Abstract
This is a prospective non-randomized cohort study of 113 consecutive patients to investigate the safety and efficacy of a short-duration intraarterial selective cooling infusion (IA-SCI) targeted into an ischemic territory combined with mechanical thrombectomy (MT) in patients with large vessel occlusion-induced acute ischemic stroke (AIS); 45/113 patients underwent IA-SCI with 350 ml 0.9% saline at 4℃ for 15 min at the discretion of the interventionalist. Key parameters such as vital signs and key laboratory values, symptomatic and any intracranial hemorrhage, coagulation abnormalities, pneumonia, urinary tract infections and mortality were not significantly different between the two groups. Final infarct volume (FIV) was assessed on noncontrast CT performed at three to seven days. After an adjusted regression analysis, the between-group difference in FIV (19.1 ml; 95% confidence interval (CI) 3.2 to 25.2; P = 0.038) significantly favored the IA-SCI group. At 90 days, no differences were found in the proportion of patients who achieved functional independence (mRS 0–2) (51.1% versus. 41.2%, adjusted odd ratio (aOR) 1.9, 95% CI 0.8–2.6, P = 0.192). Combining short-duration IA-SCI with MT was safe. There was a smaller FIV and trend towards clinical benefit that will need to be further evaluated in randomized control trials.
Keywords: Hypothermia, endovascular procedures, neuroprotection, intra-arterial infusions, reperfusion injury
Mechanical thrombectomy (MT) of intracranial large-vessel occlusion (LVO) has now been shown to be safe and effective, playing an important role in the modern therapeutic management of acute ischemic stroke (AIS).1–5 In recent randomized clinical trials, high rates of successful revascularization of intracranial LVO (ranging between 66% and 94%) were achieved with new generation stent-retrievers.1–5 However, only 46% of patients treated with MT achieved functional independence at 90 days, and approximately 15% patients died at 90 days post-treatment.6 Therefore, new ancillary therapeutic strategies are needed to further augment improvement in clinical outcomes within the AIS patient population that are treated with MT.
Therapeutic hypothermia has been suggested to be one such potential therapeutic approach offering a viable neuroprotective strategy.7 Several clinical studies in patients with AIS have shown an overall increased tolerance to ischemia with mild hypothermia, mitigating re-perfusion-related cerebral damage.8,9 However, despite promising results, there were several adverse events associated with systemic therapeutic hypothermia including pneumonia and cardiac arrhythmias seen in up to 39% of treated patients.10 Intraarterial selective cooling infusion (IA-SCI) targets the ischemic brain tissue directly thereby negating the requirement of core body temperature reduction and its associated systemic side effects.
Our previous study found that a short-duration IA-SCI with cold saline combined with MT in AIS is feasible and safe.11 However, this was a single-arm clinical study that did not have a control group and the efficacy of IA-SCI for AIS patients treated with MT is still relatively unknown. In this study, we aimed to explore the safety and efficacy outcomes of a short-duration IA-SCI in patients with AIS who underwent MT compared to a control group that was not subjected to IA-SCI.
Methods
Study design and patients selection
A prospective cohort study was conducted to provide data concerning the risks and benefits of IA-SCI for AIS patients treated with MT. Eligible patients were enrolled consecutively from March 2015 to April 2017 at the Xuanwu Hospital of Capital Medical University. Enrolled patients received IA-SCI at the interventionist's discretion after obtaining informed consent from either the patient or their legal representative. MT plus IA-SCI was compared with MT alone in AIS patients with an LVO.
The study protocol and informed consent were approved by the institutional review board of the Xuanwu Hospital Capital Medical University. The study was performed according to the ethical guideline of the Xuanwu Hospital Capital Medical University and the principles of the Declaration of Helsinki.
We selected consecutive patients who met the following inclusion criteria: (1) age between 18 and 80 years; (2) a clinical diagnosis of AIS; (3) a baseline clinical score of at least 6 points on the National Institutes of Health Stroke Scale (NIHSS), with higher values indicating more severe deficit; (4) a CT or MRI scan that excluded intracranial hemorrhage; (5) an occlusion in the M1 segment of the middle cerebral artery (MCA), demonstrated with CTA, MRA, or DSA; (6) initiation of intra-arterial treatment within 6 h of stroke onset; (7) patients or their legally acceptable representative agreed to the treatment and signed the informed consent form.
Patients were ineligible for the study if they had: (1) arterial blood pressure > 185/110 mmHg; (2) blood glucose <2.7 or >22.2 mmol/L; (3) had a prestroke functional disability of >1 on the modified Rankin scale (mRS);12 (4) laboratory evidence of coagulation abnormalities, i.e. platelet count <40 × 109/L, APTT >50 s, or INR >3.0; (5) a cardiac functional capacity was greater than class I before the current stroke (range from class I to IV, with higher values indicating worse cardiac functional capacity);13 (6) currently participating or has participated in any investigational drug or device study within 30 days.
Interventions
Xuanwu Hospital of Capital Medical University is a comprehensive stroke center in Beijing, China. Procedural competency was standardized between the five trained interventionists that performed MT at our stroke center. Each interventionalist has performed neurointerventional procedures and image interpretation for at least five years. The interventionalists have also deployed extracranial and intracranial stents proficiently and have completed at least 10 full procedures of endovascular AIS MT treatment with retrievable stents. Since February 2015, we have been using stent retrievers as standard of care for appropriate LVO patients at our center.
Patients eligible for intravenous thrombolysis should receive intravenous alteplase before MT according to the gulidelines.14,15 General or local anesthesia was chosen according to the level of patient cooperation and the medical condition of the patient. All the patients were hospitalized in the stroke care unit of Xuanwu Hospital of Capital Medical University after MT with or without IA-SCI according to the guidelines of China.
The IA-SCI method has been described previously.11 Briefly, during the procedure, a micro catheter used to deploy the stent retriever was co-axially threaded into the common femoral artery through a guiding catheter. The micro catheter was advanced through a micro guide wire up through the neck, until it reached beyond the clot responsible for the ischemic symptoms. A 50 ml cold 0.9% saline (4℃) aliquot was infused into the ischemic territory at 10 ml/min through the micro catheter (Figure 1(a)), thus allowing the cold solution to infuse into the ischemic territory prior to revascularization. After that, MT with a stent retriever was performed to recanalize the occluded vessel as soon as possible. Immediately after MT, cold 0.9% saline (4℃) was re-infused into the ischemic brain tissue through the catheter at a rate of 30 ml/min for 10 min (Figure 1(b)). In a previous in vitro simulation experiment, warm 0.9% saline (37℃) was pumped through a life-sized tube to simulate the blood flow. Using the methods of the clinical study as described herein, the catheters were put into the warm simulate blood flow and cold 0.9% saline (4℃) was infused through the micro catheter (RebarTM-18 Micro Catheter, 2.4F) at a rate of 10 ml/min. The saline temperature was 20.2 ± 1.2℃ (n = 6) when it exited the micro catheter tip immediately. During the procedure, the body was covered with a standard blanket or electric blanket to maintain core body temperature.
Figure 1.
Sketch map of the intraarterial selective cooling infusion procedure. Before recanalization, a micro catheter reached beyond the clot responsible for the ischemic symptoms, then a 50 ml cold 0.9% saline (4℃) aliquot was infused into the ischemic territory at 10 ml/min through the micro catheter (Panel A). After that, mechanical thrombectomy with a stent retriever was performed to recanalize the occluded vessel as soon as possible. Immediately after mechanical thrombectomy, cold 0.9% saline (4℃) was re-infused into the ischemic brain tissue through the catheter at a rate of 30 ml/min for 10 min (Panel B).
Situations/parameters influenced the use of IA-SCI
The decision to use IA-SCI was at the interventionists’ discretion. Factors that influenced the interventionists to choose SCI were as follows: (1) a lower Alberta stroke programme early CT score (ASPECTS) (e.g. <7); (2) poor collateral circulation (e.g. ASITN/SIR <2); (3) an overall higher risk of hemorrhage or ischemic–reperfusion injury based on the interventionalist clinical discretion.
Safety evaluation
For each patient, we recorded demographic data, vascular risk factors, comorbidities at baseline, and follow-up data, as well as the vital signs and laboratory tests before, during, and after procedure. After completing the cold saline infusion (IA-SCI group) or MT (control group), angiography was performed 10 min later to assess for underlying intracranial arterial vasospasm. Rates of symptomatic intracranial hemorrhage, any intracranial hemorrhage, coagulation abnormalities, pneumonia, and urinary tract infections at 7 days or discharge, and mortality at 90 days were also assessed. Symptomatic intracranial hemorrhage was defined according to the ECASS-III study definition16 (any hemorrhage with neurologic deterioration, as indicated by an NIHSS score that was higher by four points or more than the value at baseline or the lowest value in the first seven days, or any hemorrhage leading to death. In addition, the hemorrhage must have been identified as the predominant). Prothrombin time, partial thromboplastin time, d-dimer, and fibrin degradation product were identified for the detection of coagulation abnormality. Pneumonia and urinary tract infections were diagnosed according to the Centers for Disease Control and Prevention (CDC)/ National Healthcare Safety Network (NHSN) criteria.17
Efficacy assessments
Final infarct volume (FIV) calculations were assessed on noncontrast computed tomography (CT) scan performed at three to seven days. Other outcomes included functional independence, defined as a mRS ≤2 at 90 days, which was assessed by trained and research nurses blinded to treatment assignment at 3 months with a structured telephone interview,18 neurologic deterioration within 24 h which was defined as any decline in NIHSS of more 4 points or more.1 CT angiography (CTA) or magnetic resonance angiography (MRA) was performed at 24 h after treatment, recanalization was defined as 2 or 3 of the modified arterial occlusive lesion score.19 According to the classification of mTICI scale, grade 2 is incomplete occlusion or partial local recanalization at the target artery with any distal flow, and grade 3 is complete recanalization and restoration of the target artery with any distal flow.19 CTA or MRA at 24 h will be compared with baseline vessel imaging data, to estimate the recanalization rate.
Imaging evaluation
A noncontrast head CT scan was performed at baseline, after 24 h, and at three to seven days or at discharge if earlier. Unscheduled CT scans were performed if patients developed symptoms suggestive of an intracerebral hemorrhage. CTA or MRA were generally performed at 24 h. CT examinations were performed using a 64-detector row scanner (GE Healthcare, USA), the slice thickness was 5 mm.
FIV was calculated by manually outlining the low attenuation lesion on the noncontrast head CT and multiplying the area by slice thickness.20,21 If the infarct showed hemorrhagic conversion, the hemorrhage regions were incorporated within the boundaries of infarct. If more than one CT was performed at three to seven days, the last one was used for assessing the FIV.
A neuroradiologist and a neurologist, both blinded to the baseline characteristics and treatment, analyzed all imaging data (including pre-treatment CT scan, cerebral angiography, and post-treatment imaging) separately. Disagreement was resolved by reaching a consensus between the two examiners, or if no consensus could be reached, a third reader was involved to resolve any clinical discordance.
Statistical analysis
Statistical analyses were performed using SPSS for Windows (Version 19.0; IBM, Armonk, New York). The results are expressed as percentages for categorical variables and as mean (standard deviation, SD) or median (IQR) for the continuous variables depending on their normal distribution. The χ2 test or Fisher exact test was used for categorical variables, and the t test or Mann–Whitney U test was used for continuous variables, respectively. The repeated-measures analyses of variance (ANOVA) on different timepoints were used to assess the rectal temperature. Efficacy outcomes were compared by linear regression and logistic regression analysis, the FIV, mRS, and clinical deterioration were adjusted for major prognostic variables. The unadjusted and adjusted values were reported with 95% confidence intervals (CIs) to indicate statistical precision. The level of significance was 0.05 level (two-sided).
Based on a literature review and a previous single-center observational study,1,4,11 we assumed that the FIV of the IA-SCI group would decrease by 30% relative to that of the control group. This meant that our sample size would yield a 80% power at P = 0.05 (two-sided).
Results
From March 2015 to April 2017, a total of 239 patients were screened consecutively, 125 patients met the inclusion criteria and 12 patients were excluded (five patients had cardiac function greater than a grade 1 implying heart failure, four patients had coagulation abnormalities, one patient had cardiac function greater than grade I13 and concurrent coagulation abnormality before the current stroke, two patients had a premorbid mRS score >1). A total of 113 patients were enrolled for analysis in the current study (Figure 2). The mean age was 62.1 years, 73 patients (64.6%) were men. Of the 113 patients, 45 (39.8%) patients had IA-SCI during and after the MT. The median time from stroke onset to the first IA-SCI was 341 min in the IA-SCI group. The baseline characteristics of the patients with or without an IA-SCI were well balanced, with the exception of a statistical non-significantly higher rate of ASITN/SIR <2, higher NIHSS, and lower ASPECTS in the IA-SCI group patients (Table 1).
Figure 2.
Summary of patients’ disposition. Of 239 patients screened, 113 patients were analyzed and 45 patients received a selective brain cooling infusion. *28 patients had multiple reasons. †1 patient had multiple reasons.
Table 1.
Baseline characteristic of the patients.
| Characteristic | Total (N = 113) | Brain cooling group (N = 45) | Control group (N = 68) | P |
|---|---|---|---|---|
| Age | 62.1 ± 10.3 | 61.9 ± 9.7 | 62.2 ± 10.8 | 0.874 |
| Men | 73 (64.6%) | 28 (62.2%) | 45 (66.2%) | 0.667 |
| ASPECTSa | 9 (7–10) | 8 (7–10) | 9 (8–10) | 0.169 |
| NIHSSb | 16 (12–20) | 17 (13–21) | 16 (11–19) | 0.257 |
| Systolic blood pressure, mmHg | 155.7 ± 24.8 | 157.3 ± 25.8 | 154.6 ± 23.7 | 0.526 |
| Serum glucose, mmol/L | 6.8 (6.0–8.0) | 6.9 (6.2–8.1) | 6.8 (5.9–7.9) | 0.453 |
| Vascular risk factors | ||||
| Hypertension | 75 (66.4%) | 32 (71.1%) | 43 (63.2%) | 0.386 |
| Diabetes | 26 (23.0%) | 12 (26.7%) | 14 (20.6%) | 0.452 |
| Dyslipidemia | 64 (56.6%) | 24 (53.3%) | 40 (58.8%) | 0.564 |
| Coronary artery disease | 40 (35.4%) | 18 (40.0%) | 22 (32.4%) | 0.405 |
| Atrial fibrillation | 25 (21.9%) | 11 (25.0%) | 14 (20.6%) | 0.629 |
| smoking | 57 (50.4%) | 20 (44.4%) | 37 (54.4%) | 0.300 |
| ASITN/SIR < 2c | 52 (46.0%) | 23 (51.1%) | 29 (42.6%) | 0.377 |
| Treatment with IVT | 50 (44.2%) | 21 (46.6%) | 29 (42.6%) | 0.674 |
| Time from stroke onset to IVT | 160 (120–185) | 164 (127–185) | 158 (114–183) | 0.337 |
| General anesthesia, | 75 (66.4%) | 28 (62.2%) | 47 (69.1%) | 0.448 |
| Computed tomographic perfusion imaging | 30 (26.5%) | 11 (24.4%) | 19 (27.9%) | 0.680 |
| Time from stroke onset to groin puncture | 267 (210–298) | 278 (218–305) | 266 (210–289) | 0.322 |
| Time from puncture to first reperfusiond | 85 (54–113) | 89 (56–118) | 82 (52–111) | 0.381 |
| Time from stroke onset to first IA-SCI | – | 341 (253–391) | – | – |
Note: Data are mean ± SD, number (%), or median (IQR).
ICA: internal carotid artery; MCA: middle cerebral artery; IVT: intravenous thrombolysis; IA-SCI: intraarterial selective cooling infusion.
aThe Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a measure of the extent of stroke. Scores range from 0 to 10, with higher scores indicating fewer early ischemic changes. Scores were not available for two patients in the control group.
bScores on the National Institutes of Health Stroke Scale (NIHSS) range from 0 to 42, with higher scores indicating more severe neurologic deficits.
cAmerican Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology, ASITN/SIR of 0–1 was considered as poor collateral circulation.
dFirst reperfusion was defined as the first visualization of reflow in the middle cerebral artery, usually on deployment of a retrievable stent.
Safety
Before, during, and after the IA-SCI, the vital signs and key laboratory values were not significantly different between the two groups (Table 2). The rectal temperature was monitored every 5 min, and the minimum rectal temperature was at 10 min after the second infusion in the IA-SCI group (mean temperature was 36.5 ± 0.4℃), compared with the control group (36.7 ± 0.3℃). Repeated-measures ANOVA indicated that there were no significant differences of the rectal temperature between the two groups (P = 0.692) in the whole procedure.
Table 2.
Changes of clinical and laboratory values during mechanical thrombectomy procedure.
| Variables | Brain cooling group (N = 45) | Control group (N = 68) | P |
|---|---|---|---|
| Systolic blood pressure, mmHg | |||
| Before procedurea | 156.8 ± 24.1 | 155.1 ± 27.5 | 0.568 |
| During procedureb | 152.5 ± 27.4 | 150.3 ± 28.1 | 0.682 |
| After procedurec | 154.8 ± 25.7 | 152.6 ± 24.4 | 0.647 |
| Heart rate, bmp | |||
| Before procedurea | 74.7 ± 8.7 | 76.8 ± 7.6 | 0.178 |
| During procedureb | 75.3 ± 9.9 | 77.9 ± 10.8 | 0.198 |
| After procedurec | 72.8 ± 7.9 | 74.8 ± 8.8 | 0.221 |
| Pulse oxygen saturation, % | |||
| Before procedurea | 99.1 ± 2.8 | 99.4 ± 2.1 | 0.517 |
| During procedureb | 98.6 ± 2.4 | 98.2 ± 2.5 | 0.399 |
| After procedurec | 99.3 ± 1.8 | 98.7 ± 2.2 | 0.131 |
| Hematocrit, % | |||
| Before procedured | 45.8 ± 6.5 | 45.6 ± 8.5 | 0.894 |
| After proceduree | 45.3 ± 7.6 | 45.9 ± 7.2f | 0.688 |
| K, mmol/L | |||
| Before procedured | 4.3 ± 0.5 | 4.4 ± 0.4 | 0.242 |
| After proceduree | 4.3 ± 0.4 | 4.4 ± 0.5f | 0.281 |
| Na, mmol/L | |||
| Before procedured | 145.6 ± 7.8 | 144.7 ± 8.4 | 0.568 |
| After proceduree | 144.8 ± 8.9 | 146.8 ± 6.8f | 0.208 |
| Ca, mmol/L | |||
| Before procedured | 2.4 ± 0.3 | 2.5 ± 0.2 | 0.376 |
| After proceduree | 2.4 ± 0.4 | 2.5 ± 0.3f | 0.159 |
Note: Data are mean ± SD, number (%), or median (IQR).
aData were assessed between patients entered the intervention operating room and groin puncture.
bData were assessed at about 5 min after the recanalization.
cData were assessed at about 30 min after the recanalization.
dData were assessed at the admission.
eData were assessed within 1 h after the recanalization.
fBecause of procedural problems, data were not available for 14 patients.
Symptomatic intracranial hemorrhage was observed in three patients (6.7%) in the IA-SCI group and five patients (7.4%) in the control group (OR, 0.9; 95% CI, 0.2–4.0; P = 0.889). Similarly, no significant differences were detected in the proportion of patients with any intracranial hemorrhage (35.6% vs. 32.4%, P = 0.724), intracranial artery spasm (0% vs. 1.5%), all-cause death (20.0% vs. 26.5%, P = 0.430), coagulation disorder (2.2% vs. 2.9%, P = 0.816), pneumonia (31.1% vs. 33.8%, P = 0.536), and urinary tract infections (22.2% vs. 19.1%, P = 0.688). (Table 3)
Table 3.
Comparison of safety outcomes.
| Variables | Brain cooling group (N = 45) | Control group (N = 68) | Odds ratio (95% CI) | P |
|---|---|---|---|---|
| Symptomatic intracerebral hemorrhagea | 3 (6.7%) | 5 (7.4%) | 0.9 (0.2–4.0) | 0.889 |
| Any intracerebral hemorrhage | 16 (35.6%) | 22 (32.4%) | 1.2 (0.5–2.6) | 0.724 |
| Intracranial arterial spasm | 0 (0%) | 1 (1.5%) | – | – |
| All-cause death | 9 (20.0%) | 18 (26.5%) | 0.7 (0.3–1.7) | 0.430 |
| Death due to stroke | 7 (15.6%) | 15 (22.1%) | 0.7 (0.2–1.8) | 0.393 |
| Death due to other causes | 2 (4.4%) | 3 (4.4%) | 1.0 (0.2–6.3) | 0.993 |
| Coagulation abnormalities | 1 (2.2%) | 2 (2.9%) | 0.8 (0.1–8.5) | 0.816 |
| Pneumonia | 14 (31.1%) | 23 (33.8%) | 0.9 (0.4–1.9) | 0.536 |
| Urinary tract infections | 10 (22.2%) | 13 (19.1%) | 1.2 (0.5–3.1) | 0.688 |
Note: Data are number (%).
aSymptomatic intracerebral hemorrhage was defined according to the definition of the ECASS-III study (any hemorrhage with neurologic deterioration, as indicated by an NIHSS score that was higher by four points or more than the value at baseline or the lowest value in the first seven days, or any hemorrhage leading to death).
Efficacy
The CT imaging data at three to seven days were missing for one patient in the control group, because of early death. There were no significant differences in the interval between stroke onset and head CT image used for the calculation of FIV between the IA-SCI group (5.2 ± 1.3 days) and control group (4.9 ± 1.1 days) (P = 0.230). The mean FIV was 63.7 ± 31.8 ml (median 63 ml, IQR 36–87) in the IA-SCI group, and 77.9 ± 44.7 ml (median 67 ml, IQR 45–90) in the control group. After an adjusted for age, NIHSS at baseline, the Alberta Stroke Program Early Computed Tomography Score, diabetes, atrial fibrillation, ASITN/SIR <2, time from puncture to first reperfusion, and time from stroke onset to groin puncture, the between-group difference in FIV (19.1 ml; 95% CI, 3.2 to 25.2; P = 0.038) significantly favored the IA-SCI group (Table 4).
Table 4.
Comparison of efficacy outcomes.
| Variables | Brain cooling group (N = 45) | Control group (N = 68) | Effect variable | Unadjusted /adjusteda value (95% CI) | Unadjusted/ adjusteda P |
|---|---|---|---|---|---|
| Infarct volume,b ml | 63.7 ± 31.8 | 77.9 ± 44.7 | Beta | 14.2 ( − 1.1 – 29.5)/19.1(3.2–25.2) | 0.068/0.038 |
| 63 (36–87) | 67 (45–90) | ||||
| mRS 0–2 at 90 days | 23 (51.1%) | 28 (41.2%) | Odds ratio | 1.5 (0.7–3.2)/1.9 (0.8–2.6) | 0.299/0.192 |
| Clinical deteriorationc | 5 (11.1%) | 12 (17.6%) | Odds ratio | 0.6 (0.2–1.8)/0.5 (0.4–1.9) | 0.341/0.232 |
| Recanalizationd | 35/42 (83.3%) | 54/63 (85.7%) | Odds ratio | 0.8 (0.3–2.4)/0.7 (0.4–2.8) | 0.739/0.525 |
Adjusted for age, NIHSS at baseline, the Alberta Stroke Program Early Computed Tomography Score, diabetes, atrial fibrillation, ASITN/SIR <2, time from puncture to first reperfusion, and time from stroke onset to groin puncture.
bData for final infarct volume on noncontrast CT (performed at three to seven days) were not available for one patient in the control group, owing to imminent death.
cNeurologic deterioration within 24 h which was defined as any decline in NIHSS of more four points or more.
dRecanalization was defined as a modified Arterial Occlusive Lesion score of 2 or 3. This analysis was adjusted for the site of vessel occlusion at baseline.
All patients completed the 90-day follow-up. The absolute between-group difference in the proportion of patients who were functionally independent at 90 days (score of 0–2 on the mRS) was 9.9% points (51.1% vs. 41.2%), and patients in the IA-SCI group had lower rates of early clinical deterioration (11.1% vs. 17.6%), compared with the control group. However, the difference of functional outcome and clinical deterioration was not statistically significant. These effects remained after adjusting for major prognostic variables, with the adjusted odd ratios being 1.9 (0.8–3.2) and 0.5 (0.4–1.9), respectively. Data on recanalization at 24 h, assessed by means of CTA or MRA, were available for 105 patients. There was no significant difference in recanalization between the two groups (83.3% vs. 85.7%, adjusted odd ratio 0.7 (0.4–2.8), P = 0.525) (Table 4).
Discussion
In this prospective cohort study, we found that IA-SCI plus MT was safe for AIS patients with a proximal intracranial arterial occlusion of the anterior circulation, and the combination significantly associated with a reduction in the FIV. There was a non-significant trend towards a greater percentage of patients who had a good clinical outcome in the brain cooling infusion group, although this study was not sufficiently powered to detect such a difference. Nevertheless, it should also be considered that though not statistically significant, the IA-SCI group did have overall lower ASPECTS and ASITN/SIR values. This therefore indicates that the IA-SCI group may have had relatively larger core and a smaller penumbral volumes (due to low ASPECTS and poor collaterals) compared to control group, thus further reinforcing the potential benefit of IA-SCI.
Safety outcomes were also favorable with no significant differences between the IA-SCI group and the MT alone group. As previously reported, systemic cooling effects nearly all organs can lead to cardiovascular dysfunction, shivering (and associated paradoxical core temperature elevation), immunosuppression, and impaired coagulation.7,22 It is known that hypothermia-induced neuroprotection derives its benefits from an overall lowered brain temperature and does not require whole body cooling. Therefore, an IA-SCI approach to hypothermia might be a viable alternative to whole body hypothermia in cases of local brain injury such as ischemic stroke. In our previous study, we also found that IA-SCI of cold saline combined with endovascular recanalization therapy in AIS was feasible and safe.11 The current study which included a control group has now reinforced and confirmed our prior results.
Although we did not specifically monitor brain temperature (invasively or noninvasively), data from prior studies have shown an objective relationship between focal cooling and lower target brain temperatures. For example, various theoretical models have been developed to investigate the effects of IA-SCI on brain temperature in humans. Choi et al.23 showed that the intra-carotid infusion of cold saline (4–10℃) at 33 ml/min led to a rapid decrease of temperature by 0.84 ± 0.13℃ in the jugular venous bulb within a mean time of 8.2 min in patients undergoing follow-up cerebral angiography after previous treatment of intracranial vascular malformations. Using this human jugular venous bulb temperature data as input in a three-dimensional human brain model, another study inferred that the temperature of the ipsilateral cerebral anterior circulation territory decreased by approximately 2℃ within 10 min by implementing such cooling method.24 In a theoretical model of selective cooling using an intra-carotid cold saline infusion in the human brain, Konstas et al.25 suggested that a flow rate of 30 ml/min cold saline is sufficient to induce moderate hypothermia (33–34℃) within 10 min in the ipsilateral cerebral hemisphere. This is 18–42 times faster than the 3–7 h needed for whole body cooling by noninvasive methods.26,27 In our study, IA-SCI was performed not only after but also before recanalization. Based on prior data, we speculate that the brain temperature in the ischemic territory was potentially lowered by IA-SCI during the infusion period, and we do not objectively know the precise change of the brain temperature during IA-SCI. Whether a longer duration of cooling will have a more robust clinical effect remains to be studied and the potential of cold autologous blood infusion as an alternative coolant to initiate hypothermia remains a theoretical alternative to be studied in the future.28 On the other hand, the pre-embolectomy cooling infusion maybe of great importance in the present study. In our previous study, prereperfusion infusion itself led to a reduction of inflammatory events and improvement of the cerebral microcirculation.29 Therefore, the IA-SCI was not only to reduce local brain temperature faster than any other hypothermic approach, but also to improve the local cerebral microcirculation by “flushing” the ischemic territory prior to brain tissue reperfusion, leading to reduced reperfusion injury. Although further data are needed, it is likely that hypothermia may not the only mechanism for neuroprotection effects observed in the present clinical study.
Limitations of this observational cohort study include potential cofounders including unknown variables (such as ischemic penumbra volume) could have influenced the study results and a selection bias may also have affected the observed results. This is an inherent defect of a cohort study, although the baseline characteristics of the two groups were not significantly different in the current study. The relatively low statistical power of the current study does not allow for further statistically significant comparisons of outcomes between the two arms. Another thing to consider is the potential time delay to recanalization with intraarterial saline infusion prior to thrombectomy. However, this entails a risk benefit ratio where the potential benefits include pre thrombectomy decrease in local brain metabolism and less potential reperfusion injury, faster cooling and “flushing”29 versus risks associated with delayed recanalization. However, we found that the strategy we used in the present study was significantly associated with a reduction in the FIV after adjusting for major prognostic variables (including time from puncture to first reperfusion). This therefore indicates that the benefits of the infusion strategy in the present study are greater than the potential risks. Nevertheless, the role of IA-SCI combined with MT appears to warrant further investigation given our findings. Based on these encouraging results and the limitations of the present study, a randomized clinical trial is ongoing to further assess the efficacy of the IA-SCI plus MT for AIS patients with large vessel occlusion. (ClinicalTrials.gov number: NCT03163459)
Conclusions
In conclusion, the results of this study showed that a short-duration of IA-SCI for patients with LVO AIS symptoms treated with MT seems safe and associated with reduced FIV. These results provide useful preliminary data to warrant a future randomized clinical trial.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by National Natural Science Foundation of China (81325007, 81701287); Chang Jiang Scholars Program (No. T2014251)
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Authors’ contributions
Study concept and design: XMJ and CJW; acquisition of data: WBZ, HA, LFW, QY; analysis and interpretation of data: JC, YCD, CHL, DW, LQL; drafting of the manuscript: CJW, WJW, JGD, MH, CMW. XMJ are the guarantors of this work, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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