Massive Pulmonary Embolism Thrombolysis: Early Clinical Markers of Treatment Efficacy

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1 Originl Article 17 Mssive Pulmonry Emolism Thromolysis: Erly Clinicl Mrkers of Tretment Efficcy Elie Portnoy 1 Vihor Wdhw 2 Mrin de Crvlho Bros 3 Clifford R. Weiss 1 Brin Holly 1 Mrk L. Lessne 1,4 Kelvin Hong 1 Anoel Tmrzi 5 1 Division of Vsculr nd Interventionl Rdiology, Johns Hopkins University School of Medicine, Bltimore, Mrylnd, United Sttes 2 Deprtment of Rdiology, University of Arknss for Medicl Sciences, Little Rock, Arknss, United Sttes 3 Ciêncis Médics de Mins Geris, Belo Horizonte MG, Brzil 4 Vsculr nd Interventionl Specilists of Chrlotte Rdiology, Chrlotte, North Crolin, United Sttes 5 Division of Vsculr nd Interventionl Rdiology, Plo Alto Medicl Foundtion Address for correspondence Anoel Tmrzi, MD, PhD, Division of Vsculr nd Interventionl Rdiology, Plo Alto Medicl Foundtion, 29 Whipple Avenue, Suite 225, Redwood City, CA 962 (e-mil: tmrzi@gmil.com). J Clin Interv Rdiol ISVIR 18;2:17 22 Astrct Keywords pulmonry emolism thromolysis pulmonry rteril pressure The uthors seek to evlute hemodynmic prmeters s potentil clinicl mrkers of rel-time clinicl improvement mong ptients with mssive pulmonry emolism (PE) in correltion with post-thromolytic pulmonry rteril pressure improvement nd overll clinicl outcome. Thirteen ptients with sumssive or mssive PE were dmitted to the interventionl rdiology service nd treted with ctheter-directed thromolysis. Among the four ptients who qulified s mssive PE, systolic lood pressure (BP) nd vsopressor dependence suggested meningful trends towrd clinicl improvement, fter only 26.4% of tretment course/dose. Hemodynmic prmeters such s systolic BP nd inotropic vsopressor dependence my e considered in future tretment protocols s erly indictors of tretment response. Introduction The pulmonry emolism (PE) spectrum of disese is the third most common cuse of crdiovsculr-relted deth in the United Sttes. 1 Mssive pulmonry emolism (MPE) comprises pproximtely 5 to 1% of the PE disese spectrum, together with the more common sumssive (SMPE) nd nonmssive counterprts. 2 MPE results in disproportiontely high degree of ptient PE-relted mortlity, with n ssocited in-hospitl mortlity of 15%. 3 Peripherl intrvenous (IV) thromolytic therpy hs een the stndrd of cre for severl yers 4 ; however, there might e considerle clinicl reluctnce in its common use, predominntly sed on the concerns of posttretment itrogenic hemorrhge. As such, most MPE ptients hve remined on conservtive tretment regimens, despite their more gurded prognosis. There hs een recent regrowth of interest in chemicl thromolysis, with newer focus on ctheter-directed thromolysis (CDT), fter the development nd refinement of newer thromolytic gents reltive to those used severl decdes go. 5,6 The considerle leeding risks might e, t lest in prt, mitigted y the sustntilly lower doses tht cn e dministered loclly within the pulmonry rtery vi CDT. Additionlly, recent trils with infusion ctheters using ultrsound-ssisted mechnicl thromolysis long with chemicl thromolysis hve demonstrted improvement in complictions rtes reltive to peripherl IV chemicl thromolysis lone. 7,8 Hypotension nd systemic end-orgn hypoperfusion re typicl clinicl mnifesttions of MPE. These ptients typiclly necessitte dynmic tretment, often in n intensive cre unit (ICU), with hour-y-hour monitoring of sttus. These ptients re monitored in the rel time with numerous clinicl prmeters, including, ut not limited to, peripherl rteril lood pressure (BP), hert rte (HR), oxygen (O 2 ) sturtion, O 2 rte, nd inotropic pressor dose (when used). In this study, the uthors ttempt to identify the potentil clinicl mrkers relted to rel-time hemodynmic sttus of the ptient, which correlte with erly posttretment clinicl received July 29, 17 ccepted fter revision Jnury 9, 18 DOI /s ISSN Copyright 18 y Indin Society of Vsculr nd Interventionl Rdiology

2 18 Clinicl Biomrkers of PE Thromolysis Portnoy et l. improvement, including reduction in pulmonry rteril pressure (PAP), to quntify the time t which the ptients exhiit persistent clinicl improvement during MPE CDT. The uthors postulte tht the sme MPE disese prmeters tht define it long the PE spectrum (hypotension nd/or inotropic vsopressor dependence) nd confer its prognostic vlue reltive to lower risk PE sugroups could e used s rel-time clinicl mrkers of tretment efficcy. Mterils nd Methods Institutionl review ord pprovl ws otined for this HIPAA (Helth Insurnce Portility nd Accountility Act of 1996) complint retrospective cse series. Records of PE ptients treted y the interventionl rdiology service with CDT were nlyzed for consecutive 5-month period from April through August of 14. Thirteen ptients (6 men nd 7 women; ge rnge: 36 79; men: 54.4 yers) were strtified y PE sugroup clssifiction into mssive (MPE) or sumssive (SBPE) groups. Distinction etween MPE nd SBPE ws mde on the sis of Americn Hert Assocition (AHA) criteri, which define tht MPE hs lrge centrl pulmonry rteril emolism, resulting in sustined hypotension (systolic lood pressure [SBP] < 9 mm Hg for t lest 15 minutes or requiring inotropic support, not due to cuse other thn PE), pulselessness, or persistent profound rdycrdi. 8 Among ptients who met criteri for MPE, ongoing rel-time hemodynmic prmeters were retrospectively collected, including invsive nd noninvsive peripherl rteril BP, HR, O 2 sturtion, O 2 dministrtion, nd inotropic vsopressor dose (when used), during thromolysis. Clinicl improvement ws defined y sustined improvement in systolic BP ove 9 mm Hg without recurrent drop elow 9 mm Hg (for >15 minute s defined y AHA criteri), or y sustined reduction in vsopressor dose, with gol of systolic BP greter thn 9 mm Hg. For other prmeters, improvement ws defined y continuous clinicl progress such s downtrending tchycrdi, or decresing O 2 use. Ptients were monitored throughout their infusion period in n ICU setting. Preprocedure min PA pressures were otined vi ctheter t the time of tretment initition, s well s posttretment immeditely efore the ctheter(s) were withdrwn t the conclusion of CDT. Posttretment PAP improvement ws correlted with time course of systolic BP improvement nd vsopressor dose reduction. All ptients were treted with either unilterl or ilterl 6F EKOS infusion ctheters (EKOS Corportion, Bothell, Wshington, United Sttes) vi internl jugulr (IJ) vein ccess in the right or left pulmonry rteries. Alteplse ws the sole thromolytic gent used mong ll ptients. The technique for CDT is sed on venous ccess through the IJ vein with one or two seprte short 6F sheths, depending on need for unilterl versus ilterl ctheters needed for tht ptient. After venous ccess, the right nd left pulmonry rteries were ccessed using stndrd ctheter nd wire techniques under fluoroscopic guidnce. A limited hnd injection ws performed to confirm proper loction. Initil pressures were mesured using the ctheter ccess within the min, right, or left pulmonry rtery. Then over the wire, 5.4F 16 cm EKOS (BTG) ctheter with 12-cm infusion length ws plced either in the right or left pulmonry rtery nd secured in plce. No thromectomy devices were used. The infusion of the tissue plsminogen ctivtor (tpa) ws then initited s descried for ech ptient vi the EKOS infusion ctheter. The ptients with EKOS infusion ctheters were ll monitored in the ICU setting with criticl cre nursing stff. At the conclusion of the infusion, the pressures were induced t edside in the ICU vi the EKOS ctheters prior to removl of the ctheters t edside. The IJ sheths were then removed nd hemostsis ws chieved with mnul compression. Results Among the four ptients with MPE ( Tle 1), two qulified on the sis of hypotension lone, zero qulified on the sis of inotropic vsopressor dependence lone, nd two qulified on the sis of comintion of oth. Among the four ptients, there ws 46.3% verge reduction in PAP noted over the tretment course ( Tle 2), with CDT tretment rnging from 9.75 to 24 hours, (men = 18.8 hours) ( Figs. 1 4). Clinicl prmeters, including HR, O 2 sturtion, nd O 2 dministrtion demonstrted no meningful trend to suggest improvement (dt not shown). For exmple, the uthors noted tht HR monitoring in the four ptients did not correlte with clinicl improvement nd tretment efficcy. HR is n exmple of nonidel clinicl iomrker most likely due to the sensitive nd vrile nture of the ptient s hert rte with vsopressors, volume sttus, nd ssocited discomfort in monitored unit. On the other hnd, the four ptients exhiited meningful clinicl improvement in oth SBP nd vsopressor dependence. These improvements were recognized Tle 1 Tretment dt regrding the four treted MPE ptients Ptient Totl time (h) Rte (mg/h/cth) Totl tpa dose (mg) Numer of ctheters Initil SBP < 9 mm Hg 15 min Ptient A.5 2 Yes Yes Ptient B Yes No Ptient C Yes Yes Ptient D Yes No Averge Arevitions: MPE, mssive pulmonry emolism; SBP, systolic lood pressure; tpa, tissue plsminogen ctivtor. Pressor dependent Journl of Clinicl Interventionl Rdiology ISVIR Vol. 2 No. 1/18

3 Clinicl Biomrkers of PE Thromolysis Portnoy et l. 19 Tle 2 Ctheter-sed systolic PAP vlues nd improvements seen mong the four treted MPE ptients Ptient Systolic PAP t time of tretment initition (mm Hg) Systolic PAP t time of tretment completion (mm Hg) Ptient A Ptient B % Ptient C Ptient D Averge Arevitions: MPE, mssive pulmonry emolism; PAP, pulmonry rteril pressure. Improvement in systolic PAP (%) Ptient A - & Pressor Trend (mm/hg) Time (hours) 25 3 Infusion Rtes (ml/hr) TPA Dose Dopmine Dose Liner (systolic Bp) Fig. 1 Ptient A: A 55-yer-old mn who presented to the ED with n nterolterl non ST-segment elevtion myocrdil infrction. CTA of the chest reveled ilterl lor pulmonry emoli (A). The ptient ws hypotensive with n systolic lood pressure (BP) of mm Hg nd necessitted continuous dopmine infusion. The stndrd doule IJ ccess pproch ws used to plce ilterl infusion ctheters nd initite CDT. By hour 3 of CDT ( totl hours of tretment), the ptient remined normotensive (> 9 mm Hg) nd ws no longer vsopressor dependent (B). The tretment ws continued to completion ( mg totl) despite this improvement in clinicl sttus. He ws dischrged from ICU on dy 3 of hospitliztion nd dischrged home on dy 6. tpa, tissue plsminogen ctivtor. Ptient B - Trend (mm/hg) Infusion Rte (ml/hr) 5 4 TPA Infusion Time (hours) Liner (Systolic BP) Fig. 2 Ptient B: A 78-yer-old mn who ws found on the ground with new tril firilltion. CTA in the ED reveled lrge right lor nd smller left segmentl pulmonry emoli (A). The ptient ws mrkedly hypotensive, with systolic lood pressure (BP) s low s 74 mm Hg ut ws not vsopressor dependent. The stndrd IJ ccess pproch ws used to plce unilterl right infusion ctheter nd initite CDT. By hour 1 of CDT (22 totl hours of tretment), the ptient remined normotensive without need for ny vsopressors (B). The tretment ws continued to completion (22 mg totl) despite this improvement in clinicl sttus. The ptient ws downgrded from ICU on hospitl dy 2 nd dischrged from hospitl on dy, with dely in dischrge relted to socil nd medicl mngement of numerous underlying comoridities. tpa, tissue plsminogen ctivtor. Journl of Clinicl Interventionl Rdiology ISVIR Vol. 2 No. 1/18

4 Clinicl Biomrkers of PE Thromolysis Portnoy et l. Ptient C- nd Multiple Pressor Trend (mm/hg) 3 Infusion Rte (ml/hr) systolic BP TPADose 1 Norepinephrine Dose Time (hours) Epinephrine Dose Liner (Systolic BP Fig. 3 Ptient C: A 58-yer-old womn who presented to the ED in PEA rrest. CT reveled lrge ilterl centrl PE (A). She qulified for MPE on the sis of oth hypotension nd vsopressor dependence. She necessitted continuous infusion epinephrine long with superimposed pulse doses of norepinephrine. The stndrd doule IJ ccess pproch ws used to plce ilterl infusion ctheters nd initite CDT. By hour 2.5 of CDT (19.5 totl hours of tretment), norepinephrine doses were no longer needed, nd y hour 4 (9.75 hours of totl tretment), epinephrine dose ws downtrending. The ptient s systolic lood pressure (BP) never returned elow 9 mm Hg for > 15 minutes (AHA criteri) throughout reminder of tretment course (B). The tretment ws continued to completion (19.5 mg totl) despite this improvement in clinicl sttus. She ws downgrded from the ICU on hospitl dy 3 nd dischrged on hospitl dy 5. tpa, tissue plsminogen ctivtor. Ptient D - Trend (mm/hg 1 1 TPA Infusion ml/hr 5 Systolic BP TPA Dose Time (hours) Liner (Systolic BP) Fig. 4 Ptient D: A 43-yer-old mn who ws locted in the hospitl for multiple congenitl neurologic issues nd developed worsening hypoxi. CT reveled lrge centrl ilterl PE (A). The ptient ws mrkedly hypotensive with systolic lood pressure (BP) in s. The stndrd doule IJ ccess pproch ws used to plce ilterl infusion ctheters nd initite CDT. She improved nerly immeditely fter infusion of tissue plsminogen ctivtor (tpa). ws initilly lile during tretment, ut continuous uptrend in SBP ws noted y hour 3 of CDT (24 totl hours of tretment) (B). The tretment ws continued to completion (24. mg totl) despite this improvement in clinicl sttus. He ws dischrged from ICU on dy 13, due to neurologic complictions, nd dischrged from hospitl on dys 26 fter multiple secondry illnesses including hospitl-cquired pneumoni. y hours 3, 1, 4, nd 3 (men = 5 hours), mong the four ptients respectively ( Figs. 1 4), s erlier. This erly 5-hour clinicl improvement, noted in the setting of n 18.8-hour verge CDT tretment course, represents sustntil clinicl improvement fter only 26.4% of totl CDT tretment time nd dose. Discussion Mssive pulmonry emolism hs een proven to e more lile nd severe suset of PE thn its SMPE counterprt. Although thromolysis is considered resonle in ptients with cute mssive PE, 9 the risk of post-tretment hemorrhge does remin concern, with one met-nlysis documenting the risk of mjor leeding ssocited with IV thromolysis to e 9.2% versus 3.4% mong similr cohort treted with heprin lone. 1 Superimposed concerns exist regrding the 1.5 to 3% incidence of intrcrnil leeding, which hs een often recorded in the literture. 11 Erly dt relesed in two CDT thromolysis trils 7,8 hve shown considerle promise with this therpy. Journl of Clinicl Interventionl Rdiology ISVIR Vol. 2 No. 1/18

5 Clinicl Biomrkers of PE Thromolysis Portnoy et l. 21 A B C D E F Fig. 5 Representtive initil (A C) nd 2-month follow-up (D F) xil CT imges for ptient A. The initil CT imges demonstrted lrge ilterl lor PEs (rrows in A C). The follow-up CT done t 2 months shows complete resolution of the emoli (D F). In ddition to improved ptient sfety/leeding profiles, they hve documented erly reduction in right ventriculr/left ventriculr (RV/LV) rtios, frequently used imging prmeter in oth MPE nd SMPE ptients s mrker of disese severity, nd erly success, 24 to 48 hours posttretment. Even when chemicl thromolysis is selected s the tretment choice for this dynmic suset of disese (MPE), ptients trditionlly hve een treted with fixed dose lteplse or tpa protocols. It would seem intuitive tht the sme conventionl dignostic prmeters set forth y the AHA to define MPE, nmely hemodynmic instility nd vsopressor dependence, nd which confer significnt prognostic vlue to the ptient, could e used in rel time to scertin improvement in ptient sttus. This MPE experience demonstrtes n improvement in BP nd vsopressor dependence, within n verge of 5 hours into n verge tretment course of 18.8 hours, only 26.4% of the time course through their completed tretment. This erly improvement correltes with n verge 46.3% reduction in PAP, which took plce directly over the course of tretment. The prospect for rel-time mrkers/metrics is of significnt vlue in the cre of the MPE ptient, in severl different cpcities. Severl studies 12 in the pst decde hve reflected upon the dose-dependent risk ssocited with systemic chemicl thromolysis. Lower-dose protocols hve yielded improved leeding profiles. Furthering this rgument, the dt ville from the recent ULTIMA nd SEATTLE II trils hve gin demonstrted tht lower doses (typiclly 24 mg of lteplse over the course of 24 hours) gin confer improved leeding profiles. This finding ws gin demonstrted mong the reltively smll ptient popultion of this study, with no mjor or minor leeding encountered mong the four MPE ptients who received n verge of 21.5 mg of lteplse over n verge of 18.8 hours. Prentheticlly, this ws lso oserved mong the nine SBPE ptients s well who hd no mjor leeding events reported. If thromolysis cn e monitored, or t lest rodly quntified in the rel-time setting, doses could potentilly e modulted nd decresed mong erly responders, or conversely, incresed in those refrctory to erly therpy or those who exhiit erly clinicl decline. Criticlly ill MPE ptients t high risk for mjor leeding (i.e., recent intrcrnil hemorrhge) 13 could potentilly e treted for mere mitigtion of hypotension nd shock rther thn through full-fixed tretment protocol. Future interest lies in further vlidtion of these hemodynmic mrkers s well s evlution of new mrkers mong, which my include mixed venous O 2 sturtion, to etter evlute for progressively improving tissue perfusion nd oxygention, s well s rel-time min PAP to ssess for improving pulmonry vsculture hemodynmics nd flow. This study hs severl limittions. First, the smll smple size of four MPE ptients my e insufficient to definitively correlte with the clinicl implictions of these mrkers, which remins suject of future reserch. Second, the uthors did not hve negtive control mong tretment nonresponders, s ll of the ptients in this cohort cliniclly improved. Third, the SMPE sugroup ws not further nlyzed ecuse the focus of this study ws MPE ptients. Lstly, there my e other cliniclly useful mrkers of tretment response, which were not studied in this report. In conclusion, in MPE ptients undergoing CDT, hemodynmic prmeters such s SBP nd inotropic vsopressor dose my e considered in future tretment protocols s erly indictors of tretment response. Disclosures The uthors hve no disclosures to declre. References 1 Glynn RJ, Dnielson E, Fonsec FA, et l. A rndomized tril of rosuvsttin in the prevention of venous thromoemolism. N Engl J Med 9;3(18): Kucher N, Rossi E, De Ros M, Goldher SZ. Prognostic role of echocrdiogrphy mong ptients with cute pulmonry emolism nd systolic rteril pressure of 9 mm Hg or higher. Arch Intern Med 5;165(15): Kucher N, Rossi E, De Ros M, Goldher SZ. Mssive pulmonry emolism. Circultion 6;113(4): Keron C, Akl EA, Ornels J, et l. Antithromotic therpy for VTE disese: CHEST guideline nd expert pnel report. Chest 16;149(2): Journl of Clinicl Interventionl Rdiology ISVIR Vol. 2 No. 1/18

6 22 Clinicl Biomrkers of PE Thromolysis Portnoy et l. 5 Leeper KV Jr, Popovich J Jr, Lesser BA, et l. Tretment of mssive cute pulmonry emolism. The use of low doses of intrpulmonry rteril streptokinse comined with full doses of systemic heprin. Chest 1988;93(2): Vujic I, Young JW, Goien RP, Dwson WT, Liescher L, Shelley BE Jr. Mssive pulmonry emolism: tretment with full hepriniztion nd topicl low-dose streptokinse. Rdiology 1983;148(3): Kucher N, Boekstegers P, Müller OJ, et l. Rndomized, controlled tril of ultrsound-ssisted ctheter-directed thromolysis for cute intermedite-risk pulmonry emolism. Circultion 14;129(4): Pizz G, Hohlfelder B, Jff MR, et l; SEATTLE II Investigtors. A prospective, single-rm, multicenter tril of ultrsoundfcilitted, ctheter-directed, low-dose firinolysis for cute mssive nd sumssive pulmonry emolism: the SEATTLE II study. JACC Crdiovsc Interv 15;8(1): Jff MR, McMurtry MS, Archer SL, et l; Americn Hert Assocition Council on Crdiopulmonry, Criticl Cre, Periopertive nd Resuscittion; Americn Hert Assocition Council on Peripherl Vsculr Disese; Americn Hert Assocition Council on Arteriosclerosis, Thromosis nd Vsculr Biology. Mngement of mssive nd sumssive pulmonry emolism, iliofemorl deep vein thromosis, nd chronic thromoemolic pulmonry hypertension: scientific sttement from the Americn Hert Assocition. Circultion 11;123(16): Chtterjee S, Chkrorty A, Weinerg I, et l. Thromolysis for pulmonry emolism nd risk of ll-cuse mortlity, mjor leeding, nd intrcrnil hemorrhge: met-nlysis. JAMA 14;311(23): Meyer G, Vicut E, Dnys T, et l; PEITHO Investigtors. Firinolysis for ptients with intermedite-risk pulmonry emolism. N Engl J Med 14;37(15): Shrifi M, By C, Skrocki L, Rhimi F, Mehdipour M; MOPETT Investigtors. Moderte pulmonry emolism treted with thromolysis (from the MOPETT Tril) Am J Crdiol 13;111(2): Bottinor W, Turlington J, Rz S, et l. Life-sving systemic thromolysis in ptient with mssive pulmonry emolism nd recent hemorrhgic cererovsculr ccident. Tex Hert Inst J 14;41(2): Journl of Clinicl Interventionl Rdiology ISVIR Vol. 2 No. 1/18