Clinical Therapeutics/Volume 30, Number 9, 2008 Case Report Decrease in Blood Pressure After Intravenous Administration of Urapidil During Recombinant Tissue Plasminogen Activator Thrombolysis for Acute Ischemic Stroke Jean-Marc Bugnicourt, MD1; C&ile Duru, MD2; Candice Picard, MD2; and Olivier Godefroy, MD, PhD1 1Department of Neurolog.y and Laboratoire de Neurosciences Fonctionnelleset Pathologies (UMR CNRS 8160), Amiens UniversityHospital, Amiens, France;and 2Department of Neurology, Amiens University Hospital, Amiens, France ABSTRACT Background: In patients who are candidates for IV recombinant tissue plasminogen activator (rtPA) thrombolysis for the treatment of acute ischemic stroke, blood pressure (BP)-lowering therapy is sometimes needed for systolic BP >185 mm Hg or diastolic BP >110 mm Hg. However, there is vast uncertainty regarding the appropriate choice of an antihypertensive agent. Case summary: A 68-year-old Algerian woman (height, 161 cm; weight, 68 kg; body mass index, 26 kg/m2) was admitted to the Cardiology Unit of Amiens University Hospital, Amiens, France, for the assessment of nonvalvular atrial fibrillation. She was prescribed furosemide 40 mg/d to treat a slight left cardiac insufficiency. On day 10 of admission, the patient developed left-sided weakness. Neurologic examination revealed left hemiparesis. A computed tomography scan of the head showed no abnormality. Approximately 90 minutes after onset of the neurologic deficit, the patient had a BP of 180/100 mm Hg in both arms, an irregular pulse >75 bpm, and normal heart sounds. The patient was transferred to the Neurovascular Unit. There were no cervical or femoral bruits in this patient. During neurologic examination, the patient was alert and showed no signs of major cognitive deficit. The neurologic examination did reveal, however, minor hemisphere syndrome with left spatial neglect. There was a left lower-facial paresis. Motor examination revealed normal bulk with diminished tone in the patient's left arm and leg. Although there were no physical signs of dehydration, laboratory results revealed moderate signs of dehydration (total protein, 91 g/L [indicating proteinemia]; sodium, September 2008 147 mmol [indicating hypernatremia]; and elevated hematocrit, 42.0%). Considering the diagnosis of ischemic stroke and the duration of the symptoms (<3 hours), IV rtPA was administered. Approximately 10 minutes after intravenous rtPA administration, the patient's BP was 210/110 mm Hg, and an IV bolus of urapidil (20 mg) was administered. Approximately 2 minutes following urapidil administration, the patient developed neurologic worsening indicated by left-sided hemiplegia. Her BP was 105/60 mm Hg. The IV rtPA was immediately discontinued and volume replacement was started for 20 minutes. IV rtPA was restarted after the patient remained hemodynamically stable (15 minutes after rtPA was restarted). Following intensive physiotherapy, the patient was discharged on anticoagulation with a favorable outcome. At her 6-month follow-up, the patient had fully recovered. Conclusion: We report a probable case of hypotension associated with IV bolus of urapidil administration during rtPA thrombolysis for acute ischemic stroke in an elderly patient also treated with diuretics. (Clin Ther. 2008;30:1675-1680) @ 2008 Excerpta Medica Inc. Key words: stroke, thrombolysis, hypotension, urapidil. INTRODUCTION In the setting of acute ischemic stroke, elevated blood pressure (BP)is observed in >60% of patients. I ConsidAccepted for publicationJuly 16, 2008. doi:l 0.1016/j.clinthera.2008.09.005 0149-2918/$32.00 © 2008 Excerpta Medica Inc. All rights reserved. 1675 Clinical Therapeutics ering that both high and low BP are associated with poor outcomes, 2 the physician is faced with the dilemma of determining what levels of BP require initiation of antihypertensive therapy. Surprisingly, guidelines remain inconclusive or conflicting. The current recommendation is to avoid lowering BE 3 One exception, however, concerns patients who are otherwise candidates for treatment with IV recombinant tissue plasminogen activator (rtPA). 3 Patients with systolic BP >185 mm Hg or diastolic BP >110 mm Hg were excluded from stroke rtPA trials due to concerns regarding increased risk for bleeding. However, these patients were treated if their BP decreased below these levels either spontaneously or in response to antihypertensive medications. There is vast uncertainty regarding the appropriate antihypertensive agent. In the absence of any data supporting the administration of a specific antihypertensive agent in the setting of acute ischemic stroke, it is recommended to select medications on a case-bycase basis, as the choice of drug is influenced by other medical conditions. In such cases, labetalol and sodium nitroprusside are proposed as first-line treatment by the Stroke Council of the American Stroke Association (ASA)3 and the European Stroke Initiative (EUSI), 4 with avoidance of drugs that are rapidly absorbed and can cause precipitous reductions in BP (eg, sublingual nifedipine). 5 The ASA also recommends nicardipine, whereas the EUSI also suggests IV urapidil, nitroglycerin, and oral captopril. Urapidil is a peripheral postsynaptic %-adrenoceptor antagonist that inhibits the vasoconstrictor action of catecholamines. It reduces BP by decreasing peripheral vascular resistance. In our Neurovascular Unit, urapidil is administered on the basis of its attractive properties: immediate onset of the therapeutic effect after infusion; prompt reversibility after discontinuing the infusion; absence of reflex tachycardia; absence of rebound phenomena; and, particularly, absence of raised intracranial pressure. 6 Recent clinical studies 7,8 have reported high levels of efficacy and safety associated with IV urapidil for hypertensive emergencies or treatment of hypertension after cardiac surgery. We report a case of severe hypotension after reducing BP by IV urapidil during rtPA thrombolysis for acute ischemic stroke. CASE S U M M A R Y A 68-year-old Algerian woman (height, 161 cm; weight, 68 kg; body mass index, 26 kg/m 2) was admit1676 ted to the Cardiology Unit of Amiens University Hospital, Amiens, France, for the assessment of nonvalvular atrial fibrillation. She had no significant medical history and presented no known cardiovascular risk factors. She had no medication prior to admission. The Congestive Heart Failure, Hypertension (or treated hypertension), Age >75 years, Diabetes Mellitus, and Prior Stroke and transient ischemic attack (CHADS2) index 9 was 0 (ie, low risk for ischemic stroke or other forms of systemic thromboembolism). Transthoracic echocardiogram revealed possible pericarditis and anticoagulation was deferred. Initial laboratory tests, including complete blood count (white blood cells, 86,000 mm3; hemoglobin, 11.5 g/dL; and platelets, 204,000 mm3), electrolytes (sodium, 142 mmol/L; potassium, 4.7 mmol/L; and calcium, 2.04 mmol/L), blood glucose (5.9 mmol/L), protein (73 g/L), and renal function (creatinine, 89 pmol/L) were normal. On admission, the patient's hematocrit was 33.6%. Blood gases were not measured. With signs of dyspnea, a chest radiograph was performed and was normal. Due to the clinical examination findings that showed signs of pericardial effusion and slight left cardiac insufficiency, treatment with furosemide (40 mg/d) was started (Figure 1). On day 10 of admission, the patient suddenly developed left-sided weakness. Neurologic examination revealed left hemiparesis. A computed tomography (CT) scan of the head showed no abnormality. Ninety minutes after onset of the neurologic deficit, the patient had a BP of 180/100 mm Hg in both arms, an irregular pulse <75 bpm, and normal heart sounds. The patient was then transferred to the Neurovascular Unit. There were no cervical or femoral bruits and no signs of heart failure. On neurologic examination, the patient was alert and showed no signs of major cognitive deficit. The physical examination did, however, reveal minor hemisphere syndrome with left spatial neglect. Cranial nerve examination revealed a left homonymous visual field defect. There was a right gaze preference with otherwise full extraocular movements and no nystagmus. Pupillary light reflexes were normal. There was a left lowerfacial paresis. Motor examination revealed normal bulk with diminished tone in the patient's left arm and leg. Sensory examination was limited by the patient's anosognosia, but she appeared to present left-sided deficits to pinprick, with a left plantar-extensor response. Her National Institutes of Health Stroke Scale (NIHSS) 1° score was 16/42 (NIHSS score indicators Volume 30 Number 9 J.-M. Bugnicourt: et al. I'-,, II I z Z ._z E +o II ~._:~ "-e- ~ e- ~I -~D ~ ~ . _ ~_ ~- I E E kO II .~-- oq o . _~ C:~ Z _ ~._o z ~ e- ~- O0 ~ ~ ~ " II 0 g3 o 8E "~ o ~ ~ ~-~ g3 0 C:~ z h~L ~.0 ~ ._z E o oq k,o FEE +o ~ ' ~ $ o-D z ~ .0 ~ ~ E ~ o g3 0 z~ -6~o= ._z E~ E E o E 0 k,o Z ~ g3 ~'5_ "~ " ~ "~ ~ o "~+ E.~ a-:~o o~ ,--~ ~- ~ II "~- e0 <-~ ~ ~-~.2 ~ ~ DD "~ 0 ~ _ E = > ~ ._z ~< II o,_~ = 0 ~Oxl 0 +o "~ E .~ 0-~ :- 0 ,- ~.-~ o,_ = ~ ~"~- ~ ~.~ o ~-~ '- ~''-~ o .~ ~ o ~ ~- ~ ~.~ ~ ~: 0 +o g3 z ~q oz~ "c gE~ Z E ~ E ._z E 0 oh 4o g3 o~,,~ r~ th Ea r~ o g3 ~b o~ > oo "-.~ - o ~± I g 3 ~ September 2 0 0 8 E ~o. o~ ~ ~ 0 ..0 b,~ ~ " . . ~ ~ .~-- 0 i cO o "~ .~ _ DD~.~" 0 ~ I'~ + ~ ,z E z :~ ,,= z LL 1677 Clinical Therapeutics from 0-42, with 0 = normal physical examination and 42 = patient death). As per the protocol in our unit, a score of 4 to 24 indicates thrombolysis. No physical signs of dehydration were detected. However, laboratory studies revealed hyperproteinemia (total protein, 91 g/L), hypernatremia (sodium, 147 mmol/L), and increased hematocrit (42.0%) compared with the value on admission (33.6%) 10 days prior. Electrocardiogram showed left ventricular hypertrophy based on voltage criteria. Review of the CT scan of the head did not reveal any early signs of cerebral ischemia. IV rtPA was administered 140 minutes after symptom onset and BP was automatically measured (5-minute intervals for the first hour and then every 15 minutes for 24 hours) in the hemiparetic arm (arm affected by stroke) using a patient monitoring system (Dinamap pro 100, GE Medical Systems, Waukesha, Wisconsin). After 10 minutes, the patient's BP was 210/110 mm Hg on 2 measurements, and an IV bolus of urapidil (20 mg) was administered according to the Neurovascular Unit's internal protocol (urapidil bolus [20 mg]) followed by urapidil infusion (between 9 to 30 mg/h, for 7 days). Approximately 2 minutes following IV bolus of urapidil administration, the patient developed leftsided hemiplegia. The patient's NIHSS was 21/42 and her BP was 105/60 mm Hg. rtPA administration was discontinued and volume replacement with normal saline was started. A repeat head CT scan showed no hemorrhagic complication. After 15 minutes, the patient's BP was 170/85 mm Hg and her NIHSS score was 13/42. Hospital physicians restarted rtPA therapy when the patient became hemodynamically stable. Brain magnetic resonance imaging was performed 4 hours after rtPA administration and showed limited infarct on the territory of the right middle cerebral artery (MCA) (Figure 2A). Magnetic resonance angiography revealed distal occlusion of the right MCA (Figure 2B). Carotid ultrasonography, transthoracic, and transesophageal echocardiography were normal. Serum electrolytes were in the normal ranges. Following intensive physiotherapy, including daily reeducation (sensorimotor training) and occupational therapy, the patient was discharged from the hospital (after 20 days) on anticoagulation, with a favorable outcome. She only presented a motor weakness in the left superior limb, a left lower-facial paresis, and a left homonymous visual field defect (NIHSS score = 6). The patient was no longer dyspneic and neither 1678 cardiac nor pulmonary deterioration were detected. No weight change had occurred. At 6 months, the patient had fully recovered. DISCUSSION Blood Pressure Management In the setting of acute ischemic stroke, >60% of patients have a systolic BP above 160 mm Hg and a diastolic BP >90 mm Hg. However, management of hypertension is controversial and several questions remain unresolved.11 Previous clinical studies 2,12 have reported a U-shaped relationship between death and admission BP: both elevated and low admission BP levels were associated with high mortality rates. Theoretical reasons for lowering BP include reducing brain edema, decreasing the risk of hemorrhagic transformation, preventing further vascular damage, and minimizing the risk of early recurrence. 13 Conversely, aggressive BP treatment may lead to neurologic worsening by reducing perfusion pressure to ischemic areas of the brain. 14 Based on these results and theoretical considerations, a scientific statement from the ASA3 recommended that the patient's BP should not be treated in the acute period. Exceptions to these recommendations include patients with hypertensive encephalopathy, aortic dissection, acute renal failure, acute pulmonary edema, acute myocardial infarction, and severe hypertension, although no specific data define the levels of BP that necessitate emergency management. By consensus, both the ASA and EUSI are consistent in not recommending routine lowering of BP unless systolic BP is repeatedly >220 mm Hg or diastolic BP is >120 mm Hg. 15 When treatment is indicated, BP should be lowered cautiously; although the ASA recommends lowering BP by -15% to 25% on the first day,3 the EUSI recommends a target BP of 180/100-105 mm Hg in patients with previous hypertension and 160-180/90-100 mm Hg in patients without previous hypertension. 4 This latter recommendation supports the fact that hypertensive patients are more vulnerable to the effects of lowering BP, as observed by the shift to higher values in lower and upper limits of cerebral autoregulation, is Another exception to ASA and EUSI recommendations concerns patients who are otherwise candidates for treatment with IV rtPA. 3,4 According to both guidelines, systolic BP >185 mm Hg or diastolic BP >110 mm Hg is a contraindication to IV administration of rtPA, as excessively high BP is associated with an increased Volume 30 Number 9 J.-M. Bugnicourt et al. A Figure 2. (A) Diffusion-weighted magnetic resonance imaging showing cortical hyperintensity in the right hemisphere in favor of a limited infarct on the territory of the right middle cerebral artery (arrow), and (B) magnetic resonance angiography revealing distal occlusion of the right middle cerebral artery (arrow). risk of symptomatic hemorrhagic transformation. 17 In accordance with these guidelines, we treated our patient with urapidil, which is a first-choice antihypertensive drug as per the treatment protocol in our Neurovascular Unit. Urapidil and Hypotension The patient's Naranjo Probability Scale 18 score was 6, which indicates a probable relationship between hypotension and urapidil administration. Previous studies in patients with complicated arterial hypertension and with coronaropathies 8,19,2° with repeated bolus injections (25-125 mg) did not report any serious adverse effects of IV administration of urapidil, especially no severe or symptomatic hypotension. In our literature search, we searched for articles without language restriction in the PubMed database (January 1980-June 2008) containing terms urapidil, stroke, and adverse effects. We did not find published reports of any serious adverse effects of IV urapidil administration in ischemic stroke patients who received rtPA. However, urapidil hypersensitivity is not rare, as some authors have reported transient but asymptomatic BP decrease to 50% of systolic BP pretreatment values. 7 September 2008 The high dose used (up to 50 mg [bolus]), 8 the relatively long elimination tl/2, and its well-documented wide range of individual dose requirements 21 might explain the high incidence of hypotension observed with IV urapidil, justifying strict BP monitoring during the first few hours. However, it is recognized that the impact of reduced cerebral blood flow is related to the magnitude of the decrease and its duration. In our patient, we believe that the hypotension-induced reduction in cerebral blood flow was too brief to cause any permanent brain injury, as indicated by the subsequent favorable outcome. Finally, we hypothesized that diuretic treatment may have caused intravascular volume depletion. 22 This additional hypovolemia may be the cause of the marked hypotension observed in this patient, as volume depletion triggers reflexes such as sympathetic stimulation to maintain BP levels. Inhibition of the vasoconstrictor action of catecholamine by urapidil may therefore have induced marked hypotension. CONCLUSION We report a probable case of severe hypotension associated with IV urapidil administration during rtPA 1679 Clinical Therapeutics thrombolysis for acute ischemic stroke in an elderly patient who was also receiving diuretic therapy. REFERENCES 1. Robinson 3-, Waddington A, Ward-Closea S, et al. The predictive role of 24-hour compared to casual blood pressure levels on outcome Following acute stroke. Cerebrovasc Dis. 1997;7:264-272. 2. Castillo J, Leira R, Garcfa MM, et al. 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Should a moratorium be placed on sublingual nifedipine capsules given For hypertensive emergencies and pseudoemergencies?JAMA. 1996;276:1328-1331. 6. Kirsten R, Nelson K, Molz KH, et al. Pharmacodynamics and pharmacokinetics of urapidil in hypertensive patients: A crossover study comparing infusion with an infusion-capsule combination. EurJ Clin Pharmacol. 1987; 32:61-65. 7. Aliiotas-Reig J, Bove-Farre I, de Cabo-Frances F, AnglesCoil R. Effectiveness and safety of prehospital urapidil For hypertensive emergencies. AmJ EmergMed. 2001 ;19:130-133. 8. van der StroomJG, van Wezel HB, LangemeijerJJ, et al. A randomized multicenter double-blind comparison ofurapidil and ketanserin in hypertensive patients after coronary artery surgery.J Cardiotkorac VascAnestk. 1997;I 1:729-736. 9. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes ffor predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA. 2001 ;285:2864-2870. 10. 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Paulson OB, Waldemar G, Schmidt JF, Strandgaard S. Cerebral circulation under normal and pathologic conditions. Amy Cardiol. 1989;63:2C-5C. 17. BrottT, Lu M, Kothari R, et al. Hypertension and its treatment in the NINDS rt-PA Stroke Trial. Stroke. 1998;29: 1504-1509. 18. Naranjo CA, Busto U, Sellers EM, et al. A method For estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981 ;30:239-245. 19. Hirschl MM, Seidler D, ZeinerA, et al. Intravenous urapidil versus sublingual niFedipine in the treatment of hypertensive urgencies. AmJ EmergMed. 1993;11:653-656. 20. Hirschl MM, Binder M, Bur A, et al. Safety and efficacy of urapidil and sodium nitroprusside in the treatment of hypertensive emergencies. Intensive Care Med. 1997;23: 885-888. 21. Petry A, Wulf H, Baumg~irtel M. The influence of ketanserin or urapidil on haemodynamics, stress response and kidney function during operations for myocardial revascularisation. Anaesthesia. 1995;50:312-316. 22. Rose BD, Post TW. Clinical Physiology ofiAcid-Base and E[ectro[yte Disorders. New York, NY: McGraw-Hill; 2001:961. Address for correspondence: Jean-Marc Bugnicourt, MD, Department of Neurology, Amiens University Hospital, Place Victor Pauchet, 80054 Amiens Cedex 1, France. E-maih bugnic°urt'jean-marc@chu-amiens'fr 1680 Volume 30 Number 9