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Associated reactions during and immediately after rtPA infusion
ORIGINAL CONTRIBUTION tissue plasminogen activator, recombinant, reactions to
Associated Reactions During and Immediately After rtPA Infusion The complications of IV recombinant tissue-type plasminogen activator (rtPA) have not been previously reported specifically for the first hours after initiation of the therapy when patients are often in emergency departments or in transport. The charts of 124 patients who received rtPA between April 1986 and December I987 were retrospectively reviewed for reactions associated with rtPA infusion occurring in the first ten hours after the onset of rtPA admirlistration. Minor bleeding developed in 19% of the patients, and life-threatening bleeding in 3%. Half of the lifethreatening bleeding episodes were not predictable by history or physical examination. Arrhythmias were frequent despite the fact that all patients were maintained on IV lidocaine. N e w premature ventricular contractions occurred in 67%, accelerated idioventricular rhythm in 34%, ventricular tachycardia in 30%, and ventricular fibrillation in 2%. Many of the arrhythmias other than ventricular fibrillation had little hemodynamic consequence and did not require treatment. Neurologic episodes occurred in 3%, including two patients with intracerebral bleeding (1.5%); hypotension requiring treatment developed in 3%; and minor symptoms of allergy in 2%. Administration of rtPA in the ED requires careful patient selection to avoid bleeding complications and close monitoring to detect arrhythmias and changes in vital signs. [Linnik W, Tintinalli JE, Ramos R: Associated reactions during and immediately after rtPA infusion. Ann Emerg Med March 1989;18:234-239.]
William Linnik, MD*t Judith E Tintinalli, MD, FACFP* Renato Ramos, MDt Royal Oak, Michigan From the Departments of Emergency Medicine* and Cardiology, t William Beaumont HospitaJ, Royal Oak, Michigan. Received for publication May 24, 1988. Revision received October 31, 1988. Accepted for publication November 28, 1988. Presented at the University Association for Emergency Medicine Annual Meeting in Cincinnati, May 1988. Address for reprints: William Linnik, MD, Department of Emergency Medicine, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48072.
INTRODUCTION IV thrombolytic therapy with recombinant tissue-type plasminogen activator (rtPA) can be initiated, and is often completed, while the patient remains in the emergency department. For thrombolytic therapy to be most effective, it is strongly recommended that infusion begin in the ED as soon as the diagnosis of acute myocardial infarction (AMI) is made and contraindications to use are excluded. 1 While several rtPA trial studies 2,~ have reported the incidence of complications observed during the overall hospital course, none have categorized complications occurring during and immediately after the infusion period, when the emergency physician is responsible for care. Our purpose was to describe the incidence of associated reactions during the four hours of peripheral infusion and for six hours immediately after infusion of rtPA in patients with AMI. MATERIALS AND METHODS Charts of all patients with AMI receiving rtPA from April 1986 to December 1987 were reviewed retrospectively by the two senior authors. Nursing notes were screened for associated reactions, and rhythm strips were reviewed. All patients who received rtPA were enrolled after the infusion protocol was explained to them by a cardiology fellow, and informed consent was given by the patient. The study protocol and the retrospective chart review were approved by the hospital h u m a n investigation committee. Inclusion and exclusion criteria for study patients are listed (Figure 1). Patients eligible for rtPA in w h o m beta-blockers were not contraindicated (Figure 21 were then randomly assigned into two groups, those receiving metoprolol and those not receiving the drug.
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REACTIONS to rtPA Linnik, Tintinalli & Ramos
In the first two m o n t h s of the study, patients received a total dose of 150 mg rtPA as a peripheral IV infusion. After this period, patients received a total dose of 100 mg. For those receiving a total dose of 150 mg, rtPA was given as an IV bolus of 10 mg over one minute, 81 mg over 59 minutes, 20 mg over the next hour, and 10 mg/hr for the next four hours until the entire dose was administered. For those receiving a total dose of 100 mg, rtPA was given as an IV bolus of 6 mg over one minute, 55 mg over 59 minutes, 10 mg over the next hour, and 5 mg/hr for the next four hours until the entire dose was administered. Heparin was given as a 5,000-unit IV bolus and was followed in one hour by an IV infusion of 1,000 units/hr. Lidocaine, 1 to 1.5 mg/kg IV bolus was also given, followed by a 2 mg/min infusion for the next 24 hours. If randomized to receive beta-blocker therapy, patients were given a metoprolol 5-mg IV bolus every two m i n u t e s for three doses; 15 minutes after the third dose of m e t o p r o l o l , 50 mg was given orally if the systolic pressure remained more than 90 m m Hg and heart rate more than 50. Patients received IV nitroglycerin, m o r p h i n e , or h y d r o m o r p h o n e as needed. Lidocaine was titrated from 2 to 4 mg/min for control of ventricular ectopy, and procaine amide was also given to some patients. AMI location was defined as anterior (ST elevation in leads V1 through V4), lateral (ST elevation in leads V5, V6, I, and aVL) , o r inferior (ST elevation in leads II, III, and aVF). Bleeding was categorized by location and as either minor or major. Minor bleeding was defined as gastrointestinal bleeding not requiring transfusion, or hematomas or bleeding at catheter, gingiva, or venipuncture sites. Major bleeding was defined as life-threatening bleeding requiring transfusion, or central nervous system bleeding diagnosed by computed tomography scan. Arrhythmias were recorded if they were first documented after the onset of rtPA infusion. Arrhythmias were described as ventricular tachycardia (VT; ventricular origin, wide QRS complexes at more than 100 beats/ min, less than three-beat duration); unifocal or multifocal ventricular premature contractions (PVCs), or ventricular bigeminy or trigeminy; 20/235
ventricular fibrillation (VF}; accelerated idioventricular rhythm (AIVR; ventricular origin, wide QRS complex at less than 100 beats/min, more than three-beat duration); junctional r h y t h m ; atrial fibrillation; supraventricular tachycardia; complete heart block (CHB); Mobitz I rhythm; Mobitz II rhythm; or sinus bradycardia (rate less than 45 beats/min). Arrhythmias were further described as treated or observed or as not treated. If a specific arrhythmia occurred in one patient multiple times, it was recorded as one occurrence for the purposes of this study. N e u r o l o g i c e p i s o d e s w e r e described as presence of motor or sensory deficits or of seizure activity. Possible allergic reactions were defined as flush, rash, or pruritis occurring within 15 minutes of infusion with no other medication initiated during that time. Hypotension was defined as newonset systolic pressure less than 80 m m Hg and occurring within 15 minutes of rtPA infusion without concurrent administration of potentially h y p o t e n s i v e agents. All p a t i e n t s receiving beta-blockers, diuretics, n a r c o t i c s , or n i t r o g l y c e r i n were excluded from this category. RESULTS One hundred twenty-four patients received IV rtPA between April 1986 and December 1987, and all charts were availabie for retrospective review. One hundred one (81%) were men, with an age range of 34 to 75 years (mean, 60). Twenty-three (19%) were women, with an age range of 41 to 75 years (mean, 66). The first 34 patients in the study received 150 mg rtPA. N i n e t y s u b s e q u e n t patients received 100 mg. All patients completed the course of rtPA. Twentyn i n e p a t i e n t s (23%) r e c e i v e d IV metoprolol. Myocardial infarction location was anterior or anterior-lateral in 54 patients (44%), inferior in 63 (51%), lateral in f o u r (3%), and i n f e r i o r posterior in three (2%). Twenty-seven patients (22%) developed bleeding with minor bleeding at the gingiva, catheter, and venipuncture sites occurring in 23 (19%). Life-threatening bleeding occurred in four (3%). One patient had an unsuccessful nasal tracheal intubation and developed bleeding 30 minutes after the onset of the infusion. Protamine Annals of Emergency Medicine
sulfate, intranasal cocaine, and oxycel nasal packing were used for treatment, which lasted 72 hours. Two patients with neurologic deficits developed intracranial bleeding diagnosed on head computed tomography scan. One patient had a history of h y p e r t e n s i o n (blood pressure, 180/90 m m Hg during infusion) and developed persistent headache unresponsive to a c e t a m i n o p h e n or disc o n t i n u a t i o n of nitroglycerin infusion. The second patient maintained a normal blood pressure but developed mental status changes during the first hour of infusion. One patient, w i t h o u t ulcer history, developed spontaneous upper gastrointestinal bleeding requiring the transfusion of several units of blood. Minor bleeding that required no treatment other thaD compression dressings and had no adverse outcome occurred in 23 patients (19%). Arrhythmias occurred frequently (Table 1). New PVCs were the most common and occurred in 66 patients (53%), followed by AIVR in 42 (34%), VT in 38 (30%), ventricular bigeminy or trigeminy in 17 (14%), and VF in three (2%). Of the patients with supraventricular arrhythmias, atrial fibrillation occurred in eight (6%) and supraventricular tachycardia in one (1%). Of the patients with bradyarr h y t h m i a s , j u n c t i o n a l r h y t h m occurred in eight (6%), sinus bradycardia in five (4%), CHB in four (3%), and Mobitz II in one (1%). No patient developed Mobitz I rhythm. Of the patients with potentially lethal arrhythmias (VF, VT, and Ct-IB) (Table 2), VF was always treated with defibrillation. VT was treated in 16 (42%) of the 38 patients who had an occurrence. Patients with PVCs, ventricular bigeminy or trigeminy, and AIVR (except for the latter in one patient) were not specifically treated for these conditions because they did not result in hemodynamic deterioration. A patient with one episode of AIVR a s s o c i a t e d w i t h a s y s t o l i c blood pressure of 80 m m Hg was treated with crystalloid infusion and responded with an elevation of blood pressure. One patient with CHB was successfully paced transcutaneously. In addition, pacing was required for one patient who had an incident of sinus bradycardia and one patient who had an incident of slow junctional rhythm. Neurologic events occurred in four 18:3 March 1989
Inclusion Criteria Less than 76 years old Chest pain of at least 30 minutes' duration, with the onset no more than four hours before infusion ST segment elevation at least .1 mV in at least one of three locations: at least two of the three inferior leads (11, III, aVF); or at least two contiguous leads of the six precordial leads Vl through V6; or leads I and a V L Exclusion Criteria Inability to obtain informed consent Childbearing potential (premenopausal) Past or present bleeding disorder or significant gastrointestinal bleeding Oral anticoagulation therapy Left bundle branch block Prosthetic heart valve Dilated cardiomyopathy Serious advanced illness(es) Systolic pressure > 180 mm Hg or diastolic > 110 mm Hg Surgery within the past two weeks Previous administration of rtPA or streptokinase (within the past two weeks) CPR, defined as closed-chest massage, for more than one minute (within the past two weeks) History of stroke or transient ischemic attack Coronary artery bypass graft surgery Severe trauma (within the past six months) Coronary angioplasty (within the past six months)
Beta-blocker administered (within the past 48 hours) Calcium channel blocker administered (within the past 24 hours) Ventricular rate at rest < 55 beats/min Systolic blood pressure < 100 mm Hg Clinical or radiologic evidence of pulmonary edema Second- or third-degree heart block PR interval > .24 sec Presence of a permanent cardiac pacemaker History of bronchospasm
p a t i e n t s (3%). T w o p a t i e n t s , described above as h a v i n g bleeding complications, developed central nervous s y s t e m bleeding, w i t h right h e m i p a r e s i s in one and encephalopathic changes in the other. One patient developed weakness in the left upper extremity, but no progressive clinical signs of i n t r a c r a n i a l bleeding were demonstrated. Facial twitching that resolved spontaneously was recorded in one patient. In the latter, lidocaine levels were not obtained. Hypotension occurred in four patients (3%). Fluid boluses were required, and one patient required brief chest compressions and d o p a m i n e infusion to maintain a stable blood pressure. 18:3March 1989
Symptoms of allergy occurred in t h r e e p a t i e n t s (2%) but resolved quickly and spontaneously.
DISCUSSION Bleeding Complications Bleeding c o m p l i c a t i o n s are the m o s t feared adverse r e a c t i o n s of thrombolytic therapy. Bleeding m a y be related to c o n c o m i t a n t use of heparin. 4 However, in our study, the goal of m a i n t a i n i n g the activated c l o t t i n g t i m e at 180 seconds was maintained in all patients, and the time was the same in patients with and without bleeding complications. The short half-life of rtPA may lead to an increased reocclusion rate after d i s c o n t i n u a t i o n of t h r o m b o l y t i c therapy, s so to counter this problem, Annals of Emergency Medicine
FIGURE 1. Inclusion and exclusion criteria. FIGURE 2. Exclusion criteria for immediate IV metoproloL rtPA infusions are continued for up to six hours in some protocols. Although active t h r o m b o l y s i s ceases shortly after discontinuation of rtPA, it takes several hours to replenish fibrinogen so that the risk of continued bleeding does not t e r m i n a t e when rtPA is stopped. 3 The reported incidence of major bleeding has varied, in part, due to different definitions of major bleeding. Some studies have defined major bleeding episodes as those that require transfusions, while others have defined major bleeding episodes as those that are life threatening, such as intracranial bleeding. The studies quoted below reported the incidence of bleeding throughout the hospital stay, not just in the early hours of treatment. In one cooperative study, 5 seven of 47 patients (15%) developed major bleeding, including two with gastroi n t e s t i n a l bleeding and one w i t h bleeding at a brachial artery puncture site, which required surgical intervention. In another study involving 386 patients, 6 8% required transfusions within the first 24 hours; there was a 7.5% incidence of gastrointestinal bleeding characterized by gross blood or gniac-positive emesis or stool, and there was an 0.5% incidence of retroperitoneal and of intracranial hemol'rhage. Chesebro et al 3 reported that in 157 patients receiving rtPA, 25% required the transfusion of two or more units of blood, and 15% developed a major (undefined) drop in hematocrit. Another study 2 reported a 29% incidence of patients requiring the transfusion of one or more units of blood. Life-threatening bleeding resulting in neurologic deficits or necessity of transfusion during the rtPA infusion period and the six hours afterward was the most serious complication in our study. Life-threatening bleeding occurred in only 3% of patients but was unanticipated in half of these. Of the two patients {1.5%) who developed intracerebral bleeding diagnosed on computed tomography scan, one was normotensive and one was intermittently mildly hypertensive 236/21
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(180/90 m m Hg) during rtPA infusion. The overall reported incidence of intracranial bleeding has varied from 0.0% to 1.9% in studies involving total doses of rtPA from 80 to 150 mg. 7 Manufacturer's data s have shown an overall i n c i d e n c e of intracerebral bleeding of 0.3%. The resultant recommendations for avoiding thrombolytic therapy have therefore included the occurrence of previous neurologic events and severe h)rpertension. 7 In our institution, rtPA was withheld from any patient with a history at any time of cerebrovascular disease, including transient ischemic attack, and if any recording of the patient's systolic pressure exceeded 180 m m Hg or diastolic pressure exceeded 110 m m Hg; or if the patient had a history of a maintained diastolic blood pressure that exceeded 110 m m Hg. The incidence of stroke in association with AMI has been reported to vary from 1% to 8%, with a mean incidence of about 3%. 9 Stroke etiology in the absence of thrombolytic therapy is thrombotic or embolic, often in a s s o c i a t i o n w i t h atrial arr h y t h m i a s or low cardiac o u t p u t states. 9 There are many possible explanations for the association of rtPA with intracerebral bleeding: patients who without rtPA might have developed a thrombotic or embolic stroke might develop bleeding; prior asympt o m a t i c c e r e b r o v a s c u l a r disease might have been present; bleeding could be hypertension associated; or the effect of heparin, which is administered concomitantly, is additive to the effect of rtPA. The patient in our study with upper gastrointestinal bleeding that required transfusion had no ulcer history. The most clinically dramatic episode of bleeding occurred in a patient with attempted nasotracheal intubation in whom bleeding continued for 72 hours. It is not unreasonable to extrapolate from this single case that n a s o t r a c h e a l i n t u b a t i o n should be avoided if at all possible in patients in whom rtPA may be administered. A n a t o m i c sites of attempted invasive procedures in the ED or prehospital setting, including venipunctures and arterial punctures, should be reported to cardiac care staff as areas of potential bleeding. Although careful patient screening will keep the incidence of bleeding to 22/237
TABLE 1. Incidence of arrhythmias with and without beta-blockers With Without Beta-Blocker Beta-Blocker
(%)
Total
(%)
(%)
Ventricular Arrhythmias
Premature ventricular contractions Accelerated idioventricular rhythm Ventricular tachycardia Ventricularfibrillation
15 13 9 1
(23) (23) (24) (33)
51 29 29 2
(77) (69) (76) (67)
66 42 38 3
(53) (34) (30) (2)
0 0
(0) (0)
8 (100) 1 (100)
8 (6) 1 (1)
3 (38) 3 (60) 0 (0) 1 (100)
5 (62) 2 (40) 4 (100) 0 (0)
8 5 4 i
Supraventricular Arrhythmias
Atrial fibrillation Supraventricular tachycardia Bradyarrhythmias
Junctional rhythm Sinus bradycardia Complete heart block Mobitz II rhythm P > .25, not statistically significant.
(6) (4) (3) (1)
TABLE 2. Treatment of potentially lethal arrhythmias
Rhythm
Complete heart block Ventricular fibrillation Ventricular tachycardia Accelerated idioventricular rhythm
a minimum, bleeding probably cannot be eliminated completely, as is evidenced by one p a t i e n t in our study who developed intracerebral bleeding without any prior risk factors and another with gastrointestinal bleeding who had no history of ulcers or gastrointestinal pathology. Thus, the decision to begin thrombolytic therapy must weigh the indications for administration and contraindications to its use. rtPA should be administered with careful thought and consideration for potential adverse effects. Blood should always be obtained for type and cross-match; periodic examination for bleeding at puncture sites or invasive procedure sites is necessary; and evaluation for changes in vital signs or neurologic examination that might suggest internal or intracranial bleeding should be accomplished at regular intervals. Annals of Emergency Medicine
%
No. Patients
Treated
4 3 38 42
100 100 42 2
Hypotension There is little reported data on the association of hypotension with rtPA infusion. One study 3 reported a 3% incidence of hypotension in the first 24 hours not attributable to arrhythmia. This corresponds well with our incidence of 3% in the first ten hours, with only one patient requiring temporary low-dose vasopressor infusion to reestablish normotension.
Allergic-Type Reactions One study 8 has reported the occurrence of allergic-type reactions. In this study, 4% of the patients developed fever or chills, and 1% had urticaria. Our study demonstrated a 2% incidence of allergic-type reactions; however, all p a t i e n t s were concomitantly receiving a m i n i m u m of two other agents, IV nitroglycerin and heparin, which could have con-
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c e i v a b l y c a u s e d p r u r i t u s , r a s h , or flushing. All patients recovered quickly w i t h o u t t r e a t m e n t . Since t h e conclusion of our study, however, w e have e n c o u n t e r e d one patient w h o developed life-threatening a n g i o e d e m a , l a r y n g o s p a s m , and h y p o t e n s i o n w i t h i n five m i n u t e s of the onset of rtPA infusion. Progressive u r t i c a r i a a n d h y p o t e n s i o n resulted in rapid progression to VF. T h e acute o u t c o m e was satisfactory after d e f i b r i l l a t i o n , d i s c o n t i n u a t i o n of rtPA, and t r e a t m e n t w i t h e p i n e p h rine, d i p h e n h y d r a m i n e , a n d c o r ticosteroids.
Arrhythmias Reperfusion arrhythmias, are those that develop in association w i t h rep e r f u s i o n of t h e o c c l u d e d v e s s e l . They have b e e n d e s c r i b e d to o c c u r p r i m a r i l y i n t h e f i r s t e i g h t to 12 hours a f t e r r e p e r f u s i o n , m A r r h y t h mias reported to occur in association with r e p e r f u s i o n i n c l u d e AIVR, VT, PVCs, s i n u s bradycardia, and atrioventricular block, l°,n T h e generally held i m p r e s s i o n is t h a t r e p e r f u s i o n a r r h y t h m i a s are r e s i s t a n t to t r e a t ment w i t h c o n v e n t i o n a l antiarrhythmics 12 and generally are benign. 13 We did n o t c o r r e l a t e t h e o c c u r rence of a r r h y t h m i a s w i t h d o c u m e n t e d r e p e r f u s i o n at a n g i o g r a p h y but simply reported the incidence in the patients in our study. W h i l e general d a t a o n t h e i n c i d e n c e of arr h y t h m i a s a f t e r ANII i n t h e p r e thrombolytic era are available, TM the d u r a t i o n of o b s e r v a t i o n f o r arr h y t h m i a s after AMI, p a t i e n t selection, m e t h o d of a r r h y t h m i a d e t e c tion, c o n c u r r e n t m e d i c a t i o n s , a n d use of a n t i a r r h y t h m i c agents are ext r e m e l y v a r i a b l e , so c o m p a r i s o n s with c o n t e m p o r a r y cardiac care are difficult, if not impossible, to make. S i m i l a r l y , for a r r h y t h m i a i n c i dence, we did n o t identify a control group of p a t i e n t s in our i n s t i t u t i o n because o n l y p a t i e n t s i n t h e r t P A study received strictly controlled doses of lidocaine, nitroglycerin, and beta-blocking agents within strict time l i m i t s after onset of A M I symptoms. P a t i e n t s e x c l u d e d f r o m t h e study (Figures 1 and 2) were generally more s e r i o u s l y ill, h a d serious previous c o r o n a r y a r t e r y disease, w e r e older, and often e x c e e d e d the t i m e limitations. Therefore, we docum e n t e d the incidence of a r r h y t h m i a s that one m i g h t expect to e n c o u n t e r 18:3 March 1989
in the ED in p a t i e n t s receiving rtPA in the first ten hours after A M I b u t w h o were also receiving p r o p h y l a c t i c lidocaine, nitroglycerin, and, in some, beta-blocking agents. In our study, 67% of patients were n o t e d to develop u n i f o c a l or m u l t i focal PVCs, or v e n t r i c u l a r b i g e m i n y or t r i g e m i n y , after t h e i n i t i a t i o n of t h r o m b o l y t i c therapy, w h e r e a s t h e y w e r e n o t n o t e d before t h e r a p y was begun. Cercek et al 1° n o t e d 100% incidence of PVCs w i t h reperfusion in p a t i e n t s w h o w e r e p l a c e d on t w o channel, c o n t i n u o u s 2 4 - h o u r H o l t e r r e c o r d i n g s i m m e d i a t e l y after h o s p i talization. Cercek et al 1° also noted a 90% i n c i d e n c e of AIVR ( c o m p a r e d w i t h o u r i n c i d e n c e of 34%) a n d a 23% incidence of VT (compared w i t h our incidence of 30%). Topol et al 2 reported a 20% incidence of VT but did n o t report PVCs or AIVR. Atrioventricular block and junctional reperfusion rhythms were noted in the report by B u c k i n g h a m et al. 1~ O n l y 35 p a t i e n t s were studied, and r h y t h m s were d o c u m e n t e d only during angiography. Topol et al ~ rep o r t e d a 4% i n c i d e n c e of a t r i o v e n t r i c u l a r b l o c k as a r e p e r f u s i o n r h y t h m , but the m e t h o d of arrhythm i a d e t e c t i o n or m o n i t o r i n g was n o t described. T h e i n c i d e n c e of VF m a y be reduced w i t h successful reperfusion, ta O u r i n c i d e n c e of 2% is s i m i l a r to t h a t r e p o r t e d by T o p o l et al 2 (4%) and far less t h a n the 23% incidence reported in patients w i t h A M I receiving no t h r o m b o l y t i c therapy, is T h e incidence of a r r h y t h m i a s was higher in those p a t i e n t s w h o did n o t r e c e i v e b e t a - b l o c k e r therapy. H o w ever, patients w i t h h y p o t e n s i o n and b r a d y c a r d i a , t h a t is, p o s s i b l y t h o s e with more impaired myocardium, were excluded from beta-blocker t r e a t m e n t . In addition, the difference in i n c i d e n c e of each a r r h y t h m i a was n o t s t a t i s t i c a l l y significant. O u r data support the general i m p r e s s i o n that a r r h y t h m i a s are c o m m o n in association w i t h rtPA infusion and generally are benign. CONCLUSION A d m i n i s t r a t i o n of rtPA in t h e ED r e q u i r e s careful p a t i e n t s e l e c t i o n to avoid bleeding complications and close monitoring to detect arr h y t h m i a s and changes in vital signs and neurologic status. Life-threatening bleeding resulting Annals of Emergency Medicine
in n e u r o l o g i c d e f i c i t s or r e q u i r i n g transfusion, the m o s t serious complication in our patients, occurred in a few (four, or 3%) and was unanticipated in half of these (two, or 1.5%). Minor bleeding from venipuncture and catheters was easily managed. VT, PVCs, a n d A I V R w e r e t h e most common arrhythmias associa t e d w i t h r t P A infusion. H o w e v e r , h e m o d y n a m i c deterioration was unc o m m o n , and in m o s t i n s t a n c e s the above arrhythmias were observed and not treated. Those that were treated responded to either cardioversion or p h a r m a c o l o g i c intervention. N e u r o l o g i c deficits resulting from intracranial bleeding occurred in two p a t i e n t s (1.5%), w i t h two o t h e r episodes (extremity weakness, facial twitching) resolving spontaneously and n o t associated w i t h adverse outcome. H y p o t e n s i o n and allergic-type reactions occurred in 6% of the patients and were either observed only or easily managed.
REFERENCES
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infarction. A m J Carddol 1987;60:214-218. 11. Kuck KH, Schofer J, 8chluter M, et al: Reperfusion arrhythmia in man: Influence of intravenous lidocaine. Eur Heart J 1984;29: 163-167. 12. Buckingham TA, Devine JE, Redd RM, et ah Reperfusion arrhythmias during coronary reper-
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and blood vessels, in Hurst JW {ed): The Heart, ed 6. New York, McGraw-Hill, 1986, p 8821008. 15. Vermeer F, Simoons ML, Lubsen J: Reduced frequency of ventficular fibrillation after early thrombolysis in myocardial infarction. Lancet 1986;May 17:1147-1148.
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Associated Reactions During and Immediately After rtPA Infusion The complications of IV recombinant tissue-type plasminogen activator (rtPA) have not been previously reported specifically for the first hours after initiation of the therapy when patients are often in emergency departments or in transport. The charts of 124 patients who received rtPA between April 1986 and December I987 were retrospectively reviewed for reactions associated with rtPA infusion occurring in the first ten hours after the onset of rtPA admirlistration. Minor bleeding developed in 19% of the patients, and life-threatening bleeding in 3%. Half of the lifethreatening bleeding episodes were not predictable by history or physical examination. Arrhythmias were frequent despite the fact that all patients were maintained on IV lidocaine. N e w premature ventricular contractions occurred in 67%, accelerated idioventricular rhythm in 34%, ventricular tachycardia in 30%, and ventricular fibrillation in 2%. Many of the arrhythmias other than ventricular fibrillation had little hemodynamic consequence and did not require treatment. Neurologic episodes occurred in 3%, including two patients with intracerebral bleeding (1.5%); hypotension requiring treatment developed in 3%; and minor symptoms of allergy in 2%. Administration of rtPA in the ED requires careful patient selection to avoid bleeding complications and close monitoring to detect arrhythmias and changes in vital signs. [Linnik W, Tintinalli JE, Ramos R: Associated reactions during and immediately after rtPA infusion. Ann Emerg Med March 1989;18:234-239.]
William Linnik, MD*t Judith E Tintinalli, MD, FACFP* Renato Ramos, MDt Royal Oak, Michigan From the Departments of Emergency Medicine* and Cardiology, t William Beaumont HospitaJ, Royal Oak, Michigan. Received for publication May 24, 1988. Revision received October 31, 1988. Accepted for publication November 28, 1988. Presented at the University Association for Emergency Medicine Annual Meeting in Cincinnati, May 1988. Address for reprints: William Linnik, MD, Department of Emergency Medicine, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48072.
INTRODUCTION IV thrombolytic therapy with recombinant tissue-type plasminogen activator (rtPA) can be initiated, and is often completed, while the patient remains in the emergency department. For thrombolytic therapy to be most effective, it is strongly recommended that infusion begin in the ED as soon as the diagnosis of acute myocardial infarction (AMI) is made and contraindications to use are excluded. 1 While several rtPA trial studies 2,~ have reported the incidence of complications observed during the overall hospital course, none have categorized complications occurring during and immediately after the infusion period, when the emergency physician is responsible for care. Our purpose was to describe the incidence of associated reactions during the four hours of peripheral infusion and for six hours immediately after infusion of rtPA in patients with AMI. MATERIALS AND METHODS Charts of all patients with AMI receiving rtPA from April 1986 to December 1987 were reviewed retrospectively by the two senior authors. Nursing notes were screened for associated reactions, and rhythm strips were reviewed. All patients who received rtPA were enrolled after the infusion protocol was explained to them by a cardiology fellow, and informed consent was given by the patient. The study protocol and the retrospective chart review were approved by the hospital h u m a n investigation committee. Inclusion and exclusion criteria for study patients are listed (Figure 1). Patients eligible for rtPA in w h o m beta-blockers were not contraindicated (Figure 21 were then randomly assigned into two groups, those receiving metoprolol and those not receiving the drug.
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REACTIONS to rtPA Linnik, Tintinalli & Ramos
In the first two m o n t h s of the study, patients received a total dose of 150 mg rtPA as a peripheral IV infusion. After this period, patients received a total dose of 100 mg. For those receiving a total dose of 150 mg, rtPA was given as an IV bolus of 10 mg over one minute, 81 mg over 59 minutes, 20 mg over the next hour, and 10 mg/hr for the next four hours until the entire dose was administered. For those receiving a total dose of 100 mg, rtPA was given as an IV bolus of 6 mg over one minute, 55 mg over 59 minutes, 10 mg over the next hour, and 5 mg/hr for the next four hours until the entire dose was administered. Heparin was given as a 5,000-unit IV bolus and was followed in one hour by an IV infusion of 1,000 units/hr. Lidocaine, 1 to 1.5 mg/kg IV bolus was also given, followed by a 2 mg/min infusion for the next 24 hours. If randomized to receive beta-blocker therapy, patients were given a metoprolol 5-mg IV bolus every two m i n u t e s for three doses; 15 minutes after the third dose of m e t o p r o l o l , 50 mg was given orally if the systolic pressure remained more than 90 m m Hg and heart rate more than 50. Patients received IV nitroglycerin, m o r p h i n e , or h y d r o m o r p h o n e as needed. Lidocaine was titrated from 2 to 4 mg/min for control of ventricular ectopy, and procaine amide was also given to some patients. AMI location was defined as anterior (ST elevation in leads V1 through V4), lateral (ST elevation in leads V5, V6, I, and aVL) , o r inferior (ST elevation in leads II, III, and aVF). Bleeding was categorized by location and as either minor or major. Minor bleeding was defined as gastrointestinal bleeding not requiring transfusion, or hematomas or bleeding at catheter, gingiva, or venipuncture sites. Major bleeding was defined as life-threatening bleeding requiring transfusion, or central nervous system bleeding diagnosed by computed tomography scan. Arrhythmias were recorded if they were first documented after the onset of rtPA infusion. Arrhythmias were described as ventricular tachycardia (VT; ventricular origin, wide QRS complexes at more than 100 beats/ min, less than three-beat duration); unifocal or multifocal ventricular premature contractions (PVCs), or ventricular bigeminy or trigeminy; 20/235
ventricular fibrillation (VF}; accelerated idioventricular rhythm (AIVR; ventricular origin, wide QRS complex at less than 100 beats/min, more than three-beat duration); junctional r h y t h m ; atrial fibrillation; supraventricular tachycardia; complete heart block (CHB); Mobitz I rhythm; Mobitz II rhythm; or sinus bradycardia (rate less than 45 beats/min). Arrhythmias were further described as treated or observed or as not treated. If a specific arrhythmia occurred in one patient multiple times, it was recorded as one occurrence for the purposes of this study. N e u r o l o g i c e p i s o d e s w e r e described as presence of motor or sensory deficits or of seizure activity. Possible allergic reactions were defined as flush, rash, or pruritis occurring within 15 minutes of infusion with no other medication initiated during that time. Hypotension was defined as newonset systolic pressure less than 80 m m Hg and occurring within 15 minutes of rtPA infusion without concurrent administration of potentially h y p o t e n s i v e agents. All p a t i e n t s receiving beta-blockers, diuretics, n a r c o t i c s , or n i t r o g l y c e r i n were excluded from this category. RESULTS One hundred twenty-four patients received IV rtPA between April 1986 and December 1987, and all charts were availabie for retrospective review. One hundred one (81%) were men, with an age range of 34 to 75 years (mean, 60). Twenty-three (19%) were women, with an age range of 41 to 75 years (mean, 66). The first 34 patients in the study received 150 mg rtPA. N i n e t y s u b s e q u e n t patients received 100 mg. All patients completed the course of rtPA. Twentyn i n e p a t i e n t s (23%) r e c e i v e d IV metoprolol. Myocardial infarction location was anterior or anterior-lateral in 54 patients (44%), inferior in 63 (51%), lateral in f o u r (3%), and i n f e r i o r posterior in three (2%). Twenty-seven patients (22%) developed bleeding with minor bleeding at the gingiva, catheter, and venipuncture sites occurring in 23 (19%). Life-threatening bleeding occurred in four (3%). One patient had an unsuccessful nasal tracheal intubation and developed bleeding 30 minutes after the onset of the infusion. Protamine Annals of Emergency Medicine
sulfate, intranasal cocaine, and oxycel nasal packing were used for treatment, which lasted 72 hours. Two patients with neurologic deficits developed intracranial bleeding diagnosed on head computed tomography scan. One patient had a history of h y p e r t e n s i o n (blood pressure, 180/90 m m Hg during infusion) and developed persistent headache unresponsive to a c e t a m i n o p h e n or disc o n t i n u a t i o n of nitroglycerin infusion. The second patient maintained a normal blood pressure but developed mental status changes during the first hour of infusion. One patient, w i t h o u t ulcer history, developed spontaneous upper gastrointestinal bleeding requiring the transfusion of several units of blood. Minor bleeding that required no treatment other thaD compression dressings and had no adverse outcome occurred in 23 patients (19%). Arrhythmias occurred frequently (Table 1). New PVCs were the most common and occurred in 66 patients (53%), followed by AIVR in 42 (34%), VT in 38 (30%), ventricular bigeminy or trigeminy in 17 (14%), and VF in three (2%). Of the patients with supraventricular arrhythmias, atrial fibrillation occurred in eight (6%) and supraventricular tachycardia in one (1%). Of the patients with bradyarr h y t h m i a s , j u n c t i o n a l r h y t h m occurred in eight (6%), sinus bradycardia in five (4%), CHB in four (3%), and Mobitz II in one (1%). No patient developed Mobitz I rhythm. Of the patients with potentially lethal arrhythmias (VF, VT, and Ct-IB) (Table 2), VF was always treated with defibrillation. VT was treated in 16 (42%) of the 38 patients who had an occurrence. Patients with PVCs, ventricular bigeminy or trigeminy, and AIVR (except for the latter in one patient) were not specifically treated for these conditions because they did not result in hemodynamic deterioration. A patient with one episode of AIVR a s s o c i a t e d w i t h a s y s t o l i c blood pressure of 80 m m Hg was treated with crystalloid infusion and responded with an elevation of blood pressure. One patient with CHB was successfully paced transcutaneously. In addition, pacing was required for one patient who had an incident of sinus bradycardia and one patient who had an incident of slow junctional rhythm. Neurologic events occurred in four 18:3 March 1989
Inclusion Criteria Less than 76 years old Chest pain of at least 30 minutes' duration, with the onset no more than four hours before infusion ST segment elevation at least .1 mV in at least one of three locations: at least two of the three inferior leads (11, III, aVF); or at least two contiguous leads of the six precordial leads Vl through V6; or leads I and a V L Exclusion Criteria Inability to obtain informed consent Childbearing potential (premenopausal) Past or present bleeding disorder or significant gastrointestinal bleeding Oral anticoagulation therapy Left bundle branch block Prosthetic heart valve Dilated cardiomyopathy Serious advanced illness(es) Systolic pressure > 180 mm Hg or diastolic > 110 mm Hg Surgery within the past two weeks Previous administration of rtPA or streptokinase (within the past two weeks) CPR, defined as closed-chest massage, for more than one minute (within the past two weeks) History of stroke or transient ischemic attack Coronary artery bypass graft surgery Severe trauma (within the past six months) Coronary angioplasty (within the past six months)
Beta-blocker administered (within the past 48 hours) Calcium channel blocker administered (within the past 24 hours) Ventricular rate at rest < 55 beats/min Systolic blood pressure < 100 mm Hg Clinical or radiologic evidence of pulmonary edema Second- or third-degree heart block PR interval > .24 sec Presence of a permanent cardiac pacemaker History of bronchospasm
p a t i e n t s (3%). T w o p a t i e n t s , described above as h a v i n g bleeding complications, developed central nervous s y s t e m bleeding, w i t h right h e m i p a r e s i s in one and encephalopathic changes in the other. One patient developed weakness in the left upper extremity, but no progressive clinical signs of i n t r a c r a n i a l bleeding were demonstrated. Facial twitching that resolved spontaneously was recorded in one patient. In the latter, lidocaine levels were not obtained. Hypotension occurred in four patients (3%). Fluid boluses were required, and one patient required brief chest compressions and d o p a m i n e infusion to maintain a stable blood pressure. 18:3March 1989
Symptoms of allergy occurred in t h r e e p a t i e n t s (2%) but resolved quickly and spontaneously.
DISCUSSION Bleeding Complications Bleeding c o m p l i c a t i o n s are the m o s t feared adverse r e a c t i o n s of thrombolytic therapy. Bleeding m a y be related to c o n c o m i t a n t use of heparin. 4 However, in our study, the goal of m a i n t a i n i n g the activated c l o t t i n g t i m e at 180 seconds was maintained in all patients, and the time was the same in patients with and without bleeding complications. The short half-life of rtPA may lead to an increased reocclusion rate after d i s c o n t i n u a t i o n of t h r o m b o l y t i c therapy, s so to counter this problem, Annals of Emergency Medicine
FIGURE 1. Inclusion and exclusion criteria. FIGURE 2. Exclusion criteria for immediate IV metoproloL rtPA infusions are continued for up to six hours in some protocols. Although active t h r o m b o l y s i s ceases shortly after discontinuation of rtPA, it takes several hours to replenish fibrinogen so that the risk of continued bleeding does not t e r m i n a t e when rtPA is stopped. 3 The reported incidence of major bleeding has varied, in part, due to different definitions of major bleeding. Some studies have defined major bleeding episodes as those that require transfusions, while others have defined major bleeding episodes as those that are life threatening, such as intracranial bleeding. The studies quoted below reported the incidence of bleeding throughout the hospital stay, not just in the early hours of treatment. In one cooperative study, 5 seven of 47 patients (15%) developed major bleeding, including two with gastroi n t e s t i n a l bleeding and one w i t h bleeding at a brachial artery puncture site, which required surgical intervention. In another study involving 386 patients, 6 8% required transfusions within the first 24 hours; there was a 7.5% incidence of gastrointestinal bleeding characterized by gross blood or gniac-positive emesis or stool, and there was an 0.5% incidence of retroperitoneal and of intracranial hemol'rhage. Chesebro et al 3 reported that in 157 patients receiving rtPA, 25% required the transfusion of two or more units of blood, and 15% developed a major (undefined) drop in hematocrit. Another study 2 reported a 29% incidence of patients requiring the transfusion of one or more units of blood. Life-threatening bleeding resulting in neurologic deficits or necessity of transfusion during the rtPA infusion period and the six hours afterward was the most serious complication in our study. Life-threatening bleeding occurred in only 3% of patients but was unanticipated in half of these. Of the two patients {1.5%) who developed intracerebral bleeding diagnosed on computed tomography scan, one was normotensive and one was intermittently mildly hypertensive 236/21
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(180/90 m m Hg) during rtPA infusion. The overall reported incidence of intracranial bleeding has varied from 0.0% to 1.9% in studies involving total doses of rtPA from 80 to 150 mg. 7 Manufacturer's data s have shown an overall i n c i d e n c e of intracerebral bleeding of 0.3%. The resultant recommendations for avoiding thrombolytic therapy have therefore included the occurrence of previous neurologic events and severe h)rpertension. 7 In our institution, rtPA was withheld from any patient with a history at any time of cerebrovascular disease, including transient ischemic attack, and if any recording of the patient's systolic pressure exceeded 180 m m Hg or diastolic pressure exceeded 110 m m Hg; or if the patient had a history of a maintained diastolic blood pressure that exceeded 110 m m Hg. The incidence of stroke in association with AMI has been reported to vary from 1% to 8%, with a mean incidence of about 3%. 9 Stroke etiology in the absence of thrombolytic therapy is thrombotic or embolic, often in a s s o c i a t i o n w i t h atrial arr h y t h m i a s or low cardiac o u t p u t states. 9 There are many possible explanations for the association of rtPA with intracerebral bleeding: patients who without rtPA might have developed a thrombotic or embolic stroke might develop bleeding; prior asympt o m a t i c c e r e b r o v a s c u l a r disease might have been present; bleeding could be hypertension associated; or the effect of heparin, which is administered concomitantly, is additive to the effect of rtPA. The patient in our study with upper gastrointestinal bleeding that required transfusion had no ulcer history. The most clinically dramatic episode of bleeding occurred in a patient with attempted nasotracheal intubation in whom bleeding continued for 72 hours. It is not unreasonable to extrapolate from this single case that n a s o t r a c h e a l i n t u b a t i o n should be avoided if at all possible in patients in whom rtPA may be administered. A n a t o m i c sites of attempted invasive procedures in the ED or prehospital setting, including venipunctures and arterial punctures, should be reported to cardiac care staff as areas of potential bleeding. Although careful patient screening will keep the incidence of bleeding to 22/237
TABLE 1. Incidence of arrhythmias with and without beta-blockers With Without Beta-Blocker Beta-Blocker
(%)
Total
(%)
(%)
Ventricular Arrhythmias
Premature ventricular contractions Accelerated idioventricular rhythm Ventricular tachycardia Ventricularfibrillation
15 13 9 1
(23) (23) (24) (33)
51 29 29 2
(77) (69) (76) (67)
66 42 38 3
(53) (34) (30) (2)
0 0
(0) (0)
8 (100) 1 (100)
8 (6) 1 (1)
3 (38) 3 (60) 0 (0) 1 (100)
5 (62) 2 (40) 4 (100) 0 (0)
8 5 4 i
Supraventricular Arrhythmias
Atrial fibrillation Supraventricular tachycardia Bradyarrhythmias
Junctional rhythm Sinus bradycardia Complete heart block Mobitz II rhythm P > .25, not statistically significant.
(6) (4) (3) (1)
TABLE 2. Treatment of potentially lethal arrhythmias
Rhythm
Complete heart block Ventricular fibrillation Ventricular tachycardia Accelerated idioventricular rhythm
a minimum, bleeding probably cannot be eliminated completely, as is evidenced by one p a t i e n t in our study who developed intracerebral bleeding without any prior risk factors and another with gastrointestinal bleeding who had no history of ulcers or gastrointestinal pathology. Thus, the decision to begin thrombolytic therapy must weigh the indications for administration and contraindications to its use. rtPA should be administered with careful thought and consideration for potential adverse effects. Blood should always be obtained for type and cross-match; periodic examination for bleeding at puncture sites or invasive procedure sites is necessary; and evaluation for changes in vital signs or neurologic examination that might suggest internal or intracranial bleeding should be accomplished at regular intervals. Annals of Emergency Medicine
%
No. Patients
Treated
4 3 38 42
100 100 42 2
Hypotension There is little reported data on the association of hypotension with rtPA infusion. One study 3 reported a 3% incidence of hypotension in the first 24 hours not attributable to arrhythmia. This corresponds well with our incidence of 3% in the first ten hours, with only one patient requiring temporary low-dose vasopressor infusion to reestablish normotension.
Allergic-Type Reactions One study 8 has reported the occurrence of allergic-type reactions. In this study, 4% of the patients developed fever or chills, and 1% had urticaria. Our study demonstrated a 2% incidence of allergic-type reactions; however, all p a t i e n t s were concomitantly receiving a m i n i m u m of two other agents, IV nitroglycerin and heparin, which could have con-
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c e i v a b l y c a u s e d p r u r i t u s , r a s h , or flushing. All patients recovered quickly w i t h o u t t r e a t m e n t . Since t h e conclusion of our study, however, w e have e n c o u n t e r e d one patient w h o developed life-threatening a n g i o e d e m a , l a r y n g o s p a s m , and h y p o t e n s i o n w i t h i n five m i n u t e s of the onset of rtPA infusion. Progressive u r t i c a r i a a n d h y p o t e n s i o n resulted in rapid progression to VF. T h e acute o u t c o m e was satisfactory after d e f i b r i l l a t i o n , d i s c o n t i n u a t i o n of rtPA, and t r e a t m e n t w i t h e p i n e p h rine, d i p h e n h y d r a m i n e , a n d c o r ticosteroids.
Arrhythmias Reperfusion arrhythmias, are those that develop in association w i t h rep e r f u s i o n of t h e o c c l u d e d v e s s e l . They have b e e n d e s c r i b e d to o c c u r p r i m a r i l y i n t h e f i r s t e i g h t to 12 hours a f t e r r e p e r f u s i o n , m A r r h y t h mias reported to occur in association with r e p e r f u s i o n i n c l u d e AIVR, VT, PVCs, s i n u s bradycardia, and atrioventricular block, l°,n T h e generally held i m p r e s s i o n is t h a t r e p e r f u s i o n a r r h y t h m i a s are r e s i s t a n t to t r e a t ment w i t h c o n v e n t i o n a l antiarrhythmics 12 and generally are benign. 13 We did n o t c o r r e l a t e t h e o c c u r rence of a r r h y t h m i a s w i t h d o c u m e n t e d r e p e r f u s i o n at a n g i o g r a p h y but simply reported the incidence in the patients in our study. W h i l e general d a t a o n t h e i n c i d e n c e of arr h y t h m i a s a f t e r ANII i n t h e p r e thrombolytic era are available, TM the d u r a t i o n of o b s e r v a t i o n f o r arr h y t h m i a s after AMI, p a t i e n t selection, m e t h o d of a r r h y t h m i a d e t e c tion, c o n c u r r e n t m e d i c a t i o n s , a n d use of a n t i a r r h y t h m i c agents are ext r e m e l y v a r i a b l e , so c o m p a r i s o n s with c o n t e m p o r a r y cardiac care are difficult, if not impossible, to make. S i m i l a r l y , for a r r h y t h m i a i n c i dence, we did n o t identify a control group of p a t i e n t s in our i n s t i t u t i o n because o n l y p a t i e n t s i n t h e r t P A study received strictly controlled doses of lidocaine, nitroglycerin, and beta-blocking agents within strict time l i m i t s after onset of A M I symptoms. P a t i e n t s e x c l u d e d f r o m t h e study (Figures 1 and 2) were generally more s e r i o u s l y ill, h a d serious previous c o r o n a r y a r t e r y disease, w e r e older, and often e x c e e d e d the t i m e limitations. Therefore, we docum e n t e d the incidence of a r r h y t h m i a s that one m i g h t expect to e n c o u n t e r 18:3 March 1989
in the ED in p a t i e n t s receiving rtPA in the first ten hours after A M I b u t w h o were also receiving p r o p h y l a c t i c lidocaine, nitroglycerin, and, in some, beta-blocking agents. In our study, 67% of patients were n o t e d to develop u n i f o c a l or m u l t i focal PVCs, or v e n t r i c u l a r b i g e m i n y or t r i g e m i n y , after t h e i n i t i a t i o n of t h r o m b o l y t i c therapy, w h e r e a s t h e y w e r e n o t n o t e d before t h e r a p y was begun. Cercek et al 1° n o t e d 100% incidence of PVCs w i t h reperfusion in p a t i e n t s w h o w e r e p l a c e d on t w o channel, c o n t i n u o u s 2 4 - h o u r H o l t e r r e c o r d i n g s i m m e d i a t e l y after h o s p i talization. Cercek et al 1° also noted a 90% i n c i d e n c e of AIVR ( c o m p a r e d w i t h o u r i n c i d e n c e of 34%) a n d a 23% incidence of VT (compared w i t h our incidence of 30%). Topol et al 2 reported a 20% incidence of VT but did n o t report PVCs or AIVR. Atrioventricular block and junctional reperfusion rhythms were noted in the report by B u c k i n g h a m et al. 1~ O n l y 35 p a t i e n t s were studied, and r h y t h m s were d o c u m e n t e d only during angiography. Topol et al ~ rep o r t e d a 4% i n c i d e n c e of a t r i o v e n t r i c u l a r b l o c k as a r e p e r f u s i o n r h y t h m , but the m e t h o d of arrhythm i a d e t e c t i o n or m o n i t o r i n g was n o t described. T h e i n c i d e n c e of VF m a y be reduced w i t h successful reperfusion, ta O u r i n c i d e n c e of 2% is s i m i l a r to t h a t r e p o r t e d by T o p o l et al 2 (4%) and far less t h a n the 23% incidence reported in patients w i t h A M I receiving no t h r o m b o l y t i c therapy, is T h e incidence of a r r h y t h m i a s was higher in those p a t i e n t s w h o did n o t r e c e i v e b e t a - b l o c k e r therapy. H o w ever, patients w i t h h y p o t e n s i o n and b r a d y c a r d i a , t h a t is, p o s s i b l y t h o s e with more impaired myocardium, were excluded from beta-blocker t r e a t m e n t . In addition, the difference in i n c i d e n c e of each a r r h y t h m i a was n o t s t a t i s t i c a l l y significant. O u r data support the general i m p r e s s i o n that a r r h y t h m i a s are c o m m o n in association w i t h rtPA infusion and generally are benign. CONCLUSION A d m i n i s t r a t i o n of rtPA in t h e ED r e q u i r e s careful p a t i e n t s e l e c t i o n to avoid bleeding complications and close monitoring to detect arr h y t h m i a s and changes in vital signs and neurologic status. Life-threatening bleeding resulting Annals of Emergency Medicine
in n e u r o l o g i c d e f i c i t s or r e q u i r i n g transfusion, the m o s t serious complication in our patients, occurred in a few (four, or 3%) and was unanticipated in half of these (two, or 1.5%). Minor bleeding from venipuncture and catheters was easily managed. VT, PVCs, a n d A I V R w e r e t h e most common arrhythmias associa t e d w i t h r t P A infusion. H o w e v e r , h e m o d y n a m i c deterioration was unc o m m o n , and in m o s t i n s t a n c e s the above arrhythmias were observed and not treated. Those that were treated responded to either cardioversion or p h a r m a c o l o g i c intervention. N e u r o l o g i c deficits resulting from intracranial bleeding occurred in two p a t i e n t s (1.5%), w i t h two o t h e r episodes (extremity weakness, facial twitching) resolving spontaneously and n o t associated w i t h adverse outcome. H y p o t e n s i o n and allergic-type reactions occurred in 6% of the patients and were either observed only or easily managed.
REFERENCES
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infarction. A m J Carddol 1987;60:214-218. 11. Kuck KH, Schofer J, 8chluter M, et al: Reperfusion arrhythmia in man: Influence of intravenous lidocaine. Eur Heart J 1984;29: 163-167. 12. Buckingham TA, Devine JE, Redd RM, et ah Reperfusion arrhythmias during coronary reper-
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and blood vessels, in Hurst JW {ed): The Heart, ed 6. New York, McGraw-Hill, 1986, p 8821008. 15. Vermeer F, Simoons ML, Lubsen J: Reduced frequency of ventficular fibrillation after early thrombolysis in myocardial infarction. Lancet 1986;May 17:1147-1148.
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