Hypothermia is associated with improved neurological outcomes after mechanical thrombectomy

Abstract

Background:

Acute ischemic stroke (AIS) is the second-leading cause of death globally. Mechanical thrombectomy (MT) has improved patient prognosis but expedient treatment is still necessary to minimize anoxic injury. Lower intraoperative body temperature decreases cerebral oxygen demand, but the role of hypothermia in treatment of AIS with MT is unclear.

Methods:

We retrospectively reviewed patients undergoing MT for AIS from 2014 to 2020 at our institution. Patient demographics, comorbidities, intraoperative parameters, and outcomes were collected. Maximum body temperature was extracted from minute-by-minute anesthesia readings, and patients with maximal temperature below 36°C were considered hypothermic. Risk factors were assessed by Chi-squared and multivariate ordinal regression.

Results:

Of 68 patients, 27 (40%) were hypothermic. There was no significant association of hypothermia with patient age, comorbidities, time since last known well, number of passes intraoperatively, favorable revascularization, tissue plasminogen activator use, and immediate postoperative complications. Hypothermic patients exhibited better neurologic outcome at three-month follow-up (p=0.02). On multivariate ordinal regression, lower maximum intraoperative body temperature was associated with improved three-month outcomes (p<0.001), when adjusting for other factors influencing neurological outcomes. Other significant protective factors included younger age (p=0.03), better revascularization (p=0.03), and conscious sedation (p=0.02).

Conclusions:

Lower intraoperative body temperature during MT was independently associated with improved neurological outcome in this single center retrospective series. These results may help guide clinicians in employing therapeutic hypothermia during MT to improve long-term neurologic outcomes from AIS, although larger studies are needed.

Introduction:

Acute ischemic stroke (AIS) is the second leading cause of death globally, with 50% of survivors suffering from chronic disability.¹ Mechanical thrombectomy (MT) has improved the treatment of AIS in the setting of intracranial large vessel occlusion (LVO) with salvageable penumbra.² However, while the era of MT has led to better patient outcomes, expedient treatment remains an important predictor of functional recovery in AIS.³ The discovery and implementation of new strategies that expand the window of viability for MT may further improve neurologic outcomes among patients with AIS.⁴

Therapeutic hypothermia is a promising neuroprotective strategy for a variety of neurological disorders involving acute neuronal injury.⁵ Originally used following cardiac arrest, patients treated with mild induced hypothermia show improved neurological outcomes compared to normothermia.⁵ Preclinical studies show that therapeutic hypothermia in AIS attenuates inflammatory signaling and leads to improved neurological recovery.⁶ However, there exists little evidence investigating the role of hypothermia in humans, particularly since the introduction of MT. Lower body intraoperative temperature may reduce metabolic demand and inflammatory response in the ischemic brain, potentially extending the window for effective intervention via MT in AIS. In this study, we sought to investigate the independent impact of intraoperative hypothermia on the outcomes of AIS patients treated with MT.

Methods:

Study Design

We retrospectively reviewed AIS patients at our institution who were treated with MT from 2014 to 2020. Patients were excluded if an associated anesthesia report was not available or if the report did not contain intraoperative body temperature data. This study was approved by our institutional review board under IRB00256557, and informed consent was not required due to the retrospective nature of the study.

Chart review consisted of extracting data from anesthesia reports, neurosurgical consultation notes, radiology images, operative notes, and discharge summaries. We obtained demographic and clinical characteristics for each case including location and laterality of vessel occlusion, and patient comorbidities. Comorbidities considered for this study included hypertension, smoking, coronary artery disease, chronic obstructive pulmonary disease, diabetes, atrial fibrillation. We also determined pre-morbid functional status and calculated a baseline modified Rankin Scale (mRS) score for each patient.

Intraoperatively, we recorded the number of passes as well as whether a stent retriever was utilized in each case. We obtained the thrombolysis in cerebral infarction (TICI) score from radiology reports for each case following revascularization. Additionally, we recorded whether tissue plasminogen activator (tPA) was administered in each case and measured the total time from last known well (LKW) to revascularization of the occluded vessel. By examining minute-by-minute axillary temperature recordings available in anesthesia vital monitoring recordings, we noted start temperature, end temperature, minimum temperature, and maximum temperature for each patient during thrombectomy. Patients that did not contain thrombectomy anesthesia reports in their charts with temperature readings were excluded from this study.

For each case, we collected postoperative outcomes as well as long-term measures of recovery following MT. Postoperative outcomes considered include intracranial hemorrhage, groin hematoma, retroperitoneal hematoma, hemicraniectomy, pneumonia, urinary tract infection, deep vein thrombosis/pulmonary embolism, and tracheotomy or feeding tube placement. Following discharge, we recorded whether the patient was admitted to a rehabilitation facility or able to return home. Our primary long-term outcome of interest was mRS at 3 months follow up after MT. A poor mRS score was defined as any score >2, indicating any form of moderate disability, inability to walk without assistance, being bedridden, or death after 3 months.

We dichotomized patients by maximum intraoperative body temperature. We defined mild hypothermia as patients whose maximum intraoperative body temperature never exceeded 36°C (<36°C), and normothermia as patients whose intraoperative body temperature was equal to or greater than 36°C at any given point during MT (≥36°C).

Statistical Analysis

Continuous variables were represented as mean ± SD and categorical variables were represented as N, %. mRS was represented by median, interquartile range (IQR). Differences in continuous variables between the hypothermic and normothermic groups were calculated via student t-tests, and differences in categorical variables were calculated using Chi-squared analyses. Factors hypothesized to influence neurological outcomes following MT, including hypothermia were then included in a multivariate ordinal regression to determine association with neurological outcome.

Results:

Characteristics of patients with AIS undergoing MT

Sixty-eight patients undergoing MT with available temperature data were identified. Twenty-seven (40%) experienced mild hypothermia, defined as those with maximum intraoperative body temperatures <36°C. Neither age nor sex was significantly different between the hypothermic and normothermic cohorts. Both groups demonstrated similar rates of hypertension, smoking status, coronary artery disease, chronic obstructive pulmonary disease, diabetes, and atrial fibrillation (Table 1). Baseline mRS scores were similar between the two cohorts. There was no significant difference in LVO location.

Table 1.

Demographics of clinical characteristics of normothermic (≥36°C) and hypothermic patients (<36°C).

	Hypothermic	Normothermic	p-value
N	27	41
Age	65.4 ± 17.6	65.4 ± 18.4	1
Sex	12 (44.4%)	18 (43.9%)	0.96
Comorbidities
HTN	16 (59.3%)	29 (70.7%)	0.33
Smoking	14 (51.9%)	20 (48.8%)	0.8
CAD	4 (14.8%)	6 (14.6%)	0.93
COPD	3 (11.1%)	2 (4.88%)	0.33
Diabetes	8 (29.6%)	15 (36.6%)	0.55
Atrial fibrillation	6 (22.2%)	16 (39.0%)	0.15
Pre-morbid mRS ≤ 3	26 (97.4%)	41 (100%)	1
Location of LVO
MCA	21 (74.1%)	29 (70.1%)	0.52
ICA	3 (11%)	1 (2.44%)	0.14
Basilar	3 (11%)	11 (26.8%)	0.12

HTN: hypertension; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; LVO: Large vessel obstruction; MCA: Middle cerebral artery; mRS: modified Rankin Scale; ICA: internal carotid artery

Intraoperative characteristics of hypothermic and normothermic patients

Neither the number of passes required for revascularization (p=0.22) nor the frequency of stent-retriever use (p=0.32) significantly differed between hypothermic and normothermic patients (Table 2). TICI scores (p=0.32) and LKW to revascularization (p=0.17) were also not significantly different. In addition, tPA use did not differ between groups (p=0.81). Hypothermic patients were less likely to receive general anesthesia during their procedures (p=0.002). Neither average mean arterial pressure (p=0.32) nor anesthesia duration (p=0.26) significantly different between the cohorts.

Table 2.

Intraoperative characteristics of normothermic (≥36°C) and hypothermic patients (<36°C).

	Hypothermic	Normothermic	p-value
N	27	41
Number of passes	2.35 ± 1.41	1.92 ± 1.51	0.22
Stent-retriever use	17 (63.0%)	23 (56.1%)	0.32
TICI revascularization ≥ 2b	23 (85.2%)	38 (92.7%)	0.32
tPA use	12 (44.4%)	17 (41.4%)	0.81
LKW to revascularization (min)	405.67 ± 189.54	545.98 ± 506.03	0.17
General anesthesia	20 (74%)	41 (100%)	0.002
Average mean arterial pressure (mmHg)	93.0 ± 18.1	97.3 ± 16.3	0.32
Anesthesia duration (min)	180 ± 84	158 ± 65	0.26

TICI: thrombolysis in cerebral infarction; tPA: tissue plasminogen activator; LKW: Last known well

Immediate postoperative and long-term outcomes of patients

There were no significant differences in frequency of immediate postoperative complications between the hypothermic and normothermic groups, including intracerebral hematoma (ICH), groin hematoma, retroperitoneal hematoma, patients requiring hemicraniectomy, pneumonia, urinary tract infection, venous thromboembolism, and proportion of patients requiring tracheostomy/PEG placement (Table 3). Hypothermia was not significantly linked to improved rates of discharge to inpatient rehabilitation following MT (p=0.94). Improved neurologic outcome (p=0.02) but not mortality (p=0.19) at three-month follow-up were significantly associated with hypothermia.

Table 3.

Postoperative complications and neurological outcomes of normothermic (≥36°C) and hypothermic patients (<36°C).

	Hypothermic	Normothermic	p-value
N	27	41
ICH	7 (25.9%)	6 (14.6%)	0.25
Groin hematoma	2 (7.41%)	4 (9.76%)	0.74
Retroperitoneal hematoma	1 (3.70%)	0 (0%)	0.21
Pneumonia	3 (11.1%)	6 (14.6%)	0.96
UTI	1 (3.7%)	7 (17.1%)	0.20
DVT/PE	1 (3.70%)	3 (7.30%)	0.93
Tracheotomy/PEG	9 (33.3%)	10 (24.4%)	0.42
Discharge to inpatient rehab	9 (33.3%)	14 (34.1%)	0.94
Mortality	7 (25.9%)	17 (41.5%)	0.19
mRS >2 at three months	14 (51.9%)	33 (80.5%)	0.02

ICH: intracranial hemorrhage; UTI: urinary tract infection; DVT: deep vein thrombosis; PE: pulmonary embolism; PEG: percutaneous endoscopic gastrostomy; mRS: modified Rankin scale

Multivariate ordinal regression analysis of potential predictors of neurological outcome

Age, sex, LKW to recanalization time, TICI score, the number of passes, and hypothermia were assessed as predictors for neurologic outcome using multivariate ordinal regression analysis (Table 4). Hypothermia was independently associated with improved neurologic outcome at three-month follow-up (OR 1.32, CI 1.24–1.40, p<0.001) (Figure 1). Younger age (OR 1.03, CI 1.00–1.06, p=0.03), higher TICI revascularization score (OR 0.13, CI 0.01–0.67, p=0.02), and use of conscious sedation rather than general anesthesia (OR 7.14, CI 1.21–46.97, p=0.02) were also linked to better three-month outcomes. All other predictors did not significantly influence neurological outcome.

Table 4.

Using multivariate ordinal regression analysis age, sex, LKW to recanalization time, TICI score, the number of passes, and hypothermia were assessed as predictors for neurologic outcome at three-month follow-up from mechanical thrombectomy.

	Common OR (CI)	p-value
Maximum body temperature	1.32 (1.24–1.40)	<0.001
Age	1.03 (1.00–1.06)	0.03
Male	2.15 (0.84–5.71)	0.10
LKW to recanalization	1.00 (1.00–1.00)	0.87
TICI revascularization ≥ 2b	0.13 (0.01–0.67)	0.02
Number of passes	1.22 (0.88–1.75)	0.25
General anesthesia	7.14 (1.21–46.97)	0.02

OR: Odds Ratio; LKW: last known well; TICI: thrombolysis in cerebral infarction.

Figure 1.

Distribution of the Modified Rankin Scale scores 3 months after mechanical thrombectomy in the normothermic (≥36°C) and hypothermic (<36°C) groups.

Discussion:

Left untreated, LVO in AIS is associated with profoundly debilitating neurological outcomes, including speech, memory, motor, and personality deficits.⁷ Prior to the adoption of MT, intravenous tissue plasminogen activator was standard of care for AIS patients with LVO, with many patients arriving to healthcare centers outside the allowed time window within which they can receive treatment.⁸ The debut of MT has dramatically improved prognosis for these patients, yet time to treatment continues to remain an integral predictor of neurologic outcome in AIS with LVO.³ Interventions that prolong ischemic tolerance of brain tissue may thus improve neurologic outcomes and broaden the spectrum of patients eligible for intervention.

Therapeutic hypothermia is one such neuroprotective strategy which shows promise in expanding the window for effective therapeutic intervention in AIS. Hypothermia has long served as an adjunctive therapy employed to lower cellular metabolism during cardiac procedure.⁹ Reduced metabolism leads to a subsequent drop in oxygen consumption, which can be useful in preserving tissue temporarily subjected to anoxic conditions.¹⁰ Previous work among patients resuscitated from cardiac arrest found that those treated immediately with hypothermia exhibited improved survival rates and better neurological recovery.^{11, 12}

Separate from cerebral oxygen demand, inflammation in the ischemic penumbra can also lead to delayed expansion of the original cerebral infarct.¹³ Mild hypothermia also provides direct anti-inflammatory effects, as cooling has been shown to attenuate inflammatory signaling in preclinical models of stroke.¹⁴ Thus, hypothermia can theoretically limit the expansion of ischemic infarcts into the penumbral region, as has been shown in preclinical studies. In one report, pharmacologically induced hypothermia initiated 3.5 hours after stroke in mice led to improved functional recovery one-month post-stroke as well as an average 53% reduction in lesion size. ¹⁵ A similar mouse study applied cold saline infused directly into the ischemic area with a similar 65% reduction in infarction volume.^{15, 16} Another recent study employed an intra-carotid catheter to induce selective therapeutic hyperthermia demonstrated feasibility and safety in an ovine stroke model.¹⁷

Despite promising results from preclinical studies, investigating the efficacy of therapeutic hypothermia in humans with AIS has been more challenging. Early attempts to induce hypothermia in patients employed cooling blankets to systemically lower body temperature; however, these strategies failed to produce significant improvements in neurologic outcomes.¹⁸ While effective in quickly achieving target temperatures, some studies reported that patients subjected to hypothermia had increased incidence of pneumonia.¹⁹ These concerns prompted a shift to selective therapeutic hypothermia induction, often through endovascular infusion of cold saline directly into the brain parenchyma.²⁰ Since the adoption of selective techniques, several reports have confirmed the feasibility and safety of induced hypothermia, though few have assessed long-term patient outcomes in large randomized cohorts.^{21, 22} One of these large trials was only able to achieve their predefined cooling targets among 31% of their randomized patients, resulting in an underpowered experimental cohort that showed no improvement in neurologic recovery.²² One small prospective study found that intraarterial cooling was associated with slightly smaller infarct volumes, yet there was no associated change in long-term outcome.²³ Though current European Stroke Organization guidelines for temperature management in patients with AIS do not recommend hypothermia induction, they were defined prior to the widespread adoption of MT as standard of care in AIS.²⁴ Importantly, our findings exclusively represent patients treated with MT, where we found that hypothermic patients had improved long-term outcomes without any increase in post-operative complications. Therefore, in the era of MT intervention, our findings suggest that systemic hypothermia in AIS patients treated with MT may be associated with improved long-term outcomes.

While changing standards of care may account for some of the discrepancies seen in studies of therapeutic hypothermia, the wide variation in definition of hypothermic conditions may also have a role. Two active clinical trials employ an intravascular catheter placed in the inferior vena cava via femoral venous access to achieve a core body temperature of 33°C for a set time period post-thrombectomy (12 hours in one trial and 48 to 72 hours in the other).^{25, 26} Notably, these and other recent studies employ a relatively low temperature setpoint ranging from 33 to 35°C.^{25, 27–29} Numerous randomized human trials have characterized many major complications of mild perioperative hypothermia, including surgical wound infections, morbid cardiac events, and longer hospitalizations. These complications were significant even after as little as a 2 to 3°C drop in body temperature. In our study, we define hypothermia as patients with a maximum systemic body temperature under 36°C, which is a relatively modest change from normal body temperature. Therefore, our findings indicate that even very mild hypothermia may provide a measurable improvement in outcomes for patients without increasing the risk of major complications seen in studies aiming for a larger decrease in body temperature.

In addition to elucidating the potential relationship between intraoperative hypothermia and patient outcomes, our study also analyzed the role of additional demographic and surgical factors. As seen in previous work, we found older patients to be at greater risk of poor outcome, potentially because of a higher burden of comorbid conditions and post-operative complications.³⁰ General anesthesia (as compared to conscious sedation) is also a known risk factor for worse long-term thrombectomy outcomes.³¹ This relationship may be mediated by an anesthesia-related drop in diastolic blood pressure resulting in hypoperfusion in the acute phase of ischemic stroke.³² Patients with deficient microvascular collateral flow may also be at heightened risk of hypoperfusion when subjected to general anesthesia.³³ General anesthesia can also decrease metabolic activity which would otherwise drive oxidative stress pathways that worsen stroke effects.^{34, 35} By suppressing inflammation, anesthesia may also directly limit this post-stroke inflammatory sequelae.³⁶ While age and anesthesia are important risk factors for poor outcome following thrombectomy, intraoperative hypothermia was found to be independently associated with improved outcomes and presents a potentially modifiable variable in need of further investigation.

This study has several limitations. First, it was designed as a retrospective analysis of patient clinical data. Moreover, our study did not conduct controlled cooling of patients prior to tissue reperfusion. Both factors preclude us from confirming a causal relationship between significant predictors, including hypothermia, and neurologic outcome. Lastly, multi-institutional retrospective studies should be conducted to validate our findings in a larger cohort of AIS patients treated with MT, potentially with longer follow-up intervals.

Conclusions:

In this study, we investigated the protective factors for neurologic outcome among AIS patients treated with MT. We found that a lower intraoperative body temperature was independently associated with better neurological outcomes at three-month follow-up. These results suggest therapeutic hypothermia during MT may offer a neuroprotective benefit by promoting favorable neurological rehabilitation following AIS.