Evidence-based diagnosis and thrombolytic treatment of cardiac arrest or periarrest due to suspected pulmonary embolism.

American Journal of Emergency Medicine xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem

Review

Evidence-based diagnosis and thrombolytic treatment of cardiac arrest or periarrest due to suspected pulmonary embolism☆,☆☆ Jill K. Logan, PharmD a,⁎, Hardin Pantle, MD b, Paul Huiras, PharmD c, Edward Bessman, MD b, Leah Bright, DO d a

Department of Pharmacy, University of Maryland Baltimore Washington Medical Center, Glen Burnie, MD Department of Emergency Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD Department of Pharmacy, Boston Medical Center, Boston, MA d Department of Emergency Medicine, Johns Hopkins Hospital, Baltimore, MD b c

a r t i c l e

i n f o

Article history: Received 15 January 2014 Received in revised form 8 April 2014 Accepted 15 April 2014 Available online xxxx

a b s t r a c t When a previously healthy adult experiences atraumatic cardiac arrest, providers must quickly identify the etiology and implement potentially lifesaving interventions such as advanced cardiac life support. A subset of these patients develop cardiac arrest or periarrest due to pulmonary embolism (PE). For these patients, an early, presumptive diagnosis of PE is critical in this patient population because administration of thrombolytic therapy may significantly improve outcomes. This article reviews thrombolysis as a potential treatment option for patients in cardiac arrest or periarrest due to presumed PE, identifies features associated with a high incidence of PE, evaluates thrombolytic agents, and systemically reviews trials evaluating thrombolytics in cardiac arrest or periarrest. Despite potentially improved outcomes with thrombolytic therapy, this intervention is not without risks. Patients exposed to thrombolytics may experience major bleeding events, with the most devastating complication usually being intracranial hemorrhage. To optimize the risk-benefit ratio of thrombolytics for treatment of cardiac arrest due to PE, the clinician must correctly identify patients with a high likelihood of PE and must also select an appropriate thrombolytic agent and dosing protocol. © 2014 Published by Elsevier Inc.

1. Introduction When an adult experiences unexpected, atraumatic cardiac arrest, resuscitation efforts include a search for treatable, reversible etiologies. Massive pulmonary embolism (PE) is a potentially reversible process, which may be responsible for 8% to 13% of unexplained cardiac arrests [1–3]. In addition, patients with massive PE may present with unstable vital signs such as systolic hypotension or become unstable during their diagnostic evaluation. Thrombolytic agents offer the potential to restore normal blood flow by lysing the PE and therefore will theoretically improve outcomes for patients in cardiac arrest or periarrest due to PE. Although the Adult Advanced Cardiovascular Life Support (ACLS) guidelines are widely accepted for managing patients with cardiac arrest due to acute coronary syndrome, there is less guidance for the emergent administration of thrombolytics for cardiac arrest or periarrest due to PE [4]. The decision to administer thrombolytics prior to return of spontaneous circulation (ROSC) can be complicated by diagnostic

☆ Funding source: No funding received. ☆☆ Conflicts of interest: None of the authors report any conflicts of interest. ⁎ Corresponding author. University of Maryland Baltimore Washington Medical Center, Department of Pharmacy, 301 Hospital Drive, Glen Burnie, MD 21061 E-mail address: [email protected] (J.K. Logan).

uncertainty regarding the cause of cardiac arrest. Clinicians must rely on clinical judgment combined with limited data from history, physical examination, and bedside diagnostic tools to determine the level of suspicion of PE as well as to estimate the risk-benefit ratio for administering thrombolytics. Earlier presumptive diagnosis of PE may decrease the time to treatment of PE and can potentially improve patient outcomes. This article discusses clinical features consistent with the presumptive diagnosis of PE, provides an overview of thrombolytic agents, and presents a detailed review of the literature supporting the use of thrombolysis as a treatment option for patients in cardiac arrest or periarrest due to suspected PE. 1.1. Incidence and prevalence of cardiac arrest due to PE Although only 4.2% of PE patients will present with hemodynamic instability or in cardiac arrest, up to 65% of these cases are fatal [5,6]. Furthermore, in a prospective registry of patients with PE, Goldhaber and colleagues [5] demonstrated an increased mortality rate of 58.3% in patients presenting with hemodynamic instability compared with 15.1% for their hemodynamically stable counterparts. It is proposed that massive PE causes an acute elevation in right heart pressure, leading to decreased right ventricular output with septal shift toward the left ventricle, progressing to shock and cardiac arrest with preserved electrical activity [7]. As a result of this pathophysiology,

http://dx.doi.org/10.1016/j.ajem.2014.04.032 0735-6757/© 2014 Published by Elsevier Inc.

Please cite this article as: Logan JK, et al, Evidence-based diagnosis and thrombolytic treatment of cardiac arrest or periarrest due to suspected pulmonary embolism, Am J Emerg Med (2014), http://dx.doi.org/10.1016/j.ajem.2014.04.032

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J.K. Logan et al. / American Journal of Emergency Medicine xxx (2014) xxx–xxx

routine ACLS interventions are often largely ineffective. Thrombolytic therapy is recommended for patients who are hemodynamically unstable due to PE, with a survival benefit of 19% vs 9% for those treated only with heparin [8]. There are research data to support thrombolytics in massive PE; however, there has not been a comprehensive review of the literature to support or refute proposed published thrombolytic therapy protocols. 2. Current treatment of cardiac arrest due to presumed PE Interventions for the treatment of cardiac arrest that are of proven benefit include early bystander cardiopulmonary resuscitation (CPR), basic life support with uninterrupted chest compressions and adequate ventilation, and early cardioversion if a shockable cardiac rhythm is discovered. Thrombolytics are not routinely recommended for undifferentiated atraumatic cardiac arrest [9,10]. However, both the American Heart Association and European Resuscitation Council guidelines for 2010 recommend “considering” administration of fibrinolytic therapy when cardiac arrest is “caused by proven or suspected acute pulmonary embolus” [9,10]. Unfortunately, when a PE is suspected as the etiology of cardiac arrest, there exists little guidance to practitioners regarding the thrombolytic agent of choice, dosing, and method of administration. Furthermore, neither organization offers guidance regarding when the clinician should suspect the presence of PE. 3. Thrombolytic agents The first thrombolytic enzyme, streptokinase, was isolated in the 1940s and used successfully to treat intravascular clotting in the 1950s [11,12]. During the next 3 decades, first-generation thrombolytics, streptokinase and urokinase, were used to lyse arterial and venous clots in human trials [13–16]. Successful molecular cloning of tissue plasminogen activator (t-PA) in the early 1980s provided another breakthrough in thrombolytic therapy, and further manipulation of the molecular structure of t-PA led to the production of thirdgeneration thrombolytics such as tenecteplase and reteplase. A brief summary of the characteristics of these thrombolytics can be found in Table 1 [17,18]. The activity of all thrombolytics hinges on the ability of the medication to convert plasminogen to plasmin, which then hydrolyzes the fibrin matrix of thromboemboli resulting in clot dissolution. Mechanistically, these agents vary in the cofactors they require for activation and the specificity for plasmin production locally within a clot. Second-generation and third-generation thrombolytics differ from first-generation thrombolytics in that their activity is highly dependent on an initial binding to fibrin. Because fibrin is primarily present within a clot, this allows larger rates of clot-bound plasmin production and more targeted clot-specific fibrinolysis. Without the

presence of fibrin, modern thrombolytics (second and third generations) have little effect on circulating plasminogen. Thus, modern thrombolytics do not significantly alter unbound plasmin production or affect systemic fibrinolysis to the same extent as streptokinase [17,19]. Third-generation thrombolytics were created by modifying t-PA to extend the plasma half-life of the novel compounds. The modifications in tenecteplase increased the initial half-life of the agent to nearly 20 minutes, and as a result, it is the only fibrinolytic that is given as a single bolus [20–22]. These characteristics make it an attractive agent in cardiac arrest situations. Most trials published on thrombolytic use in cardiac arrest have assessed the efficacy of t-PA. Of all the thrombolytics, t-PA is the most extensively studied, has the most approved indications (including PE), and is highly used in hospitals across the United States. Tenecteplase, because of its ease of administration and half-life, is an attractive thrombolytic for use in cardiac arrest. It is also widely prescribed in the United States. For these reasons, these 2 agents should be the agents of choice for further research for thrombolytics in cardiac arrest.

3.1. Route of administration Thrombolytic agents are administered via peripheral or central venous access. If these standard routes of intravenous access cannot be established, thrombolytics may be administered via an intraosseous catheter. However, tissue necrosis requiring skin grafting due to subcutaneous bleeding at the intraosseous catheter site after the administration of thrombolytics has been reported in a single patient [23].

4. Patient identification It can be extremely difficult to determine the etiology of cardiac arrest while a patient is being resuscitated [24]. Unlike patients who are hemodynamically stable, patients in cardiac arrest or periarrest often cannot undergo diagnostic testing with a computed tomographic scan or a ventilation-perfusion scan. Although published clinical decision tools exist to stratify a patient’s risk for PE, these tools are primarily used to identify patients who do not require additional testing to rule out PE [25,26]. For patients who have already been diagnosed as having a PE, a variety of data points can be used to estimate the risk of mortality, including biomarkers and risk stratification models [27,28]. Unfortunately, these models and biomarkers are not designed to identify patients who are in cardiac arrest or periarrest due to massive PE, and alternative diagnostics techniques are required. Given this uncertainty, the clinician should maintain a high degree of suspicion for PE in critically ill patients who have a history or symptom profile associated with this diagnosis.

Table 1 Characteristics of thrombolytics [18,19] Streptokinase

Urokinase

t-PA

Reteplase

Tenecteplase

Generation

First

First

Second

Third

Third

Cofactor required for activation Clot-targeted plasmin production Initial half-life (min) Commonly administered as an infusion FDA-approved indications

Circulating plasminogen No 12 Yes • DVT • PE • AMI • Arteriovenous cannulation • Arterial thrombus No longer available

None No 7-20 Yes • PE

Fibrin Yes 4-10 Yes • PE • AMI • CVA-I • Venous catheter occlusion

Fibrin Yes 11-19 Yes • AMI

Fibrin Yes 15-24 No • AMI

No longer available

Yes

Yes

Yes

Available in the United States

Abbreviations: FDA, Food and Drug Administration; DVT, deep vein thrombosis; AMI, acute myocardial infarction; CVA-I, cerebrovascular accident-ischemic.



Certain physiologic precepts have a stronger association with PE than others, lending confidence to presumptive diagnosis in the absence of evident alternative etiologies. For example, patients who present in cardiac arrest with pulseless electrical activity (PEA) have a higher incidence of PE than do patients who present with other electrical rhythms such as ventricular fibrillation or asystole. In a small prospective study investigating the etiology of unexplained cardiac arrest, 25 (69%) of 36 patients presented with PEA and 9 (36%) of these 25 had a PE diagnosed by esophageal echocardiogram or autopsy [29]. Pulseless electrical activity can be subcategorized into rapid or slow electrical rhythms, narrow or wide QRS complexes, and the presence or absence of myocardial contraction on bedside ultrasound. A rapid, narrow QRS PEA rhythm with observed myocardial contraction may have a higher association with PE compared with other PEA rhythms. There have been attempts to improve the identification of patients whose arrest may be due to PE. Courtney and colleagues [7,30] studied a clinical decision making rule in both a retrospective trial and a prospective trial and found the following triad to be associated with cardiac arrest secondary to massive PE: witnessed cardiac arrest, age less than 65 to 70 years, and PEA as the initial rhythm. Courtney et al [31] also identified common prearrest complaints of patients with massive PE as respiratory difficulty, shock index greater than 0.8 (pulse divided by systolic blood pressure), and altered mental status. The outcome of this study showed that 50% of the patients meeting the clinical decision making rule triad had a PE, which improved the diagnostic likelihood of PE when compared with the previously discussed sensitivity of 36% when only assessing for PEA rhythm in unexplained cardiac arrest [29]. In addition, factors associated with patient presentation more likely to be predictive of PE were noted [31]. Although potentially difficult to ascertain during a cardiac arrest, the study identified the following factors as having the highest association with the diagnosis of PE: unilateral leg swelling, oxygen saturation less than 95%, active cancer, recent prolonged immobilization or orthopedic surgery, and recent prolonged airline travel. Medical history of consequence included history deep vein thrombosis, PE, and clotting disorders. Point-of-care ultrasound is a feasible diagnostic imaging modality available to the emergency department practitioners when resuscitating a patient in arrest or periarrest situations. Point-of-care ultrasound may identify right ventricular hypokinesis, an ominous finding that may be seen in the presence of massive PE, although it is difficult to assess during arrest [32]. This was studied by Comes et al [29], who demonstrated that right ventricular dilation in the absence of left ventricle distention visualized by esophageal echocardiogram, particularly in the setting of PEA, is suggestive of PE. In this investigation, 14 (56%) of 25 patients who presented with PEA had right ventricular enlargement without left ventricular distention and 9 of these 14 (64%) patients had a PE. Despite the lack of diagnostic certainty, it is critical to make the presumptive diagnosis of PE as soon as possible, because early administration of thrombolytic therapy is presumed to yield the greatest benefit. This presumption is based on the observation that thrombolytics are associated with improved right ventricular function, decreased pulmonary artery pressures, and increased rates of survival for patients who are hemodynamically unstable due to PE [33]. Lending support to the presumption that earlier treatment with thrombolytic therapy improves results, Er et al [34] retrospectively showed that patients with good outcomes such as ROSC or survival were treated earlier than those who did not have these outcomes. Balanced against the need for early administration of thrombolytics, however, it is critical to recognize that thrombolytics are an expensive, high-risk intervention associated with a significant risk of life-threatening bleeding complications. As detailed below, the administration of thrombolytics places patients at risk for the development of bleeding into the gastrointestinal tract, the retroperitoneal space, and other serious bleeding outcomes. Relatively few

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patients develop intracranial hemorrhage, although this complication is the most feared because of the high probability of poor neurologic outcome. 5. Primary literature review 5.1. Methodology The effect of thrombolytic therapy on PE size, resolution, and hemodynamic status has been extensively studied [35–40]. Trials included in this review address the use of thrombolytic therapy in arrest or periarrest patient populations only. A Medline search was conducted using the following search terms: thrombolytics, cardiac arrest, arrest, PE, venous thromboembolism, hemodynamically unstable, t-PA, tenecteplase, urokinase, streptokinase, and reteplase. The search was limited to prospective and retrospective clinical trials and excluded case reports, case series, and meta-analyses. Articles were included if thrombolytic therapy was administered during arrest or hemodynamically unstable situations during or before ROSC or death and excluded if given after ROSC. Furthermore, trials were only included if definite outcomes were evaluated such as ROSC or mortality. Trials with primary end points of clot size resolution or changes in imaging were not included in this review. References of all included trials were searched for additional literature meeting the inclusion criteria of this review (Table 2). 5.2. Thrombolytic therapy in periarrest As early as 1995, Jerjes-Sanchez et al [41] evaluated the efficacy of thrombolytics in patients with a massive PE. This trial was conducted as a randomized controlled trial and included previously healthy patients with a high probability of PE. Pulmonary embolism was confirmed in all patients after intervention via high-probability ventilation-perfusion scan or necropsy. All patients in the trial had a similar onset of cardiogenic shock prior to study drug administration. The active intervention in this trial compared streptokinase 1 500 000 units infused for 1 hour, followed by heparin compared with heparin monotherapy. Four patients in each group were enrolled in this trial. All patients in the streptokinase group (4/4) survived with good neurologic outcome, whereas no patients in the heparin monotherapy group (0/4) survived. This was a statistically significant difference between the 2 groups (P = .02), leading the ethics committee to recommend cessation of the trial. This trial suggests that thrombolytic therapy is safe in patients with cardiogenic shock due to massive PE with no major or minor bleeding events reported. Although these data are compelling to support administration of thrombolytic therapy to patients in cardiogenic shock due to massive PE, the small sample size makes it difficult to apply these results to a broad population. In 2003, Le Conte et al [42] retrospectively reviewed the administration of t-PA (0.6 mg/kg, maximum dose of 50 mg, administered for 15 minutes, followed by heparin) in 21 patients with massive PE and shock or cardiac arrest to assess the efficacy and bleeding events associated with this intervention. The results showed a mortality rate of 23.8% with statistically significant improvements demonstrated in the hemodynamic parameters of systolic blood pressure, diastolic blood pressure, and oxygenation status 2 hours after treatment with t-PA. Five (23%) patients experienced bleeding events controlled by compression. In 2012, Stein and Matta [33] performed a retrospective database review of the Nationwide Inpatient Sample to identify hemodynamically unstable patients with an acute PE based on billing code data (International Classification of Disease, Ninth edition). This trial hypothesized that thrombolytic therapy would reduce the fatality rate in unstable patients. This trial retrospectively identified 21 390 patients who were hemodynamically unstable due to PE and were treated with thrombolytic therapy vs 50 840 patients who were not


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Table 2 Clinical trials Author(s)

Year

Study type

Population

Thrombolytic (dose), n

Control

Outcome

Bleeding

LOEa

Abu-Laban et al [44]

2002

Prospective, randomized, placebo controlled trial

PEA arrest unresponsive to initial therapy

t-PA (100 mg infused for 15 min), n = 117

Placebo, n = 116

4 events reported (group unspecified)

1

Böttiger et al [43]

2001

Prospective observational trial

Out-of-hospital cardiac arrest

t-PA (50 mg IVP for 2 min with heparin 5000 units bolus), n = 40

Historical matched controls, n = 50

2 events reported with thrombolytics 0 with control, P = .379

2

Böttiger et al [47]

2008

Prospective, randomized, placebo controlled trial

Witnessed out-ofhospital cardiac arrest due to presumed cardiac causes

Tenecteplase (weight-based dosing), n = 525

Placebo, n = 525

2.7% ICH with thrombolytics vs 0.4% with placebo, P b .05

1

Bozeman et al [46]

2006

Prospective observational trial

Atraumatic cardiac arrest

Tenecteplase (weight-based dosing), n = 50

Concurrent group of non-traumatic cardiac arrest n = 113

1 Subarachnoid hemorrhage in the thrombolytic group

2

Er et al [34]

2009

Retrospective review

Highly selected PE patients with witnessed in hospital cardiac arrest

t-PA (mean dose of 80.5 ± 2.4 mg), n = 104

No control

9 life-threatening events

3

Fatovich et al [45]

2004

Out-of-hospital cardiac arrest

Tenecteplase (50 mg as a bolus), n = 19

Placebo n = 16

None

1

Janata et al [51]

2003

Prospective, randomized, placebo controlled trial Retrospective review

Cardiac arrest secondary to massive PE

t-PA (0.6-1 mg/kg, max of 100 mg IV push), n = 30

No thrombolytics, n = 30

No difference in major or minor bleeding

3

JerjesSanchez et al [41]

1995

Prospective, randomized, controlled trial

Unstable massive PE

Streptokinase (1 500 000 units infused for 1 h followed by heparin infusion), n = 8

Heparin infusion, n=8

• Survival to discharge: 1 patient with thrombolytics vs 0 patients with. control arm, P = .99 • No difference in ROSC, hemorrhage (major or minor), hospital LOS • ROSC: 68% with thrombolytics vs 44% with control, (P = .26) • Survival to CICU: 58% with thrombolytics vs 30% with control, P = .009 • Alive at 24 h: 35% with thrombolytic vs 22% with control, P = .171 • Survival to discharge: 15% thrombolytic group vs 8% control, no P value provided • 30 day survival: 14.7% with thrombolytics vs 17% with placebo, P = .36 • No difference in survival to admission, 24-h survival, or ROSC Presumed PE subgroup: • Alive at 30 days: 2/15 (13.3%) with thrombolytics vs 0/22 (0%) with placebo, P = .31 • ROSC: 26% ROSC with thrombolytics vs 12.4% with control, P = .004 • Survival to ICU: 12% with thrombolytics vs 0% with control, no P value provided • Survival to 24 h: 4% with thrombolytics vs 0% with control, no P value provided • Survival to discharge: 4% with thrombolytics vs 0% with controls, no P value provided SAH in the intervention group • ROSC: 38.5% • Patients who achieved ROSC were administered thrombolytics faster than those who did not: 13.6 ± 1.2 min vs 24.7 ± 0.8 min, P b .01 • Survival to discharge: 18% • ROSC: 42% with thrombolytics vs 6% with placebo, P b .05 • No difference in survival • ROSC: 67% with thrombolytics vs 43% with control P = .06, • Survival at 24 h of patients achieving ROSC: 53% with thrombolytics vs 23% with control, P = .01 • Survival to discharge: no difference • Mortality: 0% with thrombolytics vs 100% with control, P = .02

None

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Table 2 (continued) Author(s)

Year

Study type

Population

Thrombolytic (dose), n

Control

Outcome

Bleeding

LOEa

Kurkciyan et al [48]

2000


PE-induced cardiac arrest

No thrombolytic therapy, n = 21

• ROSC: 17 patients (81%) with thrombolytics vs 7 patients (33%) with placebo, P = .03

5 events reported with thrombolytics

3

Kurkciyan et al [49]

2003


Witnessed cardiac arrest due to MI. Specifically assessing the bleeding complications with lytics in cardiac arrest

t-PA (50 mg bolus or 15 mg bolus followed by 85 mg infusion for 90 min), n = 21 t-PA (15 mg bolus, 50 mg for 30 min, 35 mg on 90 min), n = 132

No t-PA, n = 133

• Survival: 63% with thrombolytics vs 35% with control, P b .001

3

Le Conte et al [42]

2003


Unstable massive PE

No control group

• Mortality: 23.8% • Improvement of SBP (in mm Hg) from 88 ± 13 to 121 ± 15 within 2 h, P b .05

Lederer et al [50]

2001


Matched controls, n = 216

• ROSC: 70.4% with thrombolytics vs 51.0% with control, P = .001

6 major events identified at autopsy with thrombolytics 1 ICH

3

Stein and Matta [33]

2012

Retrospective database review

Atraumatic out-ofhospital cardiac arrest with suspected cardiac origin Unstable massive PE

t-PA (0.6 mg/kg, maximum dose of 50 mg, infused for 15 min, followed by heparin), n = 21 t-PA (15 mg bolus followed by 50 mg infused for 30 min then 35 mg infused for 60 min), n = 108 All patients treated with thrombolytics included, agents and doses not reported, n = 21 390

Primary outcome of trial assessed bleeding: 10% major bleeding with thrombolytics vs 5% with control, P = .16 Of note: Risk of bleeding not associated with CPR 5 (23%) minor bleeding events

No thrombolytic therapy, n = 50 840

• Mortality: 15% with thrombolytics vs 47% with control, P b .001 • Treatment was favored when controlled for age and comorbidities

Not reported

3

3

Abbreviations: SBP: systolic blood pressure; ICH, intracranial hemorrhage. a Level of evidence (LOE) [54] determined using the SORT criteria with retrospective reviews considered usual practice for LOE assignment.

treated with thrombolytics. All-cause mortality was significantly lower in the thrombolytic therapy group (15%) when compared with the group not treated with thrombolytics (47%, P b .001). This trend held true when examining case mortality which was specifically attributed to PE (2.7% vs 27%, P b .001). Although these results are strongly in favor of thrombolytic therapy for this population, there were imbalances in the baseline characteristics of the study groups. The age of those treated with thrombolytics was significantly lower than that of those who were not treated. In addition, there were fewer comorbidities in the patient group who received thrombolytics. To adjust for these differences, the authors performed an age-matched evaluation that showed that thrombolytic therapy was associated with lower fatality in all decades of life. Furthermore, unstable patients with no comorbidities had lower mortality with thrombolytic therapy when compared with matched patients who did not receive this therapy. This trial supports the use of thrombolytic therapy in unstable patients with massive PE, and this recommendation is strengthened by the large sample size, age range, and control for comorbidities included. Unfortunately, this retrospective review was unable to report on which thrombolytic agents were used or which dosing strategies were used. In addition, mortality attributable to adverse events associated with thrombolytic therapy was not reported. Finally, patients were identified based on hospital billing codes, which may have erroneously included or excluded patients. Despite these limitations, this study suggests that thrombolytic agents decrease mortality among unstable patients with acute condition who have a massive PE and should be considered for patients of any age. 5.3. Thrombolytic therapy in cardiac arrest: prospective evaluations In 2001, a prospective observational trial of t-PA in cardiac arrest was published by Böttiger et al [43]. This trial was designed to examine the efficacy and safety of thrombolytic therapy in out-of-

hospital cardiac arrest after unsuccessful CPR. The thrombolytic strategy used in this trial was t-PA 50 mg combined with 5000 units of heparin administered as an intravenous push over 2 minutes after 15 minutes of unsuccessful CPR. The control group comprised a historical cohort of patients who experienced out-of-hospital cardiac arrest. This trial was designed to evaluate the safety of the protocol, ROSC, and admission to the cardiovascular intensive care unit (ICU). Of the 90 patients included in this trial, 40 were treated with t-PA. Bleeding complications were observed in 2 patients who both required transfusion due to bleeding from gastric ulcers. There were no bleeding events reported in the control group (P = .379), and no bleeding complications were related to CPR despite prolonged resuscitation efforts. Return of spontaneous circulation was seen in 68% of the thrombolytic group vs 44% of the control group (P = .026). Admission to cardiac ICU and survival to 24 hours were both improved in the thrombolytic group, with admission to cardiac ICU being statistically significant (58% vs 30% [P = .009] and 35% vs 22% [P = .171], respectively). Fifteen percent of the thrombolytic group vs 8% of the control group survived to discharge (no P value provided). This trial did not distinguish what percentage of their patient population arrested due to PE, and it only included patients who were nonresponsive to CPR possibly prolonging the time to treatment with thrombolytic therapy. Furthermore, the nonrandomized trial design limits the ability to assess the impact of the thrombolytic therapy. Despite these limitations, this trial suggests a strong association between thrombolytic therapy and improved mortality as well as a favorable safety profile for administration of thrombolytic agents in cardiac arrest. Abu-Laban et al [44] published a prospective trail regarding the use of thrombolytic therapy in 2002. This was a randomized, blinded, placebo controlled trial conducted in adult patients with PEA arrest unresponsive to initial therapy. The primary outcome of this trial was survival to hospital discharge. All patients received standard ACLS


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care, and the thrombolytic intervention was t-PA 100 mg infused for 15 minutes vs placebo. Resuscitation was continued for a minimum of 15 minutes after the infusion of the study drug. Two hundred thirtythree patients were enrolled in this trial with 117 assigned to t-PA therapy and 116 to placebo. The primary end point was survival to hospital discharge with secondary end points including ROSC, hospital length of stay, and bleeding events. One patient in the t-PA treatment arm survived to discharge, whereas no patients in the placebo group survived. No difference was found in rates of ROSC between the t-PA and placebo groups (21.4% vs 23.3%, P = .99), major hemorrhage (1.7% vs 0%, P = .50), minor hemorrhage (0.9% vs 0.9%, P = .99), or length of stay (0.4 days vs 0.5 days, P = .62). Although the results of this trial are not supportive of the use of t-PA in nonselected PEA cardiac arrest, the lack of a statistically significant difference with major or minor bleeding is promising for the safety of this therapy in cardiac arrest patients receiving CPR. In 2004, Fatovich et al [45] published the results of the TICA trial, which was a prospective randomized, blinded, controlled trial in outof-hospital cardiac arrest, comparing tenecteplase 50 mg as a bolus injection to a matched saline bolus. The primary end point was ROSC, with secondary end points including survival to discharge from the emergency department, ICU, and hospital. Thirty-five patients were enrolled in this trial with 19 patients in the tenecteplase arm and 16 in the placebo arm. A distinguishing feature of the protocol was the use of thrombolytic therapy as the first agent used in the ACLS algorithm. A significant difference was detected in the primary end point, with 42% of patients receiving tenecteplase achieving ROSC with only 6% of the placebo group (95% confidence interval, 11-61). No statistically significant difference was detected in survival, and no bleeding complications were reported. Although the difference in ROSC may yield improved outcomes in clinical practice, some key baseline differences between the groups are noteworthy. The tenecteplase group was significantly younger and had a higher incidence of ventricular fibrillation when compared with the placebo group; these are both characteristics strongly associated with better outcomes after cardiac arrest and may have substantially affected the result seen in the primary end point of this trial. In 2006, Bozeman et al [46] conducted a prospective observational trial comparing atraumatic cardiac arrest patients unresponsive to ACLS interventions who were treated with tenecteplase weight-based dosing vs a control group that presented concurrently without thrombolytic therapy. This trial enrolled 50 patients in the tenecteplase arm and 113 in the control arm to evaluate ROSC, survival to ICU admission, survival at 24 hours, and hospital discharge. Return of spontaneous circulation was achieved in 26% of tenecteplase patients and 12.4% in the control group (P = .04). No statistically significant difference was noted in survival to ICU admission, 24-hour survival, or hospital discharge. One patient in the tenecteplase group experienced an intracranial hemorrhage. Baseline characteristic differed in that patients in the tenecteplase group were younger and more likely to have experienced witnessed cardiac arrest. This issue was evaluated prospectively again in 2008 by Böttiger et al [47]. This trial assessed patients with witnessed out-of-hospital cardiac arrest due to presumed cardiac causes in a randomized, blinded, placebo controlled trial. The interventions in this group included tenecteplase dosed in a weight-based manner vs placebo. The primary end point evaluated 30-day survival and secondary end points included survival to hospital admission, ROSC, survival at 24 hours and discharge, and neurologic outcome. The trial enrolled 1050 patients with 525 in each group. No difference was observed in the 30-day survival outcome between tenecteplase and placebo (14.7% vs 17.0%, P = .36). In addition, no difference was observed in the secondary end points of survival to hospital admission, 24-hour survival, or ROSC. Similar results were observed between the groups for neurologic outcomes. Safety end point showed significantly more intracranial hemorrhage (symptomatic and nonsymptomatic) in patients who received

thrombolytic therapy (2.7% vs 0.4%; risk ratio, 6.95 [95% confidence interval, 1.59-30.41]). A subgroup analysis conducted in this trial showed that the placebo group demonstrated improved outcomes in patients presenting with ventricular fibrillation. In the subgroup of patients who were presumed to have experienced cardiac arrest secondary to PE, 2 (13.3%) of 15 were alive at 30 days in the tenecteplase group, whereas 0 of 22 presumed PE patients in the placebo group survived (P = .31). The analysis of the presented prospective clinical trials suggest that thrombolytic therapy will be beneficial in carefully selected cardiac arrest patients with the cause of cardiac arrest presumed to be secondary to PE. 5.4. Thrombolytic therapy in cardiac arrest: retrospective evaluations Aside from prospectively conducted trials, the treatment of cardiac arrest secondary to PE has also been evaluated retrospectively. A retrospective trial by Kurkciyan et al [48] was published in 2000 and evaluated the effect of t-PA in suspected PE cardiac arrest patients. Thrombolysis was administered as two 50-mg t-PA boluses for 15 minutes or as a 15-mg bolus followed by an 85-mg infusion for 90 minutes. Sixty patients were diagnosed as having PE, and 21 were treated with t-PA (6/21 administered after ROSC). Seventeen patients in the thrombolytic group achieved ROSC, and 2 survived to hospital discharge. The same author also published a retrospective cohort study of patients with witnessed cardiac arrest secondary to acute myocardial infarction treated with t-PA [49]. The primary end point of this trial was to evaluate major bleeding in this patient population. A trend toward an increased risk of major bleeding was associated with thrombolytic therapy with an odds ratio of 2.0 (P = .16). The authors reported that the risk of bleeding was not associated with the duration of CPR. Survival was assessed as a secondary end point. Sixty-three percent (83/132) of the patients in the t-PA group survived, and 35% (47/133; P b .001) survived in the control group. The review of these retrospective studies alerts practitioners that thrombolytic therapy has shown improved survival in many patient populations such as acute myocardial infarction and PE, but there is also a substantial risk of bleeding associated with this intervention. In 2001, a large retrospective observational trial was conducted in patients with atraumatic out-of-hospital cardiac arrest [50]. This trial was designed to evaluate the impact of thrombolytic therapy on ROSC and hospitalization and excluded patients with obvious noncardiac disease as the cause of their arrest. Use of t-PA was optional. The thrombolytic agent used in this trial was t-PA dosed as a 15-mg bolus followed by 50 mg infused for 30 minutes, then 35 mg infused for 60 minutes and was administered in 108 patients. Two hundred sixteen patients matched for baseline characteristics and not treated with tPA during resuscitation served as controls. Baseline characteristics differed between the groups, with the control group being significantly older than those who received t-PA therapy. Of the individuals treated with t-PA, 65 had a presumptive diagnosis of an acute myocardial infarction and 19 were presumed to have massive PE. Of the total intervention population, 70.4% experienced ROSC, compared with 51.0% of controls (P = .001). Forty-eight percent of patients treated with t-PA survived 24 hours (vs 32.9% of controls, P = .003). When looking specifically at patients with a presumptive diagnosis of PE, 57.9% survived 24 hours and 31.6% survived to discharge; corresponding data were unfortunately not presented for the control population. Adverse events attributable to thrombolytic therapy were evaluated in patients with 45 available for autopsy. At autopsy, 6 of these patients had serious bleeding events; however, the number of patients with intracranial hemorrhage and cardiac tamponade was similar between the thrombolytic and control groups. Janata et al [51] conducted a retrospective review specifically of cardiac arrest patients with the cause of arrest secondary to massive PE. The review evaluated t-PA administered at 0.6 to 1.0 mg/kg as a bolus injection, with a maximum dose of 100 mg. Patients treated



with t-PA were compared with a control group who were not treated with thrombolytics. Sixty-six patients with cardiac arrest secondary to a massive PE were reviewed with 36 of these patients treated with tPA. Major and minor bleeding events were similar between the 2 groups and were not more frequent in individuals treated with CPR for more than 10 minutes of duration. Return of spontaneous circulation showed a trend toward improvement in the t-PA group (67% vs 43%, P = .06) as well as survival to discharge (19% vs 7%, P = .15). Survival at 24 hours was significantly better in the thrombolytic group when compared with the control group (53% vs 23%, P = .01). Er et al [34] also retrospectively reviewed a similar patient population of in-hospital cardiac arrest patients with the suspected cause of arrest due to PE. Patients in this trial were treated with bolus dose tPA with an average dose of 80.5 ± 24 mg. One hundred four patients were included; 63 patients had confirmed PE and 41 patients had highly suspected PE. No control group was included in this trial, and many methodological details were not included in the trial publication. Return of spontaneous circulation was achieved in 38.5% of patients. The authors note that there was a significantly shorter time to administration of thrombolytic therapy in patients who achieved ROSC (13.6 ± 1.2 minutes) compared with patients who did not (24.7 ± 0.8 minutes, P b .001). This same trend was observed with survival to hospital discharge. Of the patients who achieved ROSC, 47.5% survived to discharge and received thrombolytic therapy earlier (11.0 ± 1.3 minutes) when compared with those who did not survive (22.5 ± 0.88 minutes, P b .01). These data imply that early treatment with thrombolytic therapy may be associated with improved outcomes. Nine of the patients who achieved ROSC experienced life-threatening bleeding, with 6 of the 9 surviving to discharge. These retrospective trials evaluating the specific population of cardiac arrest secondary to massive PE suggest that thrombolytic therapy administered in a timely manner may be associated with improved clinical outcomes. Information allowing practitioners to make an early diagnosis of massive PE in arrest situations is imperative to implementing this therapy and should be evaluated in a prospective randomized manner. 6. Discussion The above literature review shows that unstable or arresting patients experiencing massive PE will likely benefit from thrombolytic therapy. Studies with a retrospective design generally demonstrated the best outcomes, as was expected, due to the patient population having a known or high risk for PE, and possibly publication bias of positive results. Trials with a prospective design had more variation because these trials generally included a heterogeneous patient population in cardiac arrest and illustrates the potential difficulty of applying this intervention in real-time clinical practice. Analysis of the subgroup population of patients with PE in the prospective trials showed possible improved outcome after thrombolytic therapy, although these studies were not powered to look specifically at this group. This disparity emphasizes the importance of patient selection when evaluating for the efficacy of thrombolytic therapy. Patient identification is equally important for the risk mitigation of thrombolytic therapy. Current ACLS guidelines do not advocate for thrombolytic therapy unless the patient has a known PE. However, the ACLS guidelines indicate that thrombolytics should be considered for cardiac arrest due to presumed PE [52]. It is critical for the clinician to evaluate the risks and benefits of this intervention for each patient. Often, this assessment is based on the best available information, which is virtually always incomplete, sometimes contradictory and occasionally incorrect. As a result of this assessment, contraindications of thrombolytic therapy are frequently disregarded for arresting patients with a suspected PE. For example, recent surgery is a familiar contraindication to thrombolytic therapy; however, postoperative patients are at high risk for the development of a PE and may confer a

7

benefit from thrombolytics in arrest situations. Furthermore, many contraindications of thrombolytic therapy, such as severe or uncontrolled hypertension, will not be known to the emergency practitioner while resuscitating a patient in cardiac arrest. In general, despite the theoretical concern of hemorrhagic complications after thrombolytic administration, most patients in cardiac arrest due to suspected PE should receive thrombolytics because outcomes of cardiac arrest due to PE are uniformly poor. In addition to manufacturer-listed contraindications, CPR has also traditionally been considered a contraindication for thrombolytic therapy. When evaluating the prospective trials that administered this intervention to patients who did receive CPR, most did not show a significant difference in outcomes with regard to major or minor bleeding associated with CPR [43–45]. However, when examining the largest of these prospective trials, significantly more intracranial hemorrhages were identified in the thrombolytic group [47]. Despite the increased risk of bleeding, the subgroup of patients with PE in this trial still showed better outcomes with thrombolytic therapy than with placebo, again highlighting the importance of proper patient selection for thrombolytic therapy and discounting CPR as a potential contraindication in selected patients. To truly illicit the risks and benefits of this therapy, an ideal future prospective trial will incorporate a highly selected patient population based on known risk factors and diagnostic results suggestive of PE, such as the clinical decision rule triad described and right ventricular hypokinesis, to evaluate the impact of thrombolytic therapy in likely PE-induced cardiac arrest. Until future trials provide more specific guidance, current ACLS guidelines are generally congruent with the literature reviewed above, supporting the administration of thrombolytics for cardiac arrest due to confirmed or suspected PE. Once the decision is made to move forward with thrombolytic therapy in this patient population, providers caring for unstable or arresting patients are pressured to quickly administer the intervention as early administration has been shown to improve outcomes. As a result, a protocol is highly recommended and available in the literature [53]. All protocols should include factors associated with PE as well as the choice and dosing regimen of the thrombolytic agent. Although t-PA has been extensively evaluated and is approved by the Food and Drug Administration for PE as an infusion for 2 hours, the dosing for cardiac arrest or periarrest where rapid treatment is vital for improving patient outcomes is unclear. The authors recommend administration of t-PA as an initial bolus of 50 mg with a subsequent bolus of an additional 50 mg if the first dose is unsuccessful. However, there is no consensus among published guidelines for appropriate dosing in this critical patient population. Although tenecteplase does not currently have an approved indication for the treatment of PE, it should also be considered because of its significant pharmacokinetic advantage to allow optimal administration as an intravenous push dose over 5 seconds. Tenecteplase does not carry the dosing uncertainty seen with t-PA because there is a clear weight-based dosing regimen. This article offers a comprehensive review of clinical findings and history most correlated with PE, detailed information comparing and contrasting thrombolytic agents, and an extensive review of the published prospective and retrospective data evaluating meaningful patient centered outcomes, allowing the emergency medicine provider to make informed clinical decisions when caring for patients in life-threatening situations. Acknowledgment The authors thank Henry Yeh, PharmD. References [1] Hess EP, Campbell RL, White RD. Epidemiology, trends, and outcome of out-ofhospital cardiac arrest of non-cardiac origin. Resuscitation 2007;72(2):200–6.


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Thrombolytic treatment of pulmonary embolism.

Thrombolytic therapy for cardiac arrest secondary to acute pulmonary embolism: an oft overlooked strategy.

Ultra-long cardiopulmonary resuscitation with thrombolytic therapy for a sudden cardiac arrest patient with pulmonary embolism.

Thrombolytic treatment (alteplase; rt-Pa) in acute massive pulmonary embolism and cardiopulmonary arrest.

Double Bolus Thrombolysis for Suspected Massive Pulmonary Embolism during Cardiac Arrest.

Thrombolytic therapy for pulmonary embolism.

Thrombolytic therapy for the treatment of acute pulmonary embolism.

Use of thrombolytic agents to treat pulmonary embolism in pregnancy.

Treatment of Suspected Pulmonary Embolism in a Super-Obese Individual.

Cardiac rupture and time to thrombolytic treatment.

Study of Cardiac Arrest Caused by Acute Pulmonary Thromboembolism and Thrombolytic Resuscitation in a Porcine Model.

Acute pulmonary embolism due to hydatid cysts.

Diagnosis of pulmonary embolism.

Observations in anticoagulant and thrombolytic therapy in pulmonary embolism.

Computed Tomography Pulmonary Angiography for Evaluation of Patients With Suspected Pulmonary Embolism: Use or Overuse.

Ventilation-perfusion studies in suspected pulmonary embolism.

Modeling the diagnosis and treatment of pulmonary embolism.

Diagnosis and treatment of pulmonary embolism: a multidisciplinary approach.

Cardiac arrest due to liquoriceinduced hypokalaemia.

Thrombolytic and anticoagulant therapy for acute submassive pulmonary embolism.

Cardiac arrest due to baclofen withdrawal syndrome.

or hypoxia.

Education for cardiac arrest--Treatment or prevention?

Cardiac arrest due to oral potassium administration.