Intra-arterial Administration of Papaverine during Mechanical Thrombectomy for Acute Ischemic Stroke Gerasimos Baltsavias, MD,* Susmitha Yella, MD,* Rahman Abdul Al Shameri, MD,† Andreas Luft, MD,‡ and Anton Valavanis, MD*
Background: The use of stent retrievers for mechanical thrombectomy in acute ischemic stroke may induce significant vasospasm, which at the early phases of reperfusion may be crucial for rethrombosis of the recanalized vessel. We aimed to study whether the use of intra-arterial papaverine in selected cases of vasospasm was associated with improved cerebral perfusion, arterial reocclusion, or increased hemorrhagic complications. Methods: We retrospectively studied 9 consecutive patients with large artery acute occlusion, treated with stent retriever and intraarterial papaverine. Onset to administration of intravenous recombinant tissueplasminogen activator time, baseline National Institute of Health Stroke Scale, time to reperfusion, number of passes of the stent retriever, modified Rankin Scale score at discharge, postprocedural hemorrhage, onset to reperfusion time, papaverine dose, and thrombolysis in cerebral infarction grade were recorded in all patients. Results: After papaverine administration, the caliber of the infused arteries and their flow was increased in all cases. In none of the treated cases a reocclusion occurred after papaverine infusion. In one of the studied patients (11%), a parenchymal bleeding occurred 36 hours postoperatively. Conclusions: This small study suggests that intra-arterial infusion of papaverine for the treatment of cerebral vasospasm after mechanical thrombectomy in acute ischemic stroke is effective and safe. Key Words: Acute ischemic stroke—mechanical thrombectomy—stent retriever—vasospasm—papaverine. Ó 2015 by National Stroke Association
Introduction In case of a large artery occlusion, the recanalization efficacy of intravenous (IV) recombinant tissueplasminogen activator (rt-PA) has been shown to be poor compared with intra-arterial rt-PA.1-6
From the *Department of Neuroradiology, University Hospital Zurich, Zurich, Switzerland; †Department of Neurosurgery, Ch. Doppler Medical Center, Salzburg, Austria; and ‡Department of Neurology, University Hospital Zurich, Zurich, Switzerland. Received May 2, 2014; revision received July 13, 2014; accepted July 27, 2014. Address correspondence to Gerasimos Baltsavias, MD, Department of Neuroradiology, University Hospital Zurich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland E-mail: Gerasimos.Baltsavias@ usz.ch. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.052
The use of mechanical devices, such as stent retrievers for blood flow restoration, has gained importance during recent years and large vessel occlusions became a target of endovascular treatment.7-11 However, the use of stent retrievers and especially multiple passes of the device may induce significant vasospasm, which in the early phases of reperfusion may be crucial for rethrombosis of the recanalized vessel. Use of vasodilator agents in this context may decisively improve the re-established perfusion by fast and effective elimination of vasospasm. The role of these vasodilator agents has been evaluated in cases of cerebral vasospasm secondary to subarachnoid hemorrhage,12-16 but there have been only a few studies evaluating their role in ischemic stroke.17-27 The reports about the use of vasodilators during intra-arterial treatment of stroke suggested that it might be associated with higher reperfusion rates, but clinical outcomes were not significantly different.22 We aimed to study whether the combination of
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 1 (January), 2015: pp 41-47
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mechanical thrombectomy with intra-arterial papaverine in selected cases of vasospasm was associated with improved cerebral perfusion, arterial re-occlusion, or increased hemorrhagic complications.
Patients and Methods We retrospectively studied consecutive patients admitted from January 2012 to January 2014 with large artery acute occlusion and treated by mechanical thrombectomy with stent retriever and received intra-arterial papaverine as an adjunct to endovascular treatment. The indication of treatment with intra-arterial thrombectomy was based on the established criteria regarding time after onset and on the presence of a mismatch in perfusion imaging. Demographic and clinical characteristics of the patients were collected from the electronic case records. Digital angiography was performed under general anesthesia in all cases. Patients were treated with mechanical thrombectomy, by using the same stent retriever (Solitaire 2 Revascularization Device, ev3/Covidien, Irvine, CA). The decision to use papaverine was taken after detection of vasospasm induced by mechanical thrombectomy in the previously occluded segment and/or proximal to it, with evidence or suspicion of progressive flow reduction or delay in consecutive angiographic controls. Depending on the localization and extension of vasospasm, papaverine was infused through the guiding catheter or the microcatheter used for stent deployment. Papaverine was prepared as a solution of 300 mg in 100 mL of normal saline and infused with a rate of approximately 30 mg/minute. The amount of infused papaverine was determined by the response of the spastic vessels, and no fixed protocol was followed. Thrombolysis in cerebral infarction (TICI) criteria were used for evaluation of the degree of recanalization before and after treatment with papaverine.14 For this retrospective study, no institutional review board approval was necessary.
Results We identified 9 consecutive patients, 4 women and 5 men aged from 38 to 76 years (mean age, 58.1 years). Patients included in this study underwent endovascular therapy within 190-380 minutes (mean, 344 minutes) from the onset of symptoms. All patients showed angiographic evidence of significant vasospasm appearing during the procedure. Seven patients had a middle cerebral artery (MCA) occlusion, 1 patient had MCA and cervical internal carotid occlusion with evidence of chronic stenosis at the carotid bifurcation (case 5), and 1 additional patient had basilar occlusion. IV rt-PA was given to patients who presented within the 4.5 hours time window. Eight patients received IV rt-PA, whereas 1 patient (case 4) did not receive any IV rt-PA because he developed ischemia 6 hours after cardiac
surgery while on anticoagulation. The period from the onset of symptoms till administration of IV rt-PA, baseline National Institute of Health Stroke Scale, time to reperfusion, number of passes of the stent retriever, modified Rankin Scale at the time of discharge, postprocedural hemorrhage, onset to reperfusion time, papaverine dose, and TICI flow grade are summarized in Table 1. In 1 patient, remarkable vasospasm appeared after 1 stent pass, whereas in the rest of the patients, vasospasm appeared after 2-5 passes of the stent. The administered dose of papaverine ranged from 45 to 120 mg. In all cases, a full reperfusion of occluded branches (TICI grade 3 or 2b) was achieved before infusion of papaverine. After papaverine administration, the caliber of the infused arteries and their flow was clearly increased in all cases. In none of the treated cases a reocclusion occurred after papaverine infusion. In 1 patient (patient 3), a parenchymal bleeding occurred 36 hours postoperatively (11%). Another patient (patient 4) presented a small subarachnoid bleeding within 24 hours, clearly attributed to mechanical manipulations during deployment of the stent retriever. Illustrative cases: The angiographic images of 2 cases are presented shortly in Figures 1 and 2.
Discussion Calcium channel blockers (nimodipine, Nicardipine) and some peripheral vasodilators such as papaverine have been used for treatment of vasospasm after subarachnoid hemorrhage,28-36 but its use in ischemic stroke is poorly studied. Cilostazol was found to protect against ischemic brain injury and hemorrhagic transformation after transient ischemic stroke in animal studies, and sildenafil has been reported to improve cerebral perfusion in the early phase of recovery after stroke. Isosteviol has been demonstrated to have protective effects against ischemia–reperfusion injury in animal studies.17-19 Papaverine is a benzylisoquinoline alkaloid derived from opium. It has been used as a vasodilator agent for over 70 years to treat cerebral and coronary artery vasospasm.28 This powerful vasodilator acts by inhibiting cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterases in smooth muscle, leading to increased intracellular levels of cAMP and cGMP.29 Also it blocks the calcium ion channels and inhibits release of calcium. The half-life of papaverine has been estimated to be .8 hours. Rosenbaum et al23 reported on a pilot study about the safety of nicardipine for acute ischemic stroke, administered within a mean of 6.9 hours from onset, and recommended a larger study for evaluating its efficacy. Another pilot study from Japan by Shiino et al25 in animal models with calcium channel blockers (nilvadipine and nicardipine) showed that in the nilvadipine-treated
Onset to IV rt-PA, NIHSS IV rtCase min Location score PA IA rt-PA number Age Sex 1 2 3 4 5 6 7 8 9
71 48 38 67 57 49 68 49 76
F F F M M M M F M
225 210 240 Ny 210 NA 140 70 210
R MCA BA L MCA L MCA R MCA R MCA ICA T R MCA L MCA
16/42 NA 15/42 NA 6/42 8/42 21/42 13/42 25/42
35 45 55 N 23 16 30 18 70
N N N N N N N N N
mRS score
Time to reperfusion, min S/PTA S S S S S 1 Carotid stent S 1 Carotid stent S S S
O to Passes R, min 5 2 1 3 2 4 3 2 2
385 280 355 450 360 375 335 230 325
First
Last
20 20 20 30 40 16 17 30 53
105 40 35 70 60 110 110 40 109
TICI Papaverine Postoperative A score dose, mg H 2b 3 3 3 3 3 2b 3 2b
90 120 90 100 90 90 100 90 60
N N Y (.36 h) SAH (,24 h) Nz N N N N
5/6 5/6 5/6 NA 3/6 3/6 5/6 4/6 5/6
D Death NA 0/6 NA NA 0/6 1/6 6/6 0/6 0/6
Y* N N N N N Yx N N
PAPAVERINE IN MECHANICAL THROMBECTOMY
Table 1. The studied population.
Abbreviations: A, admission; BA, basilar artery; D, discharge; F, female; H, hemorrhage; IA, intra-arterial; ICA, internal carotid artery; IV, intravenous; L, left; M, male; MCA, middle cerebral artery; mRS, modified Rankin Scale; N, no; NA, not available; NIHSS, National Institute of Health Stroke Scale; O to R, onset to reperfusion; PTA, percutaneous transluminal angioplasty; R, right; rt-PA, recombinant tissue-plasminogen activator; S, Solitaire stent; SAH, subarachnoid hemorrhage; T, termination; TICI, thrombolysis in cerebral infarction; Y, yes. *Subtle hemorrhagic transformation of a small basal ganglionic infarct at the fourth postoperative day. yDeath due to septicemia after cholelithiasis operation. zNo rt-PA IV due to infarction after cardiac operation. xDeath due to malignant brain edema after large infarction.
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Figure 1. Case 2. Left vertebral injections show an acute basilar artery occlusion (left), reperfused after thrombectomy with stent retriever (middle). Vasospasm of P1 segment of posterior cerebral artery bilaterally and distal vertebral artery considerably improved after intra-arterial papaverine infusion (right).
group, neurologic deficits improved more rapidly, and the size of the infarct was significantly smaller than in the nicardipine-treated group. The additional use of calcium channel blocker in patients with acute ischemic stroke, mechanical thrombectomy, and primary angioplasty with and without thrombolytic agents showed a favorable outcome in up to 40% of patients and no case of worsening in a series of 10 cases by Shah et al.28 A recent study on the use of calcium channel blockers along with mechanical thrombectomy showed a positive association between vasodilator infusion and higher rate of reperfusion, but failed to show a significant improvement in clinical outcome.22 Papaverine hydrochloride dilates cerebral vessels, and its use as a vasodilator in cerebrovascular disease has been first proposed by Russek et al in 1948.37 Subsequently, Allcock38 confirmed angiographically the reversal of vasospasm induced by hyperventilation or intracarotid infusion of serotonin after an intracarotid papaverine injection and also in a canine model angiographically with 15 mg of papaverine. There have been a number of clinical series reporting variable efficacy of papaverine in the treatment of vasospasm after subarachnoid hemorrhage. In these studies, the use of papaverine for the maximal dose of 300 mg per vascular territory is reported to result in angiographic response in 80%-95% and in clinical response in 50%-75% of cases with minimal side effects. It increases the vessel diameter angiographically, improves the mean circulation time, and improves cerebral oxygenation.34-36 In addition, recent reports
suggest that papaverine may have a potential neuroprotective effect when used locally.39,40 Reported complications with intra-arterial administration of papaverine include rapid increases in intracranial pressure, transient neurologic deficits, including mydriasis and brain stem depression, monocular blindness, seizures, thrombocytopenia, precipitation of crystal emboli during infusion, and paradoxical exacerbation of vasospasm leading to cerebral infarction.40-44 Superselective intra-arterial infusion might limit the required dose and reduce the systemic side effects of hypotension. Sawada et al33 showed that a highly concentrated dose of papaverine has a higher risk of emboli due to precipitation. Polin et al45 suggested that the time of drug administration would be a determining factor and a slower rate of infusion to avoid complications has been recommended. The complications of papaverine can be avoided by using a slower infusion rate and lesser concentrations to avoid precipitation and crystal formation and thus emboli.46 The use of devices in mechanical thrombectomy may increase the incidence of vasospasm.7,47,48 A singlecenter study with 108 recanalization procedures using the Solitaire retriever showed occurrence of vasospasm in 14 of 108 (13%) of the target vessels. Despite occurrence of vasospasm, clinical outcome of these patients did not change.49 In another clinical study of cerebral vasospasm after mechanical thrombectomy with the Merci device (Concentric Medical, Mountain View, CA), the authors treated the vasospasm with intra-arterial administration of nicardipine in 2 cases, and they concluded that
Figure 2. Case 8. Right carotid injection (left) shows an acute MCA occlusion, which was recanalized after stent retrieval, but had remarkable vasospasm (middle), treated subsequently with local papaverine infusion (right).
PAPAVERINE IN MECHANICAL THROMBECTOMY
vasospasm after mechanical thrombectomy may be responsible for lower recanalization grades.50 The usage of stent retrievers allows immediate perfusion by opening up a channel and thus decreases the reperfusion time, which is an important predictor for a good clinical outcome.9 An important factor related to successful recanalization is the number of passes required for good flow restoration. In a systematic review about the safety and efficiency of mechanical thrombectomy with Solitaire stents, Koh et al showed that the mean number of passes for maximal recanalization was 1.4-2.5.51 In our study, we have used papaverine in a dosage ranging from 45-120 mg with a slow infusion rate of approximately 30 mg/minute. This dose was defined empirically, based on the response of the infused vessels. Thereby, potential side effects and complications as hypotension, hemorrhage, emboli, or others may be minimized. The mean number of passes of the device were 2.6 (range, 1-5) with mean number of passes for all our acute stroke cases treated with Solitaire being between 2 for MCA occlusions and 2.5 for internal carotid artery–MCA occlusions. This higher number is because of the higher number of passes required in a single case (5 passes). As the number of passes increases, the chance to induce vasospasm increases together with time to reperfusion. However, the vasospasm observed in our cases seemed to be independent of the number of device passes as it was seen in a case even after a single application. The effectiveness of the small dose can be explained by the fact that vasospasm after stent retriever thrombectomy is mechanically induced. Spasms of this kind, which occur frequently during endovascular procedures, are benign and short lasting and therefore, do not require treatment. In the context of acute stroke, the role and significance of the even short-lasting vasospasm might be different. Our rationale of papaverine use was related to the risk of rethrombosis of an artery, which was previously occluded and immediately after reperfusion presents considerable vasospasm with signs of delayed flow, possibly heralding a reocclusion. Use of alternative means, as balloon angioplasty, taking into account the nature of the vasospasm (mechanically induced, short lasting, often affecting a long arterial segment) in combination with the risks and costs of this invasive procedure, was not deemed advantageous. We consider a causative relation of the administered papaverine with an early or delayed bleeding as unlikely because of its short half-life, although a potential interaction of the drug with the developing tissue ischemia cannot be excluded with certainty. However, the rate of postoperative hemorrhage in this group of patients (11% with the caveat of the low event rate of n 5 1) was very similar to the overall rate for all cases treated with mechanical thrombectomy over the same period (9%).
45
This study shows that the use of intra-arterial vasodilator like papaverine along with mechanical thrombectomy might be of benefit in early reperfusion strategies in cases with significant vasospasm. The very short half-life of the drug may be an advantage for avoidance of interactions, which may increase the probability of hemorrhagic complications. Larger studies evaluating benefits and risks are certainly required.
Conclusion Mechanical thrombectomy using a Solitaire stent in acute ischemic stroke is often effective in recanalizing occluded arteries. Vasospasm after mechanical thrombectomy may increase the risk of rethrombosis. A low dose of papaverine with slow infusion rate is effective for the treatment of vasospasm and may benefit the patient by increasing the perfusion and decreasing the likelihood of reocclusion in selected cases. This small retrospective study suggests that intra-arterial infusion of papaverine for the treatment of cerebral vasospasm after mechanical thrombectomy in acute ischemic stroke is effective and safe.
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28. Liu JK, Tenner MS, Gottfried ON, et al. Efficacy of multiple intraarterial papaverine infusions for improvement in cerebral circulation time in patients with recurrent cerebral vasospasm. J Neurosurg 2004;100:414-421. 29. Lugnier C, Stoclet JC. Inhibition by papaverine of cGMP and cAMP phosphodiesterases from the rat heart. Biochem Pharmacol 1974;23:3071-3074. 30. Kaku Y, Yonekawa Y, Tsukahara T, et al. Superselective intra-arterial infusion of papaverine for the treatment of cerebral vasospasm after subarachnoid hemorrhage. J Neurosurg 1992;77:842-847. 31. Kassell NF, Helm G, Simmons N, et al. Treatment of cerebral vasospasm with intra-arterial papaverine. J Neurosurg 1992;77:848-852. 32. Clouston JE, Numaguchi Y, Zoarski GH, et al. Intraarterial papaverine infusion for cerebral vasospasm after subarachnoid hemorrhage. AJNR Am J Neuroradiol 1995; 16:27-38. 33. Sawada M, Hashimoto N, Tsukahara T, et al. Effectiveness of intra-arterially infused papaverine solutions of various concentrations for the treatment of cerebral vasospasm. Acta Neurochir (Wien) 1997;139:706-711. 34. Milburn JM, Moran CJ, Cross DT, et al. Effect of intraarterial papaverine on cerebral circulation time. AJNR Am J Neuroradiol 1997;18:1081-1085. 35. Milburn JM, Moran CJ, Cross DT, et al. Increase in diameters of vasospastic intracranial arteries by intraarterial papaverine administration. J Neurosurg 1998;88:38-42. 36. Fandino J, Kaku Y, Schuknecht B, et al. Improvement of cerebral oxygenation patterns and metabolic validation of superselective intraarterial infusion of papaverine for the treatment of cerebral vasospasm. J Neurosurg 1998; 89:93-100. 37. Russek HI, Zohman BL. Papaverine in cerebral angiospasm (vascular encephalopathy). J Am Med Assoc. 1948 Apr 3;136(14):930-932. 38. Allcock JM. Arterial spasm in subarachnoid haemorrhage. A clinical and experimental study. Acta Radiol Diagn (Stockh) 1966;5:73-82. 39. Brian L, Edward R, Eugene HB, et al. Spinal cord protective strategies during descending and thoracoabdominal aortic aneurysm repair in the modern era: the role of intrathecal papaverine. The 37th Annual Meeting of the Western Thoracic Surgical Association, Colorado Springs. 2011. 40. Kanako I, Tamaki I, Jan K, et al. Potentiation of NGFinduced neurite outgrowth in PC12 cells by papaverine: role played by PLC-g, IP3 receptors. Brainresearch 2011; 1377:32-40. 41. McAuliffe W, Townsend M, Eskridge JM, et al. Intracranial pressure changes induced during papaverine infusion for treatment of vasospasm. J Neurosurg 1995; 83:430-434. 42. Hendrix LE, Dion J, Jenson ME, et al. Papaverine-induced mydriasis. AJNR Am J Neuroradiol 1994;15:716-718. 43. Barr JD, Mathis JM, Horton JA. Transient severe brain stem depression during intraarterial papaverine infusion for cerebral vasospasm. AJNR Am J Neuroradiol 1994; 15:719-723. 44. Miller JA, Cross D, Moran CJ, et al. Severe thrombocytopenia following intraarterial papaverine administration for treatment of vasospasm. J Neurosurg 1995; 83:435-437. 45. Polin RS, Hansen C, German P, et al. Intra-arterially administered papaverine for the treatment of symptomatic cerebral vasospasm. Neurosurgery 1998;42:1256-1264.
PAPAVERINE IN MECHANICAL THROMBECTOMY 46. Mathis JM, Jensen ME, Dion JE. Technical considerations on intraarterial papaverine hydrochloride for cerebral vasospasm. Neuroradiology 1997;39:90-98. 47. Rishi G. Arterial vasospasm during mechanical thrombectomy for acute stroke. J Neuroimaging 2009; 19:61-64. 48. Gralla J, Schroth G, Remonda L, et al. Mechanical thrombectomy for acute ischemic stroke: thrombus-device interaction, efficiency, and complications in vivo. Stroke 2006;37:3019-3024.
47 49. Dorn F, S.S., Lockau H, et al. Endovascular Treatment of Acute Intracerebral Artery Occlusions with the Solitaire Stent: Single-Centre Experience with 108 Recanalization Procedures. Cerebrovasc Dis 2012;34:70-77. 50. Gupta R. Arterial vasospasm during mechanical thrombectomy for acute stroke. J Neuroimaging 2009;19(1):61-64. 51. JS Koh, Lee SJ, Ryu CW, Kim HS. Safety and efficacy of mechanical thrombectomy with solitaire stent retrieval for acute ischemic stroke: a systematic review. Neurointervention 2012;7(1):1-9.
Background: The use of stent retrievers for mechanical thrombectomy in acute ischemic stroke may induce significant vasospasm, which at the early phases of reperfusion may be crucial for rethrombosis of the recanalized vessel. We aimed to study whether the use of intra-arterial papaverine in selected cases of vasospasm was associated with improved cerebral perfusion, arterial reocclusion, or increased hemorrhagic complications. Methods: We retrospectively studied 9 consecutive patients with large artery acute occlusion, treated with stent retriever and intraarterial papaverine. Onset to administration of intravenous recombinant tissueplasminogen activator time, baseline National Institute of Health Stroke Scale, time to reperfusion, number of passes of the stent retriever, modified Rankin Scale score at discharge, postprocedural hemorrhage, onset to reperfusion time, papaverine dose, and thrombolysis in cerebral infarction grade were recorded in all patients. Results: After papaverine administration, the caliber of the infused arteries and their flow was increased in all cases. In none of the treated cases a reocclusion occurred after papaverine infusion. In one of the studied patients (11%), a parenchymal bleeding occurred 36 hours postoperatively. Conclusions: This small study suggests that intra-arterial infusion of papaverine for the treatment of cerebral vasospasm after mechanical thrombectomy in acute ischemic stroke is effective and safe. Key Words: Acute ischemic stroke—mechanical thrombectomy—stent retriever—vasospasm—papaverine. Ó 2015 by National Stroke Association
Introduction In case of a large artery occlusion, the recanalization efficacy of intravenous (IV) recombinant tissueplasminogen activator (rt-PA) has been shown to be poor compared with intra-arterial rt-PA.1-6
From the *Department of Neuroradiology, University Hospital Zurich, Zurich, Switzerland; †Department of Neurosurgery, Ch. Doppler Medical Center, Salzburg, Austria; and ‡Department of Neurology, University Hospital Zurich, Zurich, Switzerland. Received May 2, 2014; revision received July 13, 2014; accepted July 27, 2014. Address correspondence to Gerasimos Baltsavias, MD, Department of Neuroradiology, University Hospital Zurich, Frauenklinikstrasse 10, 8091, Zurich, Switzerland E-mail: Gerasimos.Baltsavias@ usz.ch. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.07.052
The use of mechanical devices, such as stent retrievers for blood flow restoration, has gained importance during recent years and large vessel occlusions became a target of endovascular treatment.7-11 However, the use of stent retrievers and especially multiple passes of the device may induce significant vasospasm, which in the early phases of reperfusion may be crucial for rethrombosis of the recanalized vessel. Use of vasodilator agents in this context may decisively improve the re-established perfusion by fast and effective elimination of vasospasm. The role of these vasodilator agents has been evaluated in cases of cerebral vasospasm secondary to subarachnoid hemorrhage,12-16 but there have been only a few studies evaluating their role in ischemic stroke.17-27 The reports about the use of vasodilators during intra-arterial treatment of stroke suggested that it might be associated with higher reperfusion rates, but clinical outcomes were not significantly different.22 We aimed to study whether the combination of
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 1 (January), 2015: pp 41-47
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mechanical thrombectomy with intra-arterial papaverine in selected cases of vasospasm was associated with improved cerebral perfusion, arterial re-occlusion, or increased hemorrhagic complications.
Patients and Methods We retrospectively studied consecutive patients admitted from January 2012 to January 2014 with large artery acute occlusion and treated by mechanical thrombectomy with stent retriever and received intra-arterial papaverine as an adjunct to endovascular treatment. The indication of treatment with intra-arterial thrombectomy was based on the established criteria regarding time after onset and on the presence of a mismatch in perfusion imaging. Demographic and clinical characteristics of the patients were collected from the electronic case records. Digital angiography was performed under general anesthesia in all cases. Patients were treated with mechanical thrombectomy, by using the same stent retriever (Solitaire 2 Revascularization Device, ev3/Covidien, Irvine, CA). The decision to use papaverine was taken after detection of vasospasm induced by mechanical thrombectomy in the previously occluded segment and/or proximal to it, with evidence or suspicion of progressive flow reduction or delay in consecutive angiographic controls. Depending on the localization and extension of vasospasm, papaverine was infused through the guiding catheter or the microcatheter used for stent deployment. Papaverine was prepared as a solution of 300 mg in 100 mL of normal saline and infused with a rate of approximately 30 mg/minute. The amount of infused papaverine was determined by the response of the spastic vessels, and no fixed protocol was followed. Thrombolysis in cerebral infarction (TICI) criteria were used for evaluation of the degree of recanalization before and after treatment with papaverine.14 For this retrospective study, no institutional review board approval was necessary.
Results We identified 9 consecutive patients, 4 women and 5 men aged from 38 to 76 years (mean age, 58.1 years). Patients included in this study underwent endovascular therapy within 190-380 minutes (mean, 344 minutes) from the onset of symptoms. All patients showed angiographic evidence of significant vasospasm appearing during the procedure. Seven patients had a middle cerebral artery (MCA) occlusion, 1 patient had MCA and cervical internal carotid occlusion with evidence of chronic stenosis at the carotid bifurcation (case 5), and 1 additional patient had basilar occlusion. IV rt-PA was given to patients who presented within the 4.5 hours time window. Eight patients received IV rt-PA, whereas 1 patient (case 4) did not receive any IV rt-PA because he developed ischemia 6 hours after cardiac
surgery while on anticoagulation. The period from the onset of symptoms till administration of IV rt-PA, baseline National Institute of Health Stroke Scale, time to reperfusion, number of passes of the stent retriever, modified Rankin Scale at the time of discharge, postprocedural hemorrhage, onset to reperfusion time, papaverine dose, and TICI flow grade are summarized in Table 1. In 1 patient, remarkable vasospasm appeared after 1 stent pass, whereas in the rest of the patients, vasospasm appeared after 2-5 passes of the stent. The administered dose of papaverine ranged from 45 to 120 mg. In all cases, a full reperfusion of occluded branches (TICI grade 3 or 2b) was achieved before infusion of papaverine. After papaverine administration, the caliber of the infused arteries and their flow was clearly increased in all cases. In none of the treated cases a reocclusion occurred after papaverine infusion. In 1 patient (patient 3), a parenchymal bleeding occurred 36 hours postoperatively (11%). Another patient (patient 4) presented a small subarachnoid bleeding within 24 hours, clearly attributed to mechanical manipulations during deployment of the stent retriever. Illustrative cases: The angiographic images of 2 cases are presented shortly in Figures 1 and 2.
Discussion Calcium channel blockers (nimodipine, Nicardipine) and some peripheral vasodilators such as papaverine have been used for treatment of vasospasm after subarachnoid hemorrhage,28-36 but its use in ischemic stroke is poorly studied. Cilostazol was found to protect against ischemic brain injury and hemorrhagic transformation after transient ischemic stroke in animal studies, and sildenafil has been reported to improve cerebral perfusion in the early phase of recovery after stroke. Isosteviol has been demonstrated to have protective effects against ischemia–reperfusion injury in animal studies.17-19 Papaverine is a benzylisoquinoline alkaloid derived from opium. It has been used as a vasodilator agent for over 70 years to treat cerebral and coronary artery vasospasm.28 This powerful vasodilator acts by inhibiting cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterases in smooth muscle, leading to increased intracellular levels of cAMP and cGMP.29 Also it blocks the calcium ion channels and inhibits release of calcium. The half-life of papaverine has been estimated to be .8 hours. Rosenbaum et al23 reported on a pilot study about the safety of nicardipine for acute ischemic stroke, administered within a mean of 6.9 hours from onset, and recommended a larger study for evaluating its efficacy. Another pilot study from Japan by Shiino et al25 in animal models with calcium channel blockers (nilvadipine and nicardipine) showed that in the nilvadipine-treated
Onset to IV rt-PA, NIHSS IV rtCase min Location score PA IA rt-PA number Age Sex 1 2 3 4 5 6 7 8 9
71 48 38 67 57 49 68 49 76
F F F M M M M F M
225 210 240 Ny 210 NA 140 70 210
R MCA BA L MCA L MCA R MCA R MCA ICA T R MCA L MCA
16/42 NA 15/42 NA 6/42 8/42 21/42 13/42 25/42
35 45 55 N 23 16 30 18 70
N N N N N N N N N
mRS score
Time to reperfusion, min S/PTA S S S S S 1 Carotid stent S 1 Carotid stent S S S
O to Passes R, min 5 2 1 3 2 4 3 2 2
385 280 355 450 360 375 335 230 325
First
Last
20 20 20 30 40 16 17 30 53
105 40 35 70 60 110 110 40 109
TICI Papaverine Postoperative A score dose, mg H 2b 3 3 3 3 3 2b 3 2b
90 120 90 100 90 90 100 90 60
N N Y (.36 h) SAH (,24 h) Nz N N N N
5/6 5/6 5/6 NA 3/6 3/6 5/6 4/6 5/6
D Death NA 0/6 NA NA 0/6 1/6 6/6 0/6 0/6
Y* N N N N N Yx N N
PAPAVERINE IN MECHANICAL THROMBECTOMY
Table 1. The studied population.
Abbreviations: A, admission; BA, basilar artery; D, discharge; F, female; H, hemorrhage; IA, intra-arterial; ICA, internal carotid artery; IV, intravenous; L, left; M, male; MCA, middle cerebral artery; mRS, modified Rankin Scale; N, no; NA, not available; NIHSS, National Institute of Health Stroke Scale; O to R, onset to reperfusion; PTA, percutaneous transluminal angioplasty; R, right; rt-PA, recombinant tissue-plasminogen activator; S, Solitaire stent; SAH, subarachnoid hemorrhage; T, termination; TICI, thrombolysis in cerebral infarction; Y, yes. *Subtle hemorrhagic transformation of a small basal ganglionic infarct at the fourth postoperative day. yDeath due to septicemia after cholelithiasis operation. zNo rt-PA IV due to infarction after cardiac operation. xDeath due to malignant brain edema after large infarction.
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G. BALTSAVIAS ET AL.
Figure 1. Case 2. Left vertebral injections show an acute basilar artery occlusion (left), reperfused after thrombectomy with stent retriever (middle). Vasospasm of P1 segment of posterior cerebral artery bilaterally and distal vertebral artery considerably improved after intra-arterial papaverine infusion (right).
group, neurologic deficits improved more rapidly, and the size of the infarct was significantly smaller than in the nicardipine-treated group. The additional use of calcium channel blocker in patients with acute ischemic stroke, mechanical thrombectomy, and primary angioplasty with and without thrombolytic agents showed a favorable outcome in up to 40% of patients and no case of worsening in a series of 10 cases by Shah et al.28 A recent study on the use of calcium channel blockers along with mechanical thrombectomy showed a positive association between vasodilator infusion and higher rate of reperfusion, but failed to show a significant improvement in clinical outcome.22 Papaverine hydrochloride dilates cerebral vessels, and its use as a vasodilator in cerebrovascular disease has been first proposed by Russek et al in 1948.37 Subsequently, Allcock38 confirmed angiographically the reversal of vasospasm induced by hyperventilation or intracarotid infusion of serotonin after an intracarotid papaverine injection and also in a canine model angiographically with 15 mg of papaverine. There have been a number of clinical series reporting variable efficacy of papaverine in the treatment of vasospasm after subarachnoid hemorrhage. In these studies, the use of papaverine for the maximal dose of 300 mg per vascular territory is reported to result in angiographic response in 80%-95% and in clinical response in 50%-75% of cases with minimal side effects. It increases the vessel diameter angiographically, improves the mean circulation time, and improves cerebral oxygenation.34-36 In addition, recent reports
suggest that papaverine may have a potential neuroprotective effect when used locally.39,40 Reported complications with intra-arterial administration of papaverine include rapid increases in intracranial pressure, transient neurologic deficits, including mydriasis and brain stem depression, monocular blindness, seizures, thrombocytopenia, precipitation of crystal emboli during infusion, and paradoxical exacerbation of vasospasm leading to cerebral infarction.40-44 Superselective intra-arterial infusion might limit the required dose and reduce the systemic side effects of hypotension. Sawada et al33 showed that a highly concentrated dose of papaverine has a higher risk of emboli due to precipitation. Polin et al45 suggested that the time of drug administration would be a determining factor and a slower rate of infusion to avoid complications has been recommended. The complications of papaverine can be avoided by using a slower infusion rate and lesser concentrations to avoid precipitation and crystal formation and thus emboli.46 The use of devices in mechanical thrombectomy may increase the incidence of vasospasm.7,47,48 A singlecenter study with 108 recanalization procedures using the Solitaire retriever showed occurrence of vasospasm in 14 of 108 (13%) of the target vessels. Despite occurrence of vasospasm, clinical outcome of these patients did not change.49 In another clinical study of cerebral vasospasm after mechanical thrombectomy with the Merci device (Concentric Medical, Mountain View, CA), the authors treated the vasospasm with intra-arterial administration of nicardipine in 2 cases, and they concluded that
Figure 2. Case 8. Right carotid injection (left) shows an acute MCA occlusion, which was recanalized after stent retrieval, but had remarkable vasospasm (middle), treated subsequently with local papaverine infusion (right).
PAPAVERINE IN MECHANICAL THROMBECTOMY
vasospasm after mechanical thrombectomy may be responsible for lower recanalization grades.50 The usage of stent retrievers allows immediate perfusion by opening up a channel and thus decreases the reperfusion time, which is an important predictor for a good clinical outcome.9 An important factor related to successful recanalization is the number of passes required for good flow restoration. In a systematic review about the safety and efficiency of mechanical thrombectomy with Solitaire stents, Koh et al showed that the mean number of passes for maximal recanalization was 1.4-2.5.51 In our study, we have used papaverine in a dosage ranging from 45-120 mg with a slow infusion rate of approximately 30 mg/minute. This dose was defined empirically, based on the response of the infused vessels. Thereby, potential side effects and complications as hypotension, hemorrhage, emboli, or others may be minimized. The mean number of passes of the device were 2.6 (range, 1-5) with mean number of passes for all our acute stroke cases treated with Solitaire being between 2 for MCA occlusions and 2.5 for internal carotid artery–MCA occlusions. This higher number is because of the higher number of passes required in a single case (5 passes). As the number of passes increases, the chance to induce vasospasm increases together with time to reperfusion. However, the vasospasm observed in our cases seemed to be independent of the number of device passes as it was seen in a case even after a single application. The effectiveness of the small dose can be explained by the fact that vasospasm after stent retriever thrombectomy is mechanically induced. Spasms of this kind, which occur frequently during endovascular procedures, are benign and short lasting and therefore, do not require treatment. In the context of acute stroke, the role and significance of the even short-lasting vasospasm might be different. Our rationale of papaverine use was related to the risk of rethrombosis of an artery, which was previously occluded and immediately after reperfusion presents considerable vasospasm with signs of delayed flow, possibly heralding a reocclusion. Use of alternative means, as balloon angioplasty, taking into account the nature of the vasospasm (mechanically induced, short lasting, often affecting a long arterial segment) in combination with the risks and costs of this invasive procedure, was not deemed advantageous. We consider a causative relation of the administered papaverine with an early or delayed bleeding as unlikely because of its short half-life, although a potential interaction of the drug with the developing tissue ischemia cannot be excluded with certainty. However, the rate of postoperative hemorrhage in this group of patients (11% with the caveat of the low event rate of n 5 1) was very similar to the overall rate for all cases treated with mechanical thrombectomy over the same period (9%).
45
This study shows that the use of intra-arterial vasodilator like papaverine along with mechanical thrombectomy might be of benefit in early reperfusion strategies in cases with significant vasospasm. The very short half-life of the drug may be an advantage for avoidance of interactions, which may increase the probability of hemorrhagic complications. Larger studies evaluating benefits and risks are certainly required.
Conclusion Mechanical thrombectomy using a Solitaire stent in acute ischemic stroke is often effective in recanalizing occluded arteries. Vasospasm after mechanical thrombectomy may increase the risk of rethrombosis. A low dose of papaverine with slow infusion rate is effective for the treatment of vasospasm and may benefit the patient by increasing the perfusion and decreasing the likelihood of reocclusion in selected cases. This small retrospective study suggests that intra-arterial infusion of papaverine for the treatment of cerebral vasospasm after mechanical thrombectomy in acute ischemic stroke is effective and safe.
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