Of the new management orders, additional neuroimaging was the most frequent change in management observed in both groups. Lastly, NIHSS worsening patients were less likely to receive antithrombotic therapy between 24-h to 48-h post-IV tPA (OR 0·44, 95% CI 0·20–0·96).

Table 5. Management changes after 24-h follow-up CT
 No 24-h NIHSS worsening (n = 167)24-h NIHSS worsening (n = 33)P-value
  1. DNR/DNI, do not resuscitate/Do not intubate; ICP, intracranial pressure; tPA, tissue plasminogen activator.

Antithrombotics administered 24–48 h post-IV tPA (%)130 (77·8)20 (60·6)0·0366
Any new management order, except antithrombotics (%)31 (18·6)15 (45·5)0·0008
ICP management8 (4·8)4 (12·1)0·1052
Osmotherapy6 (3·4)1 (3·0)0·8724
Blood products1 (0·6)1 (3·0)0·1996
Neurosurgical intervention3 (1·8)1 (3·0)0·6436
DNR/DNI1 (0·6)3 (9·10·0141
Additional neuroimaging12 (7·2)7 (21·2)0·0120

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aims/hypothesis
  5. Methods
  6. Results
  7. Discussion
  8. References

Our study showed that nearly 90% of NIHSS worsening patients had new findings on repeat head CT. Of patients with NIHSS worsening after tPA, about one-third had hemorrhagic infarction with half of these patients meeting criteria for sICH [12]. Additionally, 24-h CT findings appeared to affect acute stroke management in patients with 24-h NIHSS worsening. Specifically, the antithrombotic protocol was altered in over half of patients with NIHSS worsening and additional management changes were made in nearly half of NIHSS worsening patients. Our study suggests that 24-h follow-up CT findings alter standard care of post-IV tPA management predominantly in patients with 24-h neurological worsening. These findings support previous recommendations for the utility of 24-h follow-up CT scans in patients with NIHSS worsening [15].

However, the majority (83·5%) of patients in our population did not have NIHSS worsening at 24-h. Under the current American Heart Association/American Stroke Association guidelines, a 24-h CT is performed to rule out ICH before commencing antithrombotic treatment, assumedly to prevent exacerbation of HT, if present [1, 22]. [Notably, evidence is lacking regarding administration of antithrombotics in the face of HT [1].] However, since early, substantial growth of hemorrhage is frequently associated with neurological deterioration, patients without clinical signs of deterioration are less likely to be experiencing significant HT [23, 24]. Our results support this finding – less than 2% of patients without NIHSS worsening had signs of PH on 24-h CT. In other words, nearly every tPA-treated patient with stable NIHSS at 24 h had absent CT findings to prevent treatment with antithrombotics. Thus, our results suggest that routine 24-h CT scans may not be warranted in all patients treated with tPA.

Furthermore, zero patients without 24-h NIHSS worsening and baseline NIHSS ≤10 had PH on 24-h CT, results closely aligning with previous studies [14, 19, 25]. Therefore, risk assessment using baseline NIHSS threshold in combination with clinical stability or improvement may provide a more sensitive indicator for the utility of 24-h CT than just change in 24-h NIHSS alone. Two additional reasons exist for the use of a baseline NIHSS threshold: 1) early clinical improvement can accompany HT in patients with severe ischemic stroke at baseline [24], and 2) severity of NIHSS at baseline has been shown to be an independent predictor for asymptomatic ICH in IV tPA patients [14, 25]. Such a screening protocol would have eliminated the need for over half of 24-h CT scans in patients treated with IV tPA without negatively affecting patient management.

New management orders outside of antithrombotic therapy following repeat CT scan were infrequent. Moreover, additional neuroimaging accounted for over one-third of these new orders. Taken together, these findings suggest that 24-h CT findings did little for patient care, other than confirm lack of HT. These results challenge the role of routine CT scans for treated patients who do not experience an increase in NIHSS at 24 h, particularly amongst those with baseline NIHSS ≤10.

Of note, more than one in five patients with no NIHSS worsening failed to receive antithrombotic therapy between 24 and 48 h post-tPA. Possible explanations for this finding include delayed administration in the face of HT, missed orders, anticipation of neurosurgery and subsequent avoidance of antithrombotic use, or even delay due to pending interpretation of the 24-h CT scan. Further analysis, outside the scope of this study, is needed to confirm our results and appropriate a potential explanation for this finding.

We are limited by our small sample size that may limit our ability to detect existing differences between groups. Furthermore, we are limited by the retrospective nature of this investigation, which prohibits us from determining true cost-effectiveness of clinical examination over routine follow-up head imaging. A prospective investigation is warranted to better evaluate this issue. Evidence from larger samples of IV tPA treated patients would aid in determining an appropriate baseline NIHSS threshold for highest specificity of detecting adverse clinical changes. Furthermore, the interpretations of 24-h CT scans were performed retrospectively, which has the potential to introduce bias, though this was limited by the blinded evaluation of CT scans relative to baseline and 24-h NIHSS scores.

In summary, our study found that the presence of neurological deterioration was specific for both parenchymal hemorrhage and symptomatic hemorrhage. Additionally, few patients with stable or improving NIHSS scores had CT evidence at 24 h warranting deviation from the standard of care for AIS patients treated with tPA. Furthermore, no patient with baseline NIHSS ≤10 had CT findings at 24 h. If our findings are validated in larger prospective samples, revisions to the current imaging protocol post-IV tPA may be appropriate.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Aims/hypothesis
  5. Methods
  6. Results
  7. Discussion
  8. References
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