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Impaired Cerebrovascular Autoregulation in Large Vessel Occlusive Stroke after Successful Mechanical Thrombectomy: A Prospective Cohort Study
ARTICLE IN PRESS
Impaired Cerebrovascular Autoregulation in Large Vessel Occlusive Stroke after Successful Mechanical Thrombectomy: A Prospective Cohort Study Marco Meyer, MD,* Martin Juenemann, MD, MSc,‡ Tobias Braun, MD,‡ Ingo Schirotzek, MD,‡ Christian Tanislav, MD,* Kristin Engelhard, PhD, MD,† and Patrick Schramm, PhD, MD, MSc† Introduction: Successful thrombectomy improves morbidity and mortality after stroke. The present prospective, observational cohort study investigated a potential correlation between the successful restoration of tissue perfusion by mechanical thrombectomy and intact cerebrovascular autoregulation (CA). Objective: Status of CA in patients with large vessel occlusive stroke after thrombectomy. Methods: After thrombectomy CA was measured using transcranial Doppler ultrasound. For this purpose a moving correlation index (Mxa) based on spontaneous arterial blood pressure fluctuations and corresponding cerebral blood flow velocity changes was calculated. CA impairment was defined by Mxa values more than .3. Results: Twenty patients with an acute occlusion of the middle cerebral artery or distal internal carotid artery were included. A successful recanalization of the occluded vessel via interventional thrombectomy was achieved in 10 of these patients (successful recanalization group), while in 10 patients mechanical recanalization failed or could not be applied (no recanalization group). Mean Mxa at stroke side was .58 § .21 Table 2a in patients with successful intervention. At the unaffected hemisphere Mxa was .50 § .20 Table 2a in successful recanalization group and .45 § .24 Table 2b in no recanalization group without statistically significant differences. Based on the previously defined Mxa cut off more than .3, CA impairment was observable in all successful recanalized patients and in 8 of 10 patients with unsuccessful interventional treatment. Conclusions: These results suggest that brain perfusion may be affected due to impaired CA even after successful mechanical thrombectomy. Therefore, a tight blood pressure management is of great importance in post-thrombectomy stroke treatment to avoid cerebral hypo- and hyperperfusion. Key Words: Acute ischemic stroke—cerebrovascular autoregulation—large vessel occlusion—mechanical thrombectomy—neurocritical care © 2019 Elsevier Inc. All rights reserved.
From the *Department of Geriatrics, Jung-Stilling Hospital Siegen, Siegen, Germany; †Department of Anesthesiology, Johannes GutenbergUniversity, University medical hospital Mainz, Mainz, Germany; and ‡Department of Neurology, University hospital Giessen and Marburg location Giessen, Giessen, Germany. Received October 23, 2019; revision received November 27, 2019; accepted December 5, 2019. Institution where the work was performed: Department of Neurology, University hospital Giessen and Marburg location Giessen, Giessen, Germany. Funding: None. Address correspondence to Marco Meyer, MD Department of Geriatrics, Jung-Stilling Hospital Siegen, Wichernstrasse 40, 57074 Siegen, Germany. E-mail: [email protected]. 1052-3057/$ - see front matter © 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104596
Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2019: 104596
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Introduction Brain function strongly depends on a continuous oxygen and energy supply and, therefore, continuous blood flow is mandatory. To guarantee an uninterrupted adequate cerebral circulation despite changes in cerebral perfusion pressure brain perfusion is autoregulated. This so called cerebrovascular autoregulation (CA) maintains a constant cerebral blood flow (CBF) within a wide range of cerebral perfusion pressure and it is thus a key component of cerebral hemostasis.1-3 Particularly cerebrovascular diseases are associated with CA disturbances. In stroke patients, impaired CA correlates with a deteriorated clinical outcome and higher rates of secondary complications, such as increased infarct size, hemorrhagic infarct transformation, or progressive brain edema as a consequence of unregulated CBF fluctuations.4-6 The aim of the presented study was to investigate CA status immediately after successful tissue reperfusion by mechanical thrombectomy and to objectify CA time course in the investigated stroke patients with a prolonged need for analgosedation. Hypothesis: CA remains intact or recovers quickly when cerebral local perfusion is successfully restored by early mechanical thrombectomy.
Materials and Methods Patients After approval of the local ethics committee (Justus Liebig University, Giessen, Germany, No. 185/16) consecutive patients with large vessel occlusive stroke (distal internal carotid artery or proximal middle cerebral artery [MCA]) were included in the presented prospective, observational cohort study. Posterior circulation strokes were not enrolled. Requirements for study participation were an age older than 18 years, the need for invasive blood pressure management and the treatment on neurological intensive care unit (NICU). Exclusion criteria were pregnancy and the inability to insonate intracranial vessels. The informed consent of the patient or the legal representative was obtained before individual data were entered into the analysis. After presentation in the emergency room, all patients were physically examined and received computed tomography (CT) of the head, including CT angiography. In case of large vessel occlusion, the absence of an intracranial hemorrhage and respective contraindications against recombinant tissue plasminogen activator as well as a time window less than 4.5 hours, intravenous thrombolysis was initiated in a weight-adjusted dose of .9 mg/kg body weight. Hereafter, all patients were anesthetized, intubated and mechanically ventilated for mechanical thrombectomy procedure, as the standard operating procedure at that time. Previous studies in patients under general anesthesia and after traumatic brain injury showed that CA was preserved in patients treated with
propofol. Therefore, propofol was preferred for sedation in the investigated cohort.7,8 Mechanical recanalization was achieved via interventionalists with stent retriever systems (phenox pRESET thrombectomy device, phenox GmbH, Bochum, Germany or ERIC retrieval device, MicroVention Inc, Tustin, CA). The use of the different stent retrievers varied according to physician’s preference. Successful thrombectomy was defined as a thrombolysis in cerebral infarction score more than or equal to 2b. Postinterventional, all patients were transferred to the NICU for weaning procedure and extubation trial. CA was measured after arrival at the NICU during patients’ weaning time period. Patients who failed weaning trial received a further CT scan. Analgosedation was maintained in case of space-occupying infarctions to reduce brain swelling and intracranial pressure and in case of nonspace-occupying infarctions further weaning trials were performed daily. In these patients CA was measured daily and for a maximum of 4 days. The 4 days observation period was chosen because of major infarct remodeling processes and infarct size evolution during that time course. According to institutional standard operating procedure targeted MAP was above 65 mm Hg and maximum systolic blood pressure below 160 mm Hg. Acute physiology and chronic health evaluation score, along with the sequential organ failure assessment score were calculated. Additionally, the following data were recorded: National Institutes of Health Stroke Scale, modified ranking scale (mRS) at hospital discharge; days in NICU and days in hospital. Two experienced observers (M.J., T.B.) also independently evaluated CT scans. The latest scan (average time: 7 days) was used for registration and planimetric quantification of acute ischemic lesion volumes, determined by infarct area in each CT slice and the slice thickness.9
Calculation of Cerebrovascular Autoregulation Index Mxa CA was measured using transcranial Doppler ultrasound with bilateral temporal attached 2-MHz Doppler probes, fixed with a special frame (DiaMon, Compumedics DWL, Singen, Germany). CBF velocity (CBFV) was detected via the insonation of the MCA (Doppler-Box, Compumedics DWL, Singen, Germany). Invasive arterial blood pressure was measured in the radial artery (M10006B/MP70, Philips Medical Systems, Eindhoven, Netherlands), digitally converted and synchronically recorded with CBFV (Doppler-Box). Calculation of CA index Mxa was performed afterwards. Mean arterial blood pressure (MAP) and mean CBFV were averaged every 6 seconds. Then, averaged values were correlated and calculated as Pearson’s correlation index expressed as the CA index Mxa in 3-minute intervals and in total over the measurement period of 45 minutes. Mxa ranges from 1 to +1. Positive Mxa values more than .3 indicate a
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relevant association between MAP fluctuations and CBF and therefore an impaired CA; negative values point to the MAP independent CBF and signify an intact CA; while values between 0 and .3 did not permit a statement to integrity of CA.1012 The impairment of CA was assumed at Mxa more than .3 as previously described in traumatic brain injury and septic patients.10,13 Described calculations were done using MATLAB R2015a (maci64, The MathWorks, Inc, Natick, MA).
volume (P = .086), nor with mRS (P = .59). The outcome parameter mRS in successful recanalization group was 3.4 § 1.8 and significant better than in no recanalization group with 5.1 § 1.7 (P= .044). There were no differences between both groups in physiological parameters including paCO2, vital signs, CBFV, used analgosedative drug doses and catecholamine doses (Tables 1 and 2a and b). During the 4-day follow-up, in patients who failed weaning trial or stayed analgosedated due to infarct size or other complications like pneumonia, Mxa did not change substantially (Fig 2). Patients with larger stroke volumes were significant longer mechanical ventilated (P = .019).
Statistical Analysis Patients were assigned to successful recanalization group and no recanalization group. Sample size calculation was done using Student’s t test for independent groups, estimating a relevant clinically difference in Mxa between both groups of .3. A power of .8, a significance level of .05 and an estimated standard deviation of .2 revealed nine patients in each group. To guarantee a sample size of 9 patients per group 20 patients needed to be investigated. Raw datasets were described as mean § standard deviation or median with minimum and maximum values. Differences between the groups were analyzed with a 2-sided Student’s t test, and secondary parameters were analyzed via Student’s t test and Pearson’s correlation. Statistical analyses were calculated using SPSS (version 24, IBM Corporation, Armonk, NY). A significance level with P < .05 was considered to be statistically significant.
Results Twenty patients (8 male, 12 female) with a mean age of 77 § 9 years were included in the present study. Fifteen patients suffered occlusion of the MCA (7 right, 8 left) and 5 patients occlusion of the distal internal carotid artery (2 right, 3 left). Seventeen patients were subjected to local thrombectomy, and 10 of them additionally received systemic thrombolysis therapy with recombinant tissue plasminogen activator (successful recanalization group = 6 patients, no recanalization group = 4 patients) prior to thrombectomy. Ten patients with thrombolysis in cerebral infarction score more than or equal to 2b were subjected to successful recanalization group and 7 patients with unsuccessful and 3 without interventional procedure were assigned in no recanalization group. Both groups were comparable in age, sex, National Institutes of Health Stroke Scale, acute physiology and chronic health evaluation score (Table 1). Directly postinterventional, CA was impaired in both groups. In successful recanalization group Mxa was .58 § .21 at stroke side (ipsilateral hemisphere) and .50 § .20 at the contralateral hemisphere (Fig 1). In no recanalization group only the contralateral MCA could be insonated and showed a Mxa of .45 § .24 with no significant differences between the both groups (P = .59). Level of Mxa, and thus the extent of CA impairment, did not correlate with infarct
Table 1. Physiological data and outcome parameters P values No Successful recanalization recanalization (n = 10) (n = 10) Age Sex (masculine/ feminine) Stroke side (right/left) Vessel occlusion (ICA/M1/M2) Size (cm) Weight (kg) BMI (kg/m2) Arterial hypertension (n) Diabetes mellitus (n) Heart failure (n) Atrial fibrillation (n) Hyperlipidemia (n) Coronary artery disease (n) NIHSSz APACHE II SOFA paCO2 mRSy Stroke volume (cm3) Days in ICU (d) Days in hospital (d)
76.1 § 9.2 4/6
78.2 § 9.6 4/6
5/5
4/6
3/5/2
2/7/1
173 § 10 78 § 10 26.0 § 2.0 8
169 § 9 76 § 13 26.7 § 4.8 8
1
1
0 6
4 5
4
3
1
2
19.8 § 10.9 23.5 § 3.2 9.2 § 2.8 38.2 § 7.7 3.4 § 1.8 81 § 67
14.8 § 5.4 23.9 § 5.7 10.0 § 2.5 38.5 § 9.3 5.1 § 1.7 197 § 168
.211 .848 .507 .948 .044* .072
17 [2-28] 20 [10-28]
14 [2-46] 15 [2-46]
.984 .648
.623
.347 .736 .644
Abbreviations: ICA, internal carotid artery; M1, mean cerebral artery, segment 1; M2, mean cerebral artery, segment 2. The number of patients in the groups were presented as count (n). Parameters are expressed as mean § standard deviation or median and (minimum-maximum). *P < .05. † At hospital discharge. ‡ At hospital admission.
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Figure 1. The figure represents cerebrovascular autoregulation index Mxa in patients with succsessful mechanical thrombectomy (successful recanalization) and with unsuccessful thrombectomy (no recanalization). Values are expressed as box-plot with median (line), IQR (box), and range (whiskers). Gray box represents infarction side and white boxes the unaffected hemisphere.
In successful recanalization group, 2 patients and in no recanalization group 7 patients died during their ICU stay. One of the deceased no recanalization group patients suffered a malignant hemorrhagic infarct transformation.
Discussion CA is impaired in patients after large vessel occlusive stroke irrespective of successful vascular recanalization by mechanical thrombectomy. This finding was more pronounced on the ipsilateral hemisphere, but was also detectable on the contralateral hemisphere. The present study, including patients from a representative stroke collective, revealed that CA was impaired in both groups—the no recanalization group as described
earlier but also in patients following successful mechanical recanalization.5,6,14,15 Disturbed CA leads to a passive, perfusion pressure dependent CBF and may be a major factor for secondary complications like hemorrhagic infarct transformation and post infarct edema.4 An observational study investigating successful recanalized patients after thrombectomy showed that systolic blood pressure above 159 mm Hg worsens patients’ outcome.16 Possibly, this deteriorated outcome may be caused due to the impaired CA and consecutive cerebral hyperperfusion. In view of this, strict blood pressure management even after successful thrombectomy seems of utmost importance. CA impairment after mechanical thrombectomy may be also caused by reperfusion injury. The interaction of inflammatory mechanisms, an activation of the complemental system, platelet activation, and reactive oxygen species can lead to secondary tissue damages after successful reperfusion.17-21 In the present study CA was impaired in both hemispheres, which was in accordance with several previously reported investigations.6,15,20 The phenomenon of transhemispheral diaschisis or systemic inflammatory processes are discussed as possible mechanisms of bilateral CA changes.20,22-24 The sequence of ischemia and reperfusion, which also exists in successfully treated patients, triggers inflammation and possibly leads to the observed impairment of CA in both hemispheres. In a previous study focusing on 16 MCA territory stroke patients with thrombolysis therapy, CA was measured 3 times over 5 days. In patients with poor outcome CA was impaired, while it was preserved in patients with recanalization and small infarct sizes.5 In contrast, the present study showed that CA was also impaired in patients with good clinical outcomes following mechanical thrombectomy without a correlation between the ischemic lesion volume and the level of Mxa. Potentially, also the mechanical vessel irritation itself may influence CA in the presented collective. Clinical outcome and the level of CA were considered in various ways, and a relationship between the degree of CA disorder and the clinical outcome has been demonstrated.5,6,23 In the present investigation, the level of Mxa and thereby the degree of
Table 2a. Time course in patients with successful recanalization
n SOFA MAP (mm Hg) Heart rate (min1) CBFVmean ipsilateral (cm/s) CBFVmean contralateral (cm/s) Mxa ipsilteral Mxa contralateral Propofol (mg/kg¢h) Sufentanil (mg/kg¢h) Norepinephrin [mg/kg¢min]
Day 1
Day 2
Day 3
Day 4
10 9.2 § 2.8 81 § 15 68 § 18 39 § 13 38 § 13 .58 § .21 .50 § .20 2.6 § 1.1 (n = 9) .30 § .2 (n = 8) .09 § .06 (n = 8)
7 10 § 3 83 § 15 73 § 22 49 § 15 52 § 17 .66 § .17 .48 § .35 2.1 § .8 (n = 6) .31 § .2 (n = 6) .10 § .1 (n = 5)
6 12 § 2 78 § 17 77 § 23 58 §13 41 § 8 .64 § .21 .44 § .34 1.7 § 1.0 (n = 5) .37 § .2 (n = 4) .15 § .1 (n = 5)
4 10 § 6 81 § 8 74 § 22 45 § 18 43 § 11 .48 § .36 .18 § .52 1.9 § 1.0 (n = 4) .39 § .2 (n = 4) .12 § .08 (n = 4)
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Table 2b. Time course in patients with no recanalization
n SOFA MAP (mm Hg) Heart rate (min1) CBFVmean ipsilateral (cm/s) CBFVmean contralateral (cm/s) Mxa ipsilteral Mxa contralateral propofol (mg/kg¢h) sufentanil (mg/kg¢h) norepinephrin (mg/kg¢min)
Day 1
Day 2
Day 3
Day 4
10 10.0 § 2.5 77 § 15 67 § 14 0 45 § 23 na .45 § .24 2.8 § .9 (n = 9) .24 §.1 (n = 7) .06 § .02 (n = 6)
8 11 § 3 79 § 12 67 § 23 0 49 § 20 na .41 § .33 2.4 § .7 (n = 7) .29 § .1 (n = 4) .10 § .07 (n = 7)
7 11 § 4 76 § 17 84 § 29 0 45 § 15 na .34 § .25 2.2 § 1.0 (n = 4) .26 § .12 (n = 6) .15 § .1 (n = 6)
7 11 § 4 76 § 19 81 § 27 0 55 § 21 na .26 § .28 1.7 § 1.1 (n = 4) .39 § .2 (n = 4) .16 § .1 (n = 5)
Abbreviations: CBFV, cerebral blood flow velocity in mean cerebral artery; MAP, mean arterial blood pressure; Mxa, index of cerebrovascular autoregulation; n, number of patients measured; na, not available. Values in mean § standard deviation.
Figure 2. Time course of cerebrovascular autoregulation index Mxa during the first 4 days after stroke in patients with failed weaning. Lines show mean Mxa in successful recanalization group (solid line: infarction side, dashed line: unaffected side) and in unsuccsessful recanalization group (pointed line: unaffected side).
impaired CA was not associated with clinical outcome parameters. This may be due to the observational character of the study, which resulted in the withdrawal of curative therapy in 9 of 20 patients, because their relatives/ legal representatives surmised permanent serious neurological deficits. This did not allow for a severity-based outcome analysis. Interpreting the follow-up measurements, patients with effective weaning ruled out. Therefore, follow-up data from day 2 to 4 are only descriptive and represent patients with large infarct sizes or other complications like pneumonia. CA did not recover in these patients most likely due to brain swelling or systemic inflammation. Therefore, maintaining a stable CBF by tight blood pressure management is of great relevance to avoid secondary brain damages.
Conclusions Patients with major vessel occlusions experience the impairment of CA after ischemia independent of successful recanalization by mechanical thrombectomy. With CA impairment, brain is more susceptible to cerebral hyper- or hypoperfusion. Therefore, consequent blood pressure monitoring and management seems to be an essential measure in post-thrombectomy stroke treatment.
Statements of Ethics The present study was approved by the ethics committee of the Justus Liebig University, Giessen, Germany (No. 185/16). The informed consent of the patient or the
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legal representative was obtained before individual data were entered into the analysis.
Authors’ Contributions M.M., I.S., and P.S.: conceptualization. M.M. and P.S.: Data collection. M.M., M.J., T.B., and P.S.: Analysis of the data and statistics. C.T., M.M., and P.S.: Preparation of original draft. All authors: Review and editing.
Conflict of Interest Kristin Engelhard was supported by Covidien AG. Remaining authors have no conflicts of interest to declare.
References 1. Aaslid R, Lindegaard KF, Sorteberg W, et al. Cerebral autoregulation dynamics in humans. Stroke 1989;20:45-52. 2. Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev 1959;39:183-238. 3. Markus HS. Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry 2004;75:353-361. 4. Castro P, Azevedo E, Serrador J, et al. Hemorrhagic transformation and cerebral edema in acute ischemic stroke : Link to cerebral autoregulation. J Neurol Sci 2017;372:256-261. 5. Reinhard M, Wihler C, Roth M, et al. Cerebral autoregulation dynamics in acute ischemic stroke after rtPA thrombolysis. Cerebrovasc Dis 2008;26:147-155. 6. Reinhard M, Rutsch S, Lambeck J, et al. Dynamic cerebral autoregulation associates with infarct size and outcome after ischemic stroke. Acta Neurol Scand 2012;125:156-162. 7. Engelhard K, Werner C, M€ ollenberg O, et al. Effects of remifentanil/propofol in comparison with isoflurane on dynamic cerebrovascular autoregulation in humans. Acta Anaesthesiol Scand 2001;45:971-976. 8. Engelhard K, Werner C, M€ ollenberg O, et al. S(+)-ketamine/propofol maintain dynamic cerebrovascular autoregulation in humans. Can J Anaesth 2001;48:1034-1039. 9. Brott T, Marler JR, Olinger CP, et al. Measurements of acute cerebral infarction: lesion size by computed tomography. Stroke 1989;20:871-875. 10. Crippa IA, Subir a C, Vincent JL, et al. Impaired cerebral autoregulation is associated with brain dysfunction in patients with sepsis. Crit Care 2018;22:327.
11. Czosnyka M, Smielewski P, Kirkpatrick P, et al. Monitoring of cerebral autoregulation in head-injured patients. Stroke 1996;27:1829-1834. 12. Reinhard M, Roth M, M€ uller T, et al. Cerebral autoregulation in carotid artery occlusive disease assessed from spontaneous blood pressure fluctuations by the correlation coefficient index. Stroke 2003;34:21382144. 13. Sorrentino E, Budohoski KP, Kasprowicz M, et al. Critical thresholds for transcranial Doppler indices of cerebral autoregulation in traumatic brain injury. Neurocrit Care 2011;14:188-193. 14. Hillmann S, Wiedmann S, R€ ucker V, et al. Stroke unit care in germany: the german stroke registers study group (ADSR). BMC Neurol 2017;17:49. 15. Immink RV, van Montfrans GA, Stam J, et al. Dynamic cerebral autoregulation in acute lacunar and middle cerebral artery territory ischemic stroke. Stroke 2005;36:2595-2600. 16. Maier IL, Tsogkas I, Behme D, et al. High systolic blood pressure after successful endovascular treatment affects early functional outcome in acute ischemic stroke. Cerebrovasc Dis 2018;45:18-25. 17. Al-Mufti F, Amuluru K, Roth W, et al. Cerebral ischemic reperfusion injury following recanalization of large vessel occlusions. Neurosurgery 2018;82:781-789. 18. Eltzschig HK, Eckle T. Ischemia and reperfusion from mechanism to translation. Nat Med 2011;17: 1391-1401. 19. Khatri R, McKinney AM, Swenson B, et al. Blood-brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke. Neurology 2012;79(13 Suppl 1):S52-S57. 20. Stevenson SF, Doubal FN, Shuler K, et al. A systematic review of dynamic cerebral and peripheral endothelial function in lacunar stroke versus controls. Stroke 2010;41: e434-e442. 21. Yang GY, Betz AL. Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats. Stroke 1994;25:1658-1664. 22. Andrews RJ. Transhemispheric diaschisis. A review and comment. Stroke 1991;22:943-949. 23. Eames PJ, Blake MJ, Dawson SL, et al. Dynamic cerebral autoregulation and beat to beat blood pressure control are impaired in acute ischaemic stroke. J Neurol Neurosurg Psychiatry 2002;72:467-472. 24. Feeney DM, Diaschisis Baron JC. Stroke 1986;17:817-830.
Impaired Cerebrovascular Autoregulation in Large Vessel Occlusive Stroke after Successful Mechanical Thrombectomy: A Prospective Cohort Study Marco Meyer, MD,* Martin Juenemann, MD, MSc,‡ Tobias Braun, MD,‡ Ingo Schirotzek, MD,‡ Christian Tanislav, MD,* Kristin Engelhard, PhD, MD,† and Patrick Schramm, PhD, MD, MSc† Introduction: Successful thrombectomy improves morbidity and mortality after stroke. The present prospective, observational cohort study investigated a potential correlation between the successful restoration of tissue perfusion by mechanical thrombectomy and intact cerebrovascular autoregulation (CA). Objective: Status of CA in patients with large vessel occlusive stroke after thrombectomy. Methods: After thrombectomy CA was measured using transcranial Doppler ultrasound. For this purpose a moving correlation index (Mxa) based on spontaneous arterial blood pressure fluctuations and corresponding cerebral blood flow velocity changes was calculated. CA impairment was defined by Mxa values more than .3. Results: Twenty patients with an acute occlusion of the middle cerebral artery or distal internal carotid artery were included. A successful recanalization of the occluded vessel via interventional thrombectomy was achieved in 10 of these patients (successful recanalization group), while in 10 patients mechanical recanalization failed or could not be applied (no recanalization group). Mean Mxa at stroke side was .58 § .21 Table 2a in patients with successful intervention. At the unaffected hemisphere Mxa was .50 § .20 Table 2a in successful recanalization group and .45 § .24 Table 2b in no recanalization group without statistically significant differences. Based on the previously defined Mxa cut off more than .3, CA impairment was observable in all successful recanalized patients and in 8 of 10 patients with unsuccessful interventional treatment. Conclusions: These results suggest that brain perfusion may be affected due to impaired CA even after successful mechanical thrombectomy. Therefore, a tight blood pressure management is of great importance in post-thrombectomy stroke treatment to avoid cerebral hypo- and hyperperfusion. Key Words: Acute ischemic stroke—cerebrovascular autoregulation—large vessel occlusion—mechanical thrombectomy—neurocritical care © 2019 Elsevier Inc. All rights reserved.
From the *Department of Geriatrics, Jung-Stilling Hospital Siegen, Siegen, Germany; †Department of Anesthesiology, Johannes GutenbergUniversity, University medical hospital Mainz, Mainz, Germany; and ‡Department of Neurology, University hospital Giessen and Marburg location Giessen, Giessen, Germany. Received October 23, 2019; revision received November 27, 2019; accepted December 5, 2019. Institution where the work was performed: Department of Neurology, University hospital Giessen and Marburg location Giessen, Giessen, Germany. Funding: None. Address correspondence to Marco Meyer, MD Department of Geriatrics, Jung-Stilling Hospital Siegen, Wichernstrasse 40, 57074 Siegen, Germany. E-mail: [email protected]. 1052-3057/$ - see front matter © 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104596
Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2019: 104596
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ARTICLE IN PRESS M. MEYER ET AL.
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Introduction Brain function strongly depends on a continuous oxygen and energy supply and, therefore, continuous blood flow is mandatory. To guarantee an uninterrupted adequate cerebral circulation despite changes in cerebral perfusion pressure brain perfusion is autoregulated. This so called cerebrovascular autoregulation (CA) maintains a constant cerebral blood flow (CBF) within a wide range of cerebral perfusion pressure and it is thus a key component of cerebral hemostasis.1-3 Particularly cerebrovascular diseases are associated with CA disturbances. In stroke patients, impaired CA correlates with a deteriorated clinical outcome and higher rates of secondary complications, such as increased infarct size, hemorrhagic infarct transformation, or progressive brain edema as a consequence of unregulated CBF fluctuations.4-6 The aim of the presented study was to investigate CA status immediately after successful tissue reperfusion by mechanical thrombectomy and to objectify CA time course in the investigated stroke patients with a prolonged need for analgosedation. Hypothesis: CA remains intact or recovers quickly when cerebral local perfusion is successfully restored by early mechanical thrombectomy.
Materials and Methods Patients After approval of the local ethics committee (Justus Liebig University, Giessen, Germany, No. 185/16) consecutive patients with large vessel occlusive stroke (distal internal carotid artery or proximal middle cerebral artery [MCA]) were included in the presented prospective, observational cohort study. Posterior circulation strokes were not enrolled. Requirements for study participation were an age older than 18 years, the need for invasive blood pressure management and the treatment on neurological intensive care unit (NICU). Exclusion criteria were pregnancy and the inability to insonate intracranial vessels. The informed consent of the patient or the legal representative was obtained before individual data were entered into the analysis. After presentation in the emergency room, all patients were physically examined and received computed tomography (CT) of the head, including CT angiography. In case of large vessel occlusion, the absence of an intracranial hemorrhage and respective contraindications against recombinant tissue plasminogen activator as well as a time window less than 4.5 hours, intravenous thrombolysis was initiated in a weight-adjusted dose of .9 mg/kg body weight. Hereafter, all patients were anesthetized, intubated and mechanically ventilated for mechanical thrombectomy procedure, as the standard operating procedure at that time. Previous studies in patients under general anesthesia and after traumatic brain injury showed that CA was preserved in patients treated with
propofol. Therefore, propofol was preferred for sedation in the investigated cohort.7,8 Mechanical recanalization was achieved via interventionalists with stent retriever systems (phenox pRESET thrombectomy device, phenox GmbH, Bochum, Germany or ERIC retrieval device, MicroVention Inc, Tustin, CA). The use of the different stent retrievers varied according to physician’s preference. Successful thrombectomy was defined as a thrombolysis in cerebral infarction score more than or equal to 2b. Postinterventional, all patients were transferred to the NICU for weaning procedure and extubation trial. CA was measured after arrival at the NICU during patients’ weaning time period. Patients who failed weaning trial received a further CT scan. Analgosedation was maintained in case of space-occupying infarctions to reduce brain swelling and intracranial pressure and in case of nonspace-occupying infarctions further weaning trials were performed daily. In these patients CA was measured daily and for a maximum of 4 days. The 4 days observation period was chosen because of major infarct remodeling processes and infarct size evolution during that time course. According to institutional standard operating procedure targeted MAP was above 65 mm Hg and maximum systolic blood pressure below 160 mm Hg. Acute physiology and chronic health evaluation score, along with the sequential organ failure assessment score were calculated. Additionally, the following data were recorded: National Institutes of Health Stroke Scale, modified ranking scale (mRS) at hospital discharge; days in NICU and days in hospital. Two experienced observers (M.J., T.B.) also independently evaluated CT scans. The latest scan (average time: 7 days) was used for registration and planimetric quantification of acute ischemic lesion volumes, determined by infarct area in each CT slice and the slice thickness.9
Calculation of Cerebrovascular Autoregulation Index Mxa CA was measured using transcranial Doppler ultrasound with bilateral temporal attached 2-MHz Doppler probes, fixed with a special frame (DiaMon, Compumedics DWL, Singen, Germany). CBF velocity (CBFV) was detected via the insonation of the MCA (Doppler-Box, Compumedics DWL, Singen, Germany). Invasive arterial blood pressure was measured in the radial artery (M10006B/MP70, Philips Medical Systems, Eindhoven, Netherlands), digitally converted and synchronically recorded with CBFV (Doppler-Box). Calculation of CA index Mxa was performed afterwards. Mean arterial blood pressure (MAP) and mean CBFV were averaged every 6 seconds. Then, averaged values were correlated and calculated as Pearson’s correlation index expressed as the CA index Mxa in 3-minute intervals and in total over the measurement period of 45 minutes. Mxa ranges from 1 to +1. Positive Mxa values more than .3 indicate a
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relevant association between MAP fluctuations and CBF and therefore an impaired CA; negative values point to the MAP independent CBF and signify an intact CA; while values between 0 and .3 did not permit a statement to integrity of CA.1012 The impairment of CA was assumed at Mxa more than .3 as previously described in traumatic brain injury and septic patients.10,13 Described calculations were done using MATLAB R2015a (maci64, The MathWorks, Inc, Natick, MA).
volume (P = .086), nor with mRS (P = .59). The outcome parameter mRS in successful recanalization group was 3.4 § 1.8 and significant better than in no recanalization group with 5.1 § 1.7 (P= .044). There were no differences between both groups in physiological parameters including paCO2, vital signs, CBFV, used analgosedative drug doses and catecholamine doses (Tables 1 and 2a and b). During the 4-day follow-up, in patients who failed weaning trial or stayed analgosedated due to infarct size or other complications like pneumonia, Mxa did not change substantially (Fig 2). Patients with larger stroke volumes were significant longer mechanical ventilated (P = .019).
Statistical Analysis Patients were assigned to successful recanalization group and no recanalization group. Sample size calculation was done using Student’s t test for independent groups, estimating a relevant clinically difference in Mxa between both groups of .3. A power of .8, a significance level of .05 and an estimated standard deviation of .2 revealed nine patients in each group. To guarantee a sample size of 9 patients per group 20 patients needed to be investigated. Raw datasets were described as mean § standard deviation or median with minimum and maximum values. Differences between the groups were analyzed with a 2-sided Student’s t test, and secondary parameters were analyzed via Student’s t test and Pearson’s correlation. Statistical analyses were calculated using SPSS (version 24, IBM Corporation, Armonk, NY). A significance level with P < .05 was considered to be statistically significant.
Results Twenty patients (8 male, 12 female) with a mean age of 77 § 9 years were included in the present study. Fifteen patients suffered occlusion of the MCA (7 right, 8 left) and 5 patients occlusion of the distal internal carotid artery (2 right, 3 left). Seventeen patients were subjected to local thrombectomy, and 10 of them additionally received systemic thrombolysis therapy with recombinant tissue plasminogen activator (successful recanalization group = 6 patients, no recanalization group = 4 patients) prior to thrombectomy. Ten patients with thrombolysis in cerebral infarction score more than or equal to 2b were subjected to successful recanalization group and 7 patients with unsuccessful and 3 without interventional procedure were assigned in no recanalization group. Both groups were comparable in age, sex, National Institutes of Health Stroke Scale, acute physiology and chronic health evaluation score (Table 1). Directly postinterventional, CA was impaired in both groups. In successful recanalization group Mxa was .58 § .21 at stroke side (ipsilateral hemisphere) and .50 § .20 at the contralateral hemisphere (Fig 1). In no recanalization group only the contralateral MCA could be insonated and showed a Mxa of .45 § .24 with no significant differences between the both groups (P = .59). Level of Mxa, and thus the extent of CA impairment, did not correlate with infarct
Table 1. Physiological data and outcome parameters P values No Successful recanalization recanalization (n = 10) (n = 10) Age Sex (masculine/ feminine) Stroke side (right/left) Vessel occlusion (ICA/M1/M2) Size (cm) Weight (kg) BMI (kg/m2) Arterial hypertension (n) Diabetes mellitus (n) Heart failure (n) Atrial fibrillation (n) Hyperlipidemia (n) Coronary artery disease (n) NIHSSz APACHE II SOFA paCO2 mRSy Stroke volume (cm3) Days in ICU (d) Days in hospital (d)
76.1 § 9.2 4/6
78.2 § 9.6 4/6
5/5
4/6
3/5/2
2/7/1
173 § 10 78 § 10 26.0 § 2.0 8
169 § 9 76 § 13 26.7 § 4.8 8
1
1
0 6
4 5
4
3
1
2
19.8 § 10.9 23.5 § 3.2 9.2 § 2.8 38.2 § 7.7 3.4 § 1.8 81 § 67
14.8 § 5.4 23.9 § 5.7 10.0 § 2.5 38.5 § 9.3 5.1 § 1.7 197 § 168
.211 .848 .507 .948 .044* .072
17 [2-28] 20 [10-28]
14 [2-46] 15 [2-46]
.984 .648
.623
.347 .736 .644
Abbreviations: ICA, internal carotid artery; M1, mean cerebral artery, segment 1; M2, mean cerebral artery, segment 2. The number of patients in the groups were presented as count (n). Parameters are expressed as mean § standard deviation or median and (minimum-maximum). *P < .05. † At hospital discharge. ‡ At hospital admission.
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Figure 1. The figure represents cerebrovascular autoregulation index Mxa in patients with succsessful mechanical thrombectomy (successful recanalization) and with unsuccessful thrombectomy (no recanalization). Values are expressed as box-plot with median (line), IQR (box), and range (whiskers). Gray box represents infarction side and white boxes the unaffected hemisphere.
In successful recanalization group, 2 patients and in no recanalization group 7 patients died during their ICU stay. One of the deceased no recanalization group patients suffered a malignant hemorrhagic infarct transformation.
Discussion CA is impaired in patients after large vessel occlusive stroke irrespective of successful vascular recanalization by mechanical thrombectomy. This finding was more pronounced on the ipsilateral hemisphere, but was also detectable on the contralateral hemisphere. The present study, including patients from a representative stroke collective, revealed that CA was impaired in both groups—the no recanalization group as described
earlier but also in patients following successful mechanical recanalization.5,6,14,15 Disturbed CA leads to a passive, perfusion pressure dependent CBF and may be a major factor for secondary complications like hemorrhagic infarct transformation and post infarct edema.4 An observational study investigating successful recanalized patients after thrombectomy showed that systolic blood pressure above 159 mm Hg worsens patients’ outcome.16 Possibly, this deteriorated outcome may be caused due to the impaired CA and consecutive cerebral hyperperfusion. In view of this, strict blood pressure management even after successful thrombectomy seems of utmost importance. CA impairment after mechanical thrombectomy may be also caused by reperfusion injury. The interaction of inflammatory mechanisms, an activation of the complemental system, platelet activation, and reactive oxygen species can lead to secondary tissue damages after successful reperfusion.17-21 In the present study CA was impaired in both hemispheres, which was in accordance with several previously reported investigations.6,15,20 The phenomenon of transhemispheral diaschisis or systemic inflammatory processes are discussed as possible mechanisms of bilateral CA changes.20,22-24 The sequence of ischemia and reperfusion, which also exists in successfully treated patients, triggers inflammation and possibly leads to the observed impairment of CA in both hemispheres. In a previous study focusing on 16 MCA territory stroke patients with thrombolysis therapy, CA was measured 3 times over 5 days. In patients with poor outcome CA was impaired, while it was preserved in patients with recanalization and small infarct sizes.5 In contrast, the present study showed that CA was also impaired in patients with good clinical outcomes following mechanical thrombectomy without a correlation between the ischemic lesion volume and the level of Mxa. Potentially, also the mechanical vessel irritation itself may influence CA in the presented collective. Clinical outcome and the level of CA were considered in various ways, and a relationship between the degree of CA disorder and the clinical outcome has been demonstrated.5,6,23 In the present investigation, the level of Mxa and thereby the degree of
Table 2a. Time course in patients with successful recanalization
n SOFA MAP (mm Hg) Heart rate (min1) CBFVmean ipsilateral (cm/s) CBFVmean contralateral (cm/s) Mxa ipsilteral Mxa contralateral Propofol (mg/kg¢h) Sufentanil (mg/kg¢h) Norepinephrin [mg/kg¢min]
Day 1
Day 2
Day 3
Day 4
10 9.2 § 2.8 81 § 15 68 § 18 39 § 13 38 § 13 .58 § .21 .50 § .20 2.6 § 1.1 (n = 9) .30 § .2 (n = 8) .09 § .06 (n = 8)
7 10 § 3 83 § 15 73 § 22 49 § 15 52 § 17 .66 § .17 .48 § .35 2.1 § .8 (n = 6) .31 § .2 (n = 6) .10 § .1 (n = 5)
6 12 § 2 78 § 17 77 § 23 58 §13 41 § 8 .64 § .21 .44 § .34 1.7 § 1.0 (n = 5) .37 § .2 (n = 4) .15 § .1 (n = 5)
4 10 § 6 81 § 8 74 § 22 45 § 18 43 § 11 .48 § .36 .18 § .52 1.9 § 1.0 (n = 4) .39 § .2 (n = 4) .12 § .08 (n = 4)
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Table 2b. Time course in patients with no recanalization
n SOFA MAP (mm Hg) Heart rate (min1) CBFVmean ipsilateral (cm/s) CBFVmean contralateral (cm/s) Mxa ipsilteral Mxa contralateral propofol (mg/kg¢h) sufentanil (mg/kg¢h) norepinephrin (mg/kg¢min)
Day 1
Day 2
Day 3
Day 4
10 10.0 § 2.5 77 § 15 67 § 14 0 45 § 23 na .45 § .24 2.8 § .9 (n = 9) .24 §.1 (n = 7) .06 § .02 (n = 6)
8 11 § 3 79 § 12 67 § 23 0 49 § 20 na .41 § .33 2.4 § .7 (n = 7) .29 § .1 (n = 4) .10 § .07 (n = 7)
7 11 § 4 76 § 17 84 § 29 0 45 § 15 na .34 § .25 2.2 § 1.0 (n = 4) .26 § .12 (n = 6) .15 § .1 (n = 6)
7 11 § 4 76 § 19 81 § 27 0 55 § 21 na .26 § .28 1.7 § 1.1 (n = 4) .39 § .2 (n = 4) .16 § .1 (n = 5)
Abbreviations: CBFV, cerebral blood flow velocity in mean cerebral artery; MAP, mean arterial blood pressure; Mxa, index of cerebrovascular autoregulation; n, number of patients measured; na, not available. Values in mean § standard deviation.
Figure 2. Time course of cerebrovascular autoregulation index Mxa during the first 4 days after stroke in patients with failed weaning. Lines show mean Mxa in successful recanalization group (solid line: infarction side, dashed line: unaffected side) and in unsuccsessful recanalization group (pointed line: unaffected side).
impaired CA was not associated with clinical outcome parameters. This may be due to the observational character of the study, which resulted in the withdrawal of curative therapy in 9 of 20 patients, because their relatives/ legal representatives surmised permanent serious neurological deficits. This did not allow for a severity-based outcome analysis. Interpreting the follow-up measurements, patients with effective weaning ruled out. Therefore, follow-up data from day 2 to 4 are only descriptive and represent patients with large infarct sizes or other complications like pneumonia. CA did not recover in these patients most likely due to brain swelling or systemic inflammation. Therefore, maintaining a stable CBF by tight blood pressure management is of great relevance to avoid secondary brain damages.
Conclusions Patients with major vessel occlusions experience the impairment of CA after ischemia independent of successful recanalization by mechanical thrombectomy. With CA impairment, brain is more susceptible to cerebral hyper- or hypoperfusion. Therefore, consequent blood pressure monitoring and management seems to be an essential measure in post-thrombectomy stroke treatment.
Statements of Ethics The present study was approved by the ethics committee of the Justus Liebig University, Giessen, Germany (No. 185/16). The informed consent of the patient or the
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legal representative was obtained before individual data were entered into the analysis.
Authors’ Contributions M.M., I.S., and P.S.: conceptualization. M.M. and P.S.: Data collection. M.M., M.J., T.B., and P.S.: Analysis of the data and statistics. C.T., M.M., and P.S.: Preparation of original draft. All authors: Review and editing.
Conflict of Interest Kristin Engelhard was supported by Covidien AG. Remaining authors have no conflicts of interest to declare.
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