Abstract
Introduction
The aim of this study was to discuss the safety of rapid administration of 4°C hypothermic normal saline into the occluded vessels using an intra-arterial catheter to induce mild hypothermia following endovascular thrombectomy in patients with acute large vessel occlusion cerebral infarction.
Methods
We selected 78 patients with acute large vessel occlusion cerebral infarction who underwent endovascular thrombectomy in the Department of Neurology of our hospital from January 2020 to July 2022 and achieved TICI 2b recanalization.
Result
Twenty-five patients were administered 500 mL of 4°C hypothermic normal saline in the occluded vessels at a rate of 25 mL/min to induce mild hypothermia. Twenty pairs of subjects conformed to strict matching and were finally included in the statistical analysis. The two groups of patients differed significantly in white blood cell count and percentage of neutrophils (p < 0.05); however, there were no significant differences in D-dimer, procalcitonin, and BNP levels. The two groups of patients did not differ significantly with respect to the incidence of the following indicators: upper gastrointestinal bleeding; pulmonary infection; venous thrombosis; vasospasms; seizures; and chills (p > 0.05).
Conclusion
Mild therapeutic hypothermia in target vessels plus endovascular thrombectomy was shown to be safe in patients with acute large vessel occlusion cerebral infarction.
Keywords: Acute cerebral infarction, Mechanical thrombectomy, Mild therapeutic hypothermia in target vessels, Safety
Introduction
As reported in The Global Burden of Disease Study, stroke is the leading cause of mortality and disability in Chinese adults. In fact, China has the largest number of stroke patients worldwide [1]. Acute ischemic stroke is the most common type of stroke, accounting for 70–80% of all stroke cases. Acute large vessel occlusion stroke has disability and mortality rates >70% [2]. The annual incidence of anterior circulation large vessel occlusion stroke is estimated to be 12.5/100,000 in Hong Kong, China, which appears to be lower than in Western countries [3].
Currently, the most effective treatment for acute large vessel occlusion cerebral infarction is immediate recanalization therapy to restore blood supply in the occluded vessels and salvage the ischemic penumbra. Previous studies have confirmed that of which 13 studies reported cumulative risk of stroke recurrence in 9,115 survivors. The pooled cumulative risk was 3.1% (95% CI, 1.7–4.4) at 30 days, 11.1% (95% CI, 9.0–13.3) at 1 year, 26.4% (95% CI, 20.1–32.8) at 5 years, and 39.2% (95% CI, 27.2–51.2) at 10 years after initial stroke [4].
In 2015, several international clinical trials (MR cLEAN, EscAPE, SWIFT PRIME, REVASCAT, and EX-TEND IA) confirmed that mechanical thrombectomy outperformed the standard internal medicine treatment in anterior circulation large vessel occlusion [5–9]. Based on the findings of the subsequently published DEFUSE 3 and DAWN studies, the time window for mechanical thrombectomy was extended to 24 h and the recanalization rate reached 60–90%. Among patients achieving successful recanalization, the 30-day good prognosis rate (modified Rankin scale [mRS] score ≤2) was only 40–50% [10, 11]. This result indicated the possibility that multiple factors are involved in cell apoptosis following ischemia. Endovascular recanalization that acts on a single target appears to have limited efficacy in salvaging ischemic tissues. Previous studies concluded that mild therapeutic hypothermia following ischemic injury reduces the metabolic rate of ischemic tissues and energy consumption [12]. This therapy was also shown to alleviate free radical injury and toxicity of excitatory amino acids [13] and inhibit the inflammatory response and cell apoptosis [14]. In recent years, endovascular thrombectomy has been used in combination with selective mild therapeutic hypothermia to reduce cell injury and complications associated with mild systemic hypothermia, such as chills, venous thromboses, and pulmonary infections [15]; however, this combination therapy is still in clinical trials and the safety has not been fully appraised. Chen [16] reviewed the clinical data of 26 patients receiving mild therapeutic hypothermia in target vessels. The incidence of seizures, pulmonary infections, and target vessel spasms was also reported; the safety of mild therapeutic hypothermia in target vessels was confirmed. Of note, the study was retrospective and included a small number of cases [16]. In addition, the absence of a control group weakened the reliability. In this study, we aimed to discuss the safety of rapid administration of 4°C hypothermic normal saline into the occluded vessels using an intra-arterial catheter to induce mild hypothermia following endovascular thrombectomy in patients with acute large vessel occlusion cerebral infarction.
Materials and Method
Study Registration
The clinical trial was registered in Huizhou Science and Technology Bureau, Guangdong, China (N0 2020Y203). All subjects signed a written consent form.
Clinical Data
Patients admitted to our hospital between January 2020 and July 2022 and undergoing endovascular thrombectomy for acute large vessel occlusion cerebral infarction were selected. Those patients achieving TICI 2b recanalization were randomly divided into two groups. The treatment group (mild therapeutic hypothermia) was given 500 mL of hypothermic normal saline (4°C) at 25 mL/m and other steps followed previous literature published [17]. The control group did not receive mild therapeutic hypothermia. Patient age, gender, history of diabetes, hypertension, coronary heart disease, and smoking status were recorded. The incidence of intraoperative seizures and heart failure was noted intraoperatively. Target vessel spasms were checked by angiography. The following indicators were also observed within 24 h postoperatively: white blood cell count; percentage of neutrophils; procalcitonin (PCT) level; D-dimer (D2) level; and BNP level. The incidence of pneumonia, lower limb deep vein thrombosis, and upper gastrointestinal bleeding within 1 week after operation were observed and counted.
Statistical Analysis
All statistical analyses were performed using SPSS 22.0 software. Measurement data obeying a normal distribution with homogeneity of variances are expressed as a mean ± standard deviation. A t test was used for intergroup comparisons of measurement data. Measurement data not obeying a normal distribution and not meeting the assumption of homogeneity of variances are expressed as medians and interquartile ranges. The rank-sum test was used for comparisons between the two groups. Enumeration data are expressed as cases (percentages) and compared between groups using a pairwise χ2 test. A p value <0.05 was statistically significant.
Result
A total of 76 patients were recruited, including 25 patients who received mild therapeutic hypothermia. Controls were matched to these subjects at a 1:1 ratio with respect to age, gender, history of hypertension and diabetes, smoking status, etiology, and occluded vessels. Finally, 20 pairs of subjects were included in the statistical analysis (Table 1).
Table 1.
Baseline patient characteristics
| Feature | Treatment group | Control group | p value |
|---|---|---|---|
| Patients, N | 20 | 20 | |
| Average age (mean±SD), years | 56.1±10.78 | 57.0±10.57 | 0.792 |
| Female, N (%) | 4 (20) | 4 (20) | |
| Symptom onset GCS score | 10.5±4.12 | 10.6±3.75 | 0.9364 |
| Time from symptom onset to completion of EVT, h | 7.5±4.07 | 6.9±3.84 | 0.6343 |
| ASPECTS score | 8.4±1.05 | 8.4±0.83 | >0.9999 |
| NIHSS score | 14.1±6.01 | 13.4±4.35 | 0.6754 |
| mTICI score >2b, % | 80 | 85 | – |
| Risk factor, N (%) | |||
| Hypertension | 15 | 15 | |
| Diabetes | 5 | 5 | |
| Smoker | 11 | 11 | |
| Occluded vessels, N (%) | |||
| ICA-MCA | 15 (37.5) | 15 (37.5) | |
| VA-BA | 5 (25) | 5 (25) | |
| Etiology, N (%) | |||
| Atherosclerotic lesions | 4 (20) | 3 (15) | |
| Cardioembolic events | 6 (30) | 5 (25) | |
| Revascularization strategy, N (%) | |||
| Balloon dilation+stenting | 7 (35) | 8 (40) | |
| Aspiration using a suction catheter | 4 (20) | 5 (25) | |
| Endovascular stent thrombectomy | 17 (85) | 14 (70) | |
The white blood cell counts in the two groups were compared using a paired t test. The white blood cell count was significantly lower in patients who did and did not receive mild therapeutic hypothermia.
The PCT, D2, and levels and percentage of neutrophils were compared between the two groups using a paired-samples rank-sum test. The percentage of neutrophils was significantly lower in the group of patients who did and did not receive mild therapeutic hypothermia. No differences were detected in the PCT, D2, and BNP levels between the patients who did and did not receive mild therapeutic hypothermia.
Based on the paired χ2 test, the incidence of deep vein thrombosis, pneumonia, seizures, and gastrointestinal bleeding did not differ between the two groups. No vasospasm, episodes of heart failure, or chills occurred in either group (Table 2).
Table 2.
Comparison of indicators between the group that did and did not receive mild therapeutic hypothermia
| Treatment group (n = 20) | Control group (n = 20) | t/Z/χ2 | p value | |
|---|---|---|---|---|
| WBC | 10.30±3.61 | 12.93±3.20 | 2.277 | *0.035 |
| PCT | 0.07 (0.02, 0.16) | 0.03 (0.02, 0.06) | 1.477 | 0.140 |
| Patients, % | 74.00 (62.78, 81.23) | 80.15 (74.20, 83.50) | 2.875 | **0.004 |
| Pneumonia | 10 (50.0) | 9 (45.0) | 0.000 | 1.000 |
| Cerebral angiospasm | 0 (0.0) | 0 (0.0) | – | – |
| Deep vein thrombosis | 3 (15.0) | 3 (15.0) | 0.167 | 1.00 |
| D2 | 1.03 (0.40, 3.65) | 1.70 (0.80, 3.20) | 1.539 | 0.124 |
| Epilepsy | 0 (0.0) | 3 (15.0) | 1.333 | 0.248 |
| Gastrointestinal bleeding | 1 (5.0) | 2 (10.0) | 0.000 | 1.000 |
| BNP | 161.50 (87.75, 1,384.58) | 288.00 (77.90, 1,022.00) | 0.402 | 0.687 |
| Heart failure | 0 (0.0) | 0 (0.0) | – | – |
| Chills | 0 (0.0) | 0 (0.0) | – | – |
*p value <0.05.
**p value <0.01.
Discussion
Stroke is a leading cause of death and disability worldwide and incurs a heavy economic burden. At present, the recanalization rate following mechanical thrombectomy reaches 60–90% in large blood vessel occlusion stroke (TICI grade 2b and higher); however, approximately 50% of patients have a good prognosis (mRS<2) at 90 days poststroke [5–7]. Restoring blood flow in the shortest time possible is only one necessary condition for achieving a good prognosis. A series of complex pathobiochemical processes secondary to ischemia, including oxidative stress, calcium overload, free radical toxicity, and reperfusion injury, play key roles in the functional recovery of nerve cells. A large number of animal experiments have shown that mild therapeutic hypothermia exerts a significant neuroprotective effect for hypoxic and ischemic brain cells. Notably, mild hypothermia was induced in most clinical trials on the body surface or systematically by endovascular administration. These routes of administrating therapeutic hypothermia are usually associated with a variety of side effects, such as chills, pulmonary infections, and deep vein thromboses. To address this problem, selective mild therapeutic hypothermia in target vessels was proposed. After successful recanalization is achieved, mild hypothermia is induced by administrating low-temperature normal saline into the offending vessel via a catheter. Whether adverse events may be triggered by such a procedure, such as increasing the incidence of heart failure episodes due to higher cardiac load, distal vasospasm induced by local cold stimulation, abnormal discharge of neurons, and deep vein thrombosis, has not been established.
Stroke-Related Pneumonia
Stroke-related pneumonia is one of the most common poststroke complications. This medical condition may be caused by the following: aspiration during stroke onset; reduced lung activity due to prolonged immobilization; swallowing dysfunction caused by impaired innervation of laryngeal muscles; and poststroke immune function reduction. In addition, stroke-related pneumonia in patients receiving systemic mild therapeutic hypothermia is related to low body temperature [18]. According to another report, insulin resistance caused by hypothermia and the ensuing hyperglycemia may also increase the risk of infections. Xu et al. [19] conducted a comparative analysis of intra-arterial thrombolysis plus systemic mild therapeutic hypothermia in patients with cerebral infarction. Xu et al. [20] found that mild therapeutic hypothermia had no impact on the poststroke incidence of stroke-related pneumonia and gastrointestinal bleeding. In the present study, 10 patients who received mild therapeutic hypothermia had stroke-related pneumonia and were treated with antibiotics. Among patients not receiving mild therapeutic hypothermia, 9 had stroke-related pneumonia and were treated with antibiotics. The incidence of stroke-related pneumonia was not significantly different between the two groups. This result agreed with the findings of Xu et al. [19]. We further compared the inflammatory indicators within 24 h poststroke between the two groups, including white blood cell count, percentage of neutrophils, and PCT level. The white blood cell count in the patients who received mild therapeutic hypothermia was significantly lower than the patients who did not receive mild therapeutic hypothermia. The percentage of neutrophils was also lower in the former group than in the latter group. These results suggest a protective effect of mild therapeutic hypothermia against stroke-related pneumonia; however, this finding contradicts to what has been reported previously [18] for unknown reasons. It has been presumed that mild therapeutic hypothermia decreases the detection rate and concentration of PCT and CRP [20]. Zhou [21] carried out a matched analysis among 201 stroke patients and arrived at the same conclusion, i.e., mild therapeutic hypothermia has no significant impact on the incidence of poststroke infections. Nevertheless, the time to the onset of infection was longer in the mild therapeutic hypothermia group than in the non-mild therapeutic hypothermia group. This result indicated that mild therapeutic hypothermia delayed poststroke infections. We did not record the time to the onset of poststroke infections. A statistical analysis was not performed on the time to the onset of poststroke infections. We performed a statistical analysis of inflammatory markers within 24 h poststroke between the two groups. Our results showed that these indicators were significantly lower in patients receiving mild therapeutic hypothermia than in those who did not receive this therapy. This finding served as indirect evidence that mild therapeutic hypothermia delayed poststroke pneumonia. In light of the incidence of infections in the two groups, mild therapeutic hypothermia had no definite effect in preventing stroke-related pneumonia. Taken together, local mild therapeutic hypothermia in target vessels did not increase the incidence of stroke-related pneumonia. Rather, this therapy delayed the onset of stroke-related pneumonia.
Mild Hypothermia and Deep Vein Thrombosis
A previous study showed that hypothermia blanket and other equipment used for inducing systemic mild hypothermia was a risk factor for deep vein thrombosis in lower extremities [22]. Other researchers conducted a multicenter controlled study of the safety of selective head cooling with mild therapeutic hypothermia in 217 newborns with hypoxic-ischemic encephalopathy. It was found that this therapy did not result in a significant difference in the incidence of deep vein thrombosis in the newborns [23].
DVT may be suspected when clinical symptoms, such as edema, pain, and erythema, appear on the lower extremities, and D-dimer levels rise above normal. However, these are nonspecific indicators; therefore, radiologic imaging is important for diagnosing DVT [24]. Xiao et al. [25] conducted a clinical randomized controlled study in cerebral hemorrhage patients receiving systemic mild therapeutic hypothermia. They found that the incidence of deep vein thrombosis was significantly lower in patients receiving this therapy than in the controls. However, it remains uncertain whether mild therapeutic hypothermia may cause deep vein thrombosis. A series of complex physiopathologic mechanisms after the stroke and stroke-related complications may be involved in this process. Recruitment bias was inevitable in the previous clinical trials due to a lack of equilibration of clinical factors that potentially affected deep vein thrombosis. Such clinical trials were more likely to arrive at unscientific conclusions. In the present study, the controls were matched to the cases at a 1:1 ratio with respect to age, gender, etiology, and underlying diseases. With potentially confounding factors excluded, we finally arrived at the conclusion that mild therapeutic hypothermia in target vessels did not necessarily induce poststroke deep vein thrombosis.
Mild Hypothermia and Seizures
An existing study [26] demonstrated that systemic mild hypothermia effectively inhibited the abnormal discharge of neurons, thereby reducing seizures and alleviating cerebral edema and nerve function deficit. So far, there have been few reports on whether direct injection of hypothermic normal saline into the carotid artery will trigger abnormal discharge of neurons, leading to seizures. An animal experiment [27] showed that mild therapeutic hypothermia blocked the expressions of common pathway protein associated with seizures, thereby inhibiting the abnormal discharge of hippocampal neurons. However, this conclusion has not been confirmed by clinical trials yet. We did not observe seizures in either group during the operation, while 3 controls had seizures after operation. However, the differences were not statistically significant between the two groups. We should not jump to the conclusion that mild therapeutic hypothermia in target vessels was positively or negatively associated with seizures, for the following reasons. First, the time of therapeutic hypothermia only lasted for 20 min, which was not sufficient to alter local neurotransmitters of the brain; second, the two groups of patients received the operation under general anesthesia, which might conceal the potential influence of hypothermia on neurons. This might explain the absence of significant differences between the two groups.
Mild Hypothermia, Stress Ulcers, and Heart Failure
Peng et al. [28] delivered mild therapeutic hypothermia for varying durations following intravenous thrombolysis in 127 Chinese patients with acute cerebral infarction. Peng et al. [28] concluded that mild therapeutic hypothermia did not increase the incidence of gastrointestinal bleeding. Rapid infusion of hypothermic normal saline into target vessels carries a risk of inducing cardiac insufficiency, at least in theory. Previous studies generally induced hypothermia by body surface cooling or heat transfer in large arteries, but few discussed the risk of this therapy inducing cardiac insufficiency. Chen et al. [16] reported 26 patients with acute cerebral infarction who received local mild therapeutic hypothermia via an arterial catheter in which no cardiac insufficiency was observed. In the present study, no signs of heart failure were reported during operation in either group, including an increase in blood pressure and heart rate. In addition, there was no significant difference in the BNP level within 24 h postoperatively between the two groups. We concluded that the rapid infusion of hypothermic normal saline to induce mild hypothermia had no noticeable impact on cardiac function. This finding was attributed to low blood pressure under general anesthesia and short-term maintenance of mild therapeutic hypothermia. The volume of fluid infused into the target vessels was too small to increase the cardiac load.
Mild Therapeutic Hypothermia, Vasospasm, and Chills
Several patients in each group had vasospasm caused by mechanical thrombectomy. The symptoms were alleviated after intra-catheter administration of papaverine. Angiography during mild therapeutic hypothermia did not reveal signs of target vessel spasm. This finding indicated that local endovascular administration of hypothermic normal saline did not induce vasospasm, which agreed with the conclusions by the team led by Ji. In previous studies, chills were inevitable during systemic mild therapeutic hypothermia. The underlying mechanism involves hypothalamic signaling to the skeletal muscles to produce more heat by doing work in case of systemic hypothermia, thereby promoting rewarming. Chills are among the most common complications associated with systemic mild hypothermia. In this study, we only delivered local mild hypothermia for the target vessels of the brain. The infused hypothermic fluid passed through the ischemic brain tissues and entered systemic circulation via venous efflux. The temperature of the infused fluid itself would rapidly rise to the normal temperature. Hypothermia only lasted for a short period of time and involved a small volume of cold normal saline. The influence on systemic body temperature was negligible. None of our patients had chills. Because the operation was performed under general anesthesia, the occurrence of chills was avoided.
Because 500 mL of hypothermic fluid is infused into the target vessels via the arterial catheter within 20 min, the catheter diameter may affect the vascular intima or hemodynamics. If the catheter diameter is too small, the hypothermic normal saline will be ejected from the catheter opening, resulting in considerable pressure. If the catheter opening is closely pressed against the vascular wall with fluid ejected from the catheter, mechanical damage may be caused to the vascular intima. Unstable plaques in the vascular wall subjected to the pressure of the fluid flow may be dislocated. In that case, rapid infusion of hypothermic normal saline into the target vessels will result in an infinite dilution of red blood cells, which further reduces the blood oxygen level and blood glucose concentration. Such practice may have an adverse impact on nerve cell metabolism, especially when delivering the endovascular therapy in posterior circulation. We recommend placement of the infusion catheter at the subclavian artery proximal to the origin of vertebral artery for mild therapeutic hypothermia in posterior circulation stroke, though the efficacy of mild therapeutic hypothermia may be weakened.
Conclusion
Our study had the following limitations. First, only a small number of matched pairs were included in the statistical analysis due to the need for equilibration with respect to age, sex, etiology, underlying diseases, and occluded vessels. It is necessary to expand the sample size in the future. Second, mild hypothermia was induced by rapid infusion of hypothermic normal saline into the target vessels and maintained only for a short period of time. Mild therapeutic hypothermia performed according to this procedure, however, only achieved a limited efficacy. In contrast, the risk associated with mild hypothermia may be higher by increasing the volume of the hypothermic fluid and prolonging the duration of hypothermia. In the future, local heat transfer in target vessels may be used to resolve the undesired defects associated with short duration of hypothermia and circulatory overload in mild therapeutic hypothermia.
Statement of Ethics
The clinical trial was registered in Huizhou Science and Technology Bureau, Guangdong, China (N0.2020Y203).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
None.
Author Contributions
Jiang Li contributed in the study concepts and study design and wrote the main manuscript text; Shaonian Tang and Juannli Liu performed the literature research and data acquisition; Wenlin He, Jinjin Yan, and Zhiyong Huang were involved in the data acquisition and data analysis; Xuesong Li participated in the manuscript editing and was the guarantor of integrity of the entire study. All authors read and approved the final manuscript.
Funding Statement
None.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.