Thrombolytic therapy efficacy in cardiopulmonary resuscitation: Investigating the effect of recombinant tissue plasminogen activator (Review)

Introduction

Cardiopulmonary resuscitation (CPR) is a life-saving emergency technique used after cardiac arrest to restore spontaneous circulation and maintain oxygenated blood flow to vital organs, particularly the brain and heart (1). It involves chest compressions and artificial ventilation; compressions simulate the heart's pumping action, while ventilation supplies oxygen to the lungs (2).

Despite its importance, CPR faces challenges. Survival rates for out-of-hospital cardiac arrests remain low, with only 5–10% of patients surviving to hospital discharge (3). Several factors affect outcomes, including delays in CPR initiation, the quality of compressions, the cause of the arrest and reversible conditions such as pulmonary embolism or myocardial infarction (4,5). Inadequate advanced interventions and post-resuscitation care also reduce success rates, driving ongoing efforts to enhance CPR effectiveness and neurological outcomes (6).

Thrombolytic therapy, or fibrinolysis, uses drugs to dissolve clots that block critical blood vessels (7). In cardiac arrest, thrombolysis targets clots contributing to circulatory failure, such as those from myocardial infarction or pulmonary embolism (8). This strategy is well-established in acute myocardial infarction and ischemic stroke, where prompt clot dissolution improves perfusion and limits tissue damage (9). Applying thrombolytics during CPR is based on the premise that thrombotic occlusions may trigger or worsen cardiac arrest (10). By incorporating thrombolytic agents into CPR protocols, blood flow is considered to be more effectively restored, thereby enhancing the chances of successful resuscitation and improving overall outcomes (8). However, this approach carries bleeding risks, so its use requires careful risk-benefit assessment.

Recombinant tissue plasminogen activator (rtPA) is a bioengineered version of a naturally occurring enzyme that plays a critical role in the breakdown of blood clots. rtPA converts plasminogen, a blood protein, into plasmin, an enzyme that dissolves fibrin clots (11). Due to its targeted action on fibrin, rtPA is highly effective in dissolving clots while minimizing systemic effects (12). In the context of thrombolytic therapy for CPR, rtPA is considered one of the most promising agents. Its efficacy has been well-documented in the treatment of acute ischemic stroke and myocardial infarction, leading researchers to explore its potential benefits in cardiac arrest scenarios (13). rtPA presents advantages over conventional TPA, including a more favorable pharmacokinetic profile that enables faster thrombolysis, which is crucial in cardiac arrest. Additionally, rtPA has a lower risk of immunogenic reactions, enhancing its safety (14). The administration of rtPA during CPR could potentially address the thrombotic component of certain cardiac arrests, thus enhancing the likelihood of restoring spontaneous circulation (15). The present review aims to critically analyze the efficacy of thrombolytic therapy, specifically focusing on the role of rtPA in CPR. The present review evaluated the current evidence surrounding rtPA administration during CPR, considering its effect on patient outcomes, such as survival rates, neurological function and long-term prognosis. By synthesizing available research findings the present review provided insights into the potential benefits, limitations and optimal protocols for implementing rtPA in CPR protocols, ultimately contributing to informed decision-making and advancements in resuscitative care strategies.

Mechanism of action of thrombolytic therapy in CPR

The fibrinolytic pathway and clot dissolution

The fibrinolytic pathway is a crucial biological mechanism responsible for the breakdown of thrombi. This pathway removes unnecessary or harmful clots, maintaining vascular patency and normal blood flow, but it can also disrupt normal hemostasis, increasing the risk of bleeding (16). The process begins with activating plasminogen, a precursor glycoprotein converted into its active form, plasmin (17). Plasmin is a serine protease that digests fibrin, the primary protein constituent of blood clots (18) (Fig. 1). The fibrinolytic system can be activated via two pathways: The intrinsic pathway, initiated by contact with negatively charged surfaces, and the extrinsic pathway, which is triggered by tissue plasminogen activator (tPA) or urokinase plasminogen activator (uPA) released from endothelial cells in response to injury or stress (17,19). In considering thrombolytic therapy, a comparative analysis of tPA and uPA is crucial. tPA is widely preferred for its rapid action and specificity for fibrin-bound plasminogen, making it effective in acute ischemic stroke and myocardial infarction. However, its use may be restricted by bleeding risks and contraindications (20,21). Conversely, uPA, while less commonly used, offers advantages in patients with higher bleeding risk or contraindications to tPA and it can be effective in various thrombotic conditions, including pulmonary embolism. A thorough comparison of these agents can guide clinicians in making informed decisions tailored to individual patient needs and specific clinical scenarios (22).

Figure 1. Mechanisms of rtPA in CPR. From clot formation to the restoration of normal blood flow, rtPA plays a critical role in enhancing patient outcomes during cardiac emergencies. Created with BioRender.com. rtPA, recombinant tissue plasminogen activator; CPR, cardiopulmonary resuscitation; uPA, urokinase plasminogen activator; PAI-1, plasminogen activator inhibitor-1.

The use of tPA and uPA carries inherent bleeding risks and specific contraindications. For tPA, the reported risk of symptomatic intracranial hemorrhage (ICH) is ~6.4% when administered for acute ischemic stroke, with overall bleeding risks reaching 10–15%. Contraindications for tPA include recent intracranial hemorrhage, active bleeding, significant head trauma, major surgery within the past three months and severe uncontrolled hypertension (23). By contrast, uPA is associated with a lower overall bleeding risk, estimated at 1–2% for major events, although its specific risk profile is less characterized compared with tPA (24). Regarding efficacy, tPA has demonstrated 30–35% effectiveness in achieving functional independence in ischemic stroke patients and is effective in myocardial infarction and pulmonary embolism (25). In comparison, uPA has shown variable efficacy rates, typically lower than tPA and is not as widely accepted in acute stroke or myocardial infarction. tPA has high fibrin specificity, a half-life of <5 min and is administered via bolus and infusion over 90 min, while uPA lacks fibrin specificity, has a half-life of 10–20 min and is given as an infusion. The two agents have similar ICH risks, but tPA shows higher rates of recanalization and improved long-term recovery outcomes (26). In terms of roles in stroke, tPA is critical for acute thrombolysis, affecting vascular permeability and inflammation, while uPA promotes synaptic recovery during the recovery phase. tPA disrupts the blood-brain barrier, increasing permeability and leukocyte infiltration, whereas uPA may enhance neovascularization (27). Overall, tPA can enhance synaptic plasticity but may induce excitotoxicity, while uPA supports neuronal recovery and synaptic repair. Understanding these parameters is crucial for optimizing thrombolytic therapy and managing associated risks effectively.

Role of rtPA in converting plasminogen to plasmin

rtPA is a synthetic form of the naturally occurring tPA designed for therapeutic use to enhance clot dissolution (28). rtPA functions by binding to fibrin within the clot and converting the adjacent plasminogen to plasmin (29). This localized conversion is critical as it ensures that plasmin is generated primarily at the site of the thrombus, minimizing systemic activation, which could lead to widespread bleeding complications (30,31). Once administered, rtPA enhances the conversion efficiency of plasminogen to plasmin, amplifying the fibrinolytic activity at the site of the thrombus. This increase in plasmin leads to the more rapid and effective breakdown of fibrin, the structural framework of the clot. By dissolving the fibrin mesh, rtPA facilitates the disintegration of the thrombus, thereby restoring blood flow through the occluded vessel (32).

In comparing rTPA with conventional plasminogen activators such as TPA, several key differences emerge that highlight the advantages of rTPA in clinical practice. rTPA specifically targets fibrin-bound plasminogen, which enhances fibrinolysis directly at the site of the clot. This targeted action increases its effectiveness in dissolving thrombi, a critical factor in acute ischemic events (33). Furthermore, rTPA demonstrates a more rapid onset of action compared with conventional TPA, allowing for quicker therapeutic effects in urgent situations. This rapid response is crucial for improving patient outcomes in acute stroke management. The pharmacological profile of rTPA also emphasizes its preferential action on clot-bound fibrin, which markedly boosts its efficacy in thrombus dissolution (34). The safety profile of rTPA is more thoroughly characterized in the literature, with studies indicating a clearer understanding of its potential adverse drug reactions (35). Notably, while both agents carry a risk of bleeding, the specific safety data of rTPA provide clinicians with more reliable information for risk assessment. Additionally, rTPA has a shorter half-life, which is beneficial for managing acute ischemic events, as it allows for rapid clinical adjustments based on the patient's response (36). These distinctions not only elucidate the pharmacological advantages of rTPA but also underscore its role in improving therapeutic outcomes in patients requiring acute thrombolytic therapy (37).

Potential benefits of thrombolysis in restoring coronary and pulmonary blood flow

Thrombolytic therapy, particularly with agents such as rtPA, holds significant potential benefits during CPR. Thrombotic occlusions during cardiac arrest can impair coronary and pulmonary circulation, worsening myocardial and cerebral ischemia and lowering resuscitation success rates. By dissolving these clots, thrombolytic therapy can restore blood flow and improve oxygen delivery to vital organs (38). In acute myocardial infarction or massive pulmonary embolism (PE)-induced arrest, rtPA can rapidly dissolve the causative thrombi, reestablish coronary perfusion and potentially convert non-perfusing rhythms, such as ventricular fibrillation or pulseless electrical activity, into perfusing ones (39,40). Similarly, in PE, thrombolysis can alleviate the obstruction in the pulmonary arteries, reduce right ventricular strain and enhance cardiac output. Restoring coronary and pulmonary circulation during CPR can improve resuscitation efficacy, stabilize hemodynamics and increase return of spontaneous circulation (ROSC) rates (41). Reducing ischemic time may also lessen post-resuscitation myocardial dysfunction and limit ischemic damage to the heart and other organs (42,43). Consequently, integrating thrombolytic therapy into CPR protocols, especially in cases where thrombotic occlusions are suspected, can be a crucial strategy to improve survival outcomes and neurological recovery in cardiac arrest patients (44).

Diagnosing PE and ST-elevation myocardial infarction (STEMI) during CPR poses significant challenges for clinicians. Rapid decision-making is crucial, often relying on clinical history, symptoms and immediate ECG findings. In STEMI, chest pain and ST-segment elevation guide diagnosis, while PE may present with sudden dyspnea and hemodynamic instability (45). To confirm thrombotic causes quickly, point-of-care ultrasound and imaging techniques such as computed tomography pulmonary angiography are helpful, though not always available during CPR. Clinicians may also use risk stratification tools, such as the Wells score for PE and the TIMI score for STEMI (38), along with biomarkers such as cardiac troponins and D-dimer levels, to inform their decisions regarding rtPA administration. Ultimately, timely identification requires a high level of clinical awareness and effective teamwork (46).

Application of thrombolytic therapy in CPR

Clinical studies and trials evaluating thrombolytic therapy in CPR

Thrombolytic therapy, particularly rtPA, has been explored as an adjunct to standard CPR protocols in several clinical studies and trials (Fig. 2). For instance, the TICA trial indicated that rtPA could improve ROSC rates, with reported rates of ~35% in the rtPA group compared with ~20% in standard CPR cases (47). However, it also raised concerns about safety, necessitating further research on optimal dosing and outcomes. In a study by Bozeman et al (48), the use of tenecteplase (TNK) after failed Advanced Cardiac Life Support (ACLS) measures resulted in a ROSC rate of 26% compared with 12.4% in the control group (P=0.04). Additionally, 12% of TNK patients survived to admission compared with none in the control group (P=0.0007). This study emphasized the potential benefit of timely intervention, as TNK was given after an average of 30 min of cardiac arrest.

Figure 2. The potential benefits of thrombolytic therapy, particularly rtPA, in improving rates of ROSC during CPR are highlighted. It emphasizes observed outcomes, such as increased ROSC rates and early survival, while also addressing significant challenges and limitations, including the risk of bleeding complications, variable patient responses and logistical hurdles in therapy administration. Together, these elements underscore the complex considerations that healthcare providers must navigate when integrating thrombolytic therapy into CPR protocols. Created with BioRender.com. rtPA, recombinant tissue plasminogen activator; ROSC, return of spontaneous circulation; CPR, cardiopulmonary resuscitation.

In a prospective study, 108 patients received rtPA during CPR, while 216 matched controls received standard CPR without thrombolysis. The rtPA group demonstrated markedly improved outcomes, with ROSC achieved in 70.4% compared with 51.0% in the control group. Additionally, 24-h survival was 48.1% in the rtPA group compared with 32.9% in controls. Survival to hospital discharge was also higher in the rtPA group at 25.9%, although exact comparative data for the control group was not specified. Among patients with presumed PE, outcomes were even more favorable: 24-h survival was 57.9% and discharge survival reached 31.6%. Bleeding complications occurred in 5.6% of rtPA patients, including one case of intracranial hemorrhage (0.9%), which was equal to the ICH rate of the control group (0.9%) (30). In a retrospective study of 66 patients with CA, rtPA administered during or shortly after CPR was associated with improved early survival outcomes compared with standard CPR protocols. ROSC was achieved in 67% of patients in the rtPA group compared with 43% in the standard CPR protocol group and 24-h survival was markedly higher at 53% compared with 23% in controls. Importantly, prolonged CPR (≥10 min) did not correlate with increased bleeding risk. The data suggest that administration of rtPA during CPR for CA could improve ROSC and short-term survival compared with the standard CPR protocols (49).

In another prospective study involving 90 patients with out-of-hospital cardiac arrest, 40 received rt-PA during CPR, while 50 received standard CPR alone. Thrombolytic therapy markedly improved clinical outcomes. ROSC occurred in 68% of rt-PA patients compared with 44% of controls and 58% were admitted to a cardiac intensive care unit compared with 30% of controls. Although 24-h survival (35 vs. 22%) and hospital discharge rates (15 vs. 8%) favored the rtPA group, these differences were not statistically significant. Notably, no bleeding complications related to CPR were observed. However, two rtPA patients experienced gastrointestinal bleeding requiring transfusion, occurring 2- and 12-days post-arrest (19). In a randomized, double-blind, placebo-controlled trial involving 233 patients with cardiac arrest and presumed cardiovascular etiology, the efficacy of tPA during CPR was evaluated against standard CPR alone. Patients were randomized to receive either tPA or placebo in addition to standard CPR. ROSC occurred in 21.4% of the tPA group and 23.3% of the placebo group, showing no significant benefit. Only one patient (0.9%) in the tPA group survived to hospital discharge, compared with none in the placebo group. Four tPA patients survived more than 24 h post-admission, but this did not translate into improved overall outcomes (50).

The Thrombolysis in Cardiac Arrest (TROICA) study (51), an international multicenter trial, evaluated the efficacy and safety of tenecteplase during CPR for out-of-hospital cardiac arrest. Despite its larger scale, TROICA found no significant improvement in long-term survival or neurological outcomes compared with placebo. The study reported ROSC rates of ~30% in the rtPA group compared with 20% in the control group. Timing was critical; rtPA was administered as soon as feasible after ROSC, typically within 30 min. However, the quality of post-resuscitation care varied, which may have obscured the potential benefits of thrombolysis. Furthermore, Bakkum et al (36) demonstrated that an accelerated regimen of rtPA (0.6 mg/kg in 15 min) resulted in a trend toward higher ROSC rates (67 compared with 43%; P=0.06) compared with no thrombolysis in patients with pulmonary embolism-induced circulatory arrest. Amini et al (35) investigated the efficacy and safety of reduced doses of rtPA in patients with acute pulmonary embolism, comparing it to standard doses and anticoagulation therapy. Analyzing data from 13 studies, including four observational studies with 4,223 patients and nine randomized controlled trials involving 780 patients, the authors found that the reduced dose was associated with a markedly lower incidence of total bleeding events (RR 5.08; 95%CI 1.39–18.6) compared with anticoagulants. Furthermore, when comparing standard and reduced doses of rtPA, the standard dose showed a greater incidence of bleeding (RR 1.48; 95%CI 1.00–2.19). Importantly, there were no significant differences in all-cause mortality or recurrence of PE between the treatment groups, suggesting that a reduced dose of rtPA offers a safer alternative without compromising efficacy. Doelare et al (52) investigated the relationship between fibrinogen levels and major bleeding risk during catheter-directed thrombolysis for acute limb ischemia. Of 443 patients treated with rtPA, the overall incidence of major bleeding was 7%. Patients with fibrinogen levels below 1.0 g/l had a markedly higher bleeding rate (15 vs. 6%; P=0.041), highlighting low fibrinogen as a critical risk factor. Additionally, high-dose thrombolytic regimens and older age were independent predictors of major bleeding. The TROICA study reported a lower incidence of major bleeding complications at ~3%, attributed to careful patient selection and monitoring (51). The contrasting results across these studies may be attributed to several factors, including variability in patient characteristics (such as age or comorbidities) that may influence outcomes, as seen in the TROICA study where patient selection criteria were stringent (53). The timing of rtPA administration markedly affected outcomes; studies that administered rtPA more quickly after cardiac arrest generally reported improved results. Additionally, differences in dosing strategies (standard compared with accelerated or reduced doses) could explain variations in efficacy and safety profiles observed in different trials (54). Finally, variability in post-resuscitation care protocols across studies can markedly affect observed outcomes. Factors such as the availability of advanced monitoring, therapeutic hypothermia and comprehensive cardiac care can differ widely between institutions and trials. Inconsistent care may obscure the potential benefits of thrombolytic therapy, as optimal post-resuscitation management is crucial for patient recovery and overall survival (55) (Table I). It is important to note that neurological outcomes have not been evaluated in most of these studies.

Table I. Comparison of rtPA and standard CPR protocols.

Table I.

Comparison of rtPA and standard CPR protocols.

Trial or first author/s, year	Intervention	ROSC rates	Survival rates	Key findings	(Refs.)
Böttiger et al, 2001	rtPA	68 (rtPA) vs. 44% (control)	24 h: 35 vs. 22%; discharge: 15 vs. 8%	rtPA improved outcomes, but survival differences were not statistically significant. No CPR-related bleeding; 2 GI bleeds in rtPA group	(19)
Lederer et al, 2001	rtPA	70.4% (rtPA) vs. 51.0% (control)	24 h survival: 48.1 vs. 32.9%; discharge: 25.9% (rtPA); control not specified	rtPA improved ROSC and survival. PE subgroup had even higher 24 h (57.9%) and discharge (31.6%) survival. Bleeding: 5.6, ICH: 0.9% (same as control)	(30)
Amini et al, 2021	Reduced dose rtPA	Not specified	No significant differences	Reduced doses led to fewer bleeding events without compromising efficacy	(35)
Bakkum et al, 2021	Accelerated rtPA	67 (accelerated) vs. 43% (no thrombolysis)	Not specified	Higher ROSC rates with accelerated dosing for pulmonary embolism	(36)
TICA trial, 2004	rtPA	35 (rtPA) vs. 20% (standard CPR)	Not specified	Improved ROSC with rtPA; raised safety concerns	(47)
Bozeman et al, 2006	Tenecteplase (rtPA)	26 (rtPA) vs. 12.4% (control)	12 (rtPA) vs. 0% (control)	Emphasized timely intervention; rtPA given after 30 min	(48)
Janata et al, 2003	rtPA	67 (rtPA) vs. 43% (control)	24 h survival: 53 vs. 23%	rtPA improved ROSC and 24h survival. No increased bleeding with prolonged CPR.	(49)
Abu-Laban et al, 2002	tPA	21.4 (tPA) vs. 23.3% (placebo)	Discharge: 0.9 (tPA) vs. 0% (placebo); 4 tPA patients survived >24h	No significant benefit of tPA. Only one discharge survivor in tPA group	(50)
TROICA study, 2005	Tenecteplase (rtPA)	30 (rtPA) vs. 20% (control)	No significant improvement	No long-term survival benefit; variability in post-resuscitation care	(51)
Doelare et al, 2023	rtPA	Not specified	Major bleeding incidence: 7%	High fibrinogen levels linked to increased bleeding risk	(52)

[i] rtPA, recombinant tissue plasminogen activator; CPR, cardiopulmonary resuscitation; ROSC, return of spontaneous circulation.

Efficacy outcomes, rates of ROSC and survival to hospital admission and discharge

The efficacy of thrombolytic therapy in the context of CPR is primarily measured through rates of ROSC, survival to hospital admission and survival to hospital discharge with favorable neurological outcomes (56). In studies where thrombolytics were administered, an increase in ROSC rates was often observed (57). For instance, a meta-analysis of several small trials indicated a statistically significant improvement in ROSC rates when rtPA was used. However, the effect on survival to hospital discharge remains less definitive (58). This highlights the need to distinguish between short-term efficacy (such as ROSC and hospital admission) and long-term outcomes (such as survival to discharge and neurological recovery). While some studies have reported higher survival rates for hospital admission, these improvements do not always translate to long-term survival or favorable neurological outcomes (59). The TROICA trial, for example, found no significant difference in survival to hospital discharge between the thrombolytic and placebo groups, highlighting the complexity and potential limitations of thrombolytic therapy in CPR. Moreover, even when ROSC is achieved, the potential for hypoxic brain injury and subsequent neurological impairment remains high, underlining the importance of evaluating therapies not only for their ability to restore circulation but also for their influence on neurological prognosis and functional recovery (60,61). Future studies and clinical protocols should prioritize these distinctions to improved assess the true benefit of thrombolytic therapy in cardiac arrest scenarios.

Comparison of outcomes between thrombolytic therapy and standard CPR protocols

The data reveals potential benefits and notable risks when comparing outcomes between thrombolytic therapy and standard CPR protocols. Standard CPR protocols, which do not include thrombolytics, have established benchmarks for ROSC and survival rates. Thrombolytic therapy, in theory, offers an advantage by addressing underlying thrombotic causes of cardiac arrest, potentially enhancing coronary and cerebral perfusion during resuscitation efforts (19). However, while some studies suggest improved ROSC rates with thrombolytics, the overall survival to hospital discharge and neurological outcomes do not consistently show significant improvements over standard protocols (62). Moreover, the risk of adverse effects, particularly hemorrhagic complications, remains a critical concern. Bleeding risks associated with thrombolytic therapy can offset potential benefits, especially in the context of traumatic cardiac arrests or in patients with underlying conditions predisposing them to hemorrhage (63).

Indications and patient selection for thrombolytic therapy in CPR

Identification of suitable candidates for thrombolytic treatment in CPR

Identifying suitable candidates for thrombolytic therapy during CPR involves assessing the underlying cause of cardiac arrest, the patient's medical history and the likelihood of a favorable outcome from thrombolysis. Thrombolytic therapy, particularly with rtPA, is most beneficial in cases where cardiac arrest is due to PE, MI or other thrombotic events (64). Clinicians should prioritize patients with witnessed arrest, a short duration of arrest before the initiation of CPR and those without severe comorbidities (65). The presence of risk factors such as recent surgery, active bleeding, or a history of hemorrhagic stroke generally contraindicates the use of thrombolytics due to the elevated risk of bleeding complications (44,58). If available, advanced imaging techniques such as echocardiography or computed tomography scans can help confirm the presence of thrombi, guiding the decision to administer rtPA (44). Thrombolytic therapy in CPR involves careful consideration of various factors, including indications such as pulmonary embolism and myocardial infarction (44), as well as exclusion criteria like active bleeding and recent surgery (66) (Table II). Patient selection is critical, taking into account age, sex, and pre-existing conditions such as carotid artery stenosis (67,68). Administering therapy promptly can improve survival and neurological outcomes (69,70). This therapy should be coupled with adjunctive treatments (71), and careful monitoring (72), while adhering to established clinical guidelines for individualized care (73).

Table II. Overview of indications and patient criteria for thrombolytic therapy in CPR.

Table II.

Overview of indications and patient criteria for thrombolytic therapy in CPR.

First author/s, year	Category	Details	(Refs.)
Javaudin et al, 2019	Indications	1. Pulmonary embolism: Suspected or confirmed massive pulmonary embolism causing cardiac arrest.	(44)
		2. Myocardial infarction: ST-elevation myocardial infarction leading to cardiac arrest.
Page et al, 2021	Exclusion criteria	1. Active internal bleeding: contraindicated due to the risk of exacerbating bleeding.	(66)
		2. Recent surgery or trauma: Due to bleeding risk within the past 2–4 weeks.
Higgins, 2011/Blum et al, 2019	Patient selection	1. Age levels: Males under 75 and females under 70 are often preferred for thrombolytic therapy due to a more favorable risk-to-benefit ratio.	(67,68)
		2. Sex factors: Sex differences were observed, with more females excluded due to clinical risk factors associated with age, such as carotid artery stenosis and history of previous strokes.
		3. Health conditions: Significant health conditions impacting eligibility for thrombolytic therapy included:
		• Carotid artery stenosis: Higher exclusion rates in both males and females.
		• Atrial fibrillation: Particularly affected male patients.
		• Previous stroke: Increased likelihood of exclusion for both sexes.
		4. Time since arrest: Best outcomes if administered within min to a few h of arrest.
Stang, 2010/Qiao et al, 2024	Outcomes	1. Survival rates: Increased survival rates in selected patients, particularly those with pulmonary embolism.	(69,70)
		2. Neurological outcomes: Improves functional recovery and reduces post-stroke complications, such as sleep disturbances, epilepsy, anxiety and depression, thereby enhancing overall quality of life.
Broderick et al, 2021	Adjunctive therapies	1. Anticoagulation: Heparin, in forms such as low molecular weight heparin or unfractionated heparin, is used alongside Warfarin, which is started after thrombolytic treatment to prevent re-thrombosis.	(71)
		2. Mechanical support: Use devices such as extracorporeal membrane oxygenation for hemodynamic support in select cases.
Kluft et al, 2017	Monitoring and follow-up	1. Bleeding risks: Continuous monitoring for bleeding complications involves clinical assessments for signs such as bruising and unusual mucosal bleeding, regular laboratory tests to evaluate coagulation parameters such as activated partial thromboplastin time and prothrombin time and event reporting to document bleeding occurrences, categorizing them as major or minor based on severity.	(72)
		2. Cardiac function: Regular assessment of cardiac function post-therapy.
Renard et al, 2011	Clinical guidelines	1. The American Heart Association and the American College of Cardiology guidelines: Follow specific protocols for thrombolytic administration in CPR.	(73)
		2. Individualized care: Decisions tailored based on patient condition and response.

[i] CPR, cardiopulmonary resuscitation.

Considerations for timing, dosing and administration route of rtPA

The timing of thrombolytic therapy during CPR is crucial for its effectiveness. The administration of rtPA should occur as early as possible after cardiac arrest, ideally within the first few min of CPR, to maximize the chances of restoring spontaneous circulation (74). This approach is supported by findings from observational studies and case series, which indicate that early administration of thrombolytics, particularly within the first 10–15 min of arrest, is associated with improved ROSC and neurological outcomes. Additionally, recommendations from the European Resuscitation Council and the American Heart Association suggest considering thrombolytics during CPR in patients with suspected or confirmed PE, provided that administration does not markedly delay other resuscitative efforts (65,75–77).

The standard dosing regimen for rtPA in the context of CPR often involves a bolus injection followed by a continuous infusion. However, protocols may vary based on institutional practices and patient-specific factors (54). The typical dose ranges from 50–100 mg of rtPA, administered over 15–60 min as observed in studies and clinical guidelines addressing massive PE and cardiac arrest management (75–77). In practice, a 50 mg bolus may be used in out-of-hospital settings to allow rapid administration, whereas a 100 mg infusion over 2 h is common in in-hospital PE protocols, adapted for use during prolonged resuscitation. The administration route is typically intravenous, but intraosseous access can be considered if intravenous access is not readily available. Continuous monitoring of the patient during and after the administration is essential to manage potential complications, such as bleeding or allergic reactions and to assess the effectiveness of the therapy. These recommendations are increasingly being refined through accumulating evidence from registry data, observational cohorts and ongoing randomized controlled trials (78–82) (Table III).

Table III. Factors to consider regarding the timing, dosing and administration route of rtPA.

Table III.

Factors to consider regarding the timing, dosing and administration route of rtPA.

First author/s, year	Factor	Key considerations	(Refs.)
Nadkarni et al, 2006	Timing	Early administration: Best outcomes observed when administered within 3–4.5 h of symptom onset.	(80)
		Delayed treatment: Reduced efficacy and increased risk of complications beyond 4.5 h.
		Extended window: Some guidelines suggest up to 6 h in specific cases with advanced imaging.
		Monitoring: Continuous assessment of symptoms and contraindications.
Nolan et al, 2007	Dosing	Standard dose: Typically, 0.9 mg/kg body weight, with a maximum dose of 90 mg.	(81)
		Initial bolus: 10% of the total dose given as an initial intravenous bolus over 1 min.
		Infusion: Remaining 90% infused over 60 min.
		Adjustments: Dose adjustments may be necessary for patients with renal or hepatic impairment or extreme body weight.
		Pediatric considerations: Different dosing strategies are required, not well established for children.
Miyazaki et al, 2019	Administration route	IV: Standard and most commonly used route for administration. IA: Used in cases where IV administration is contraindicated or unsuc cessful, often combined with mechanical thrombectomy.	(82)
		Combination therapy: IV rtPA followed by IA intervention in selected cases for improved outcomes.
		Site of administration: Ensure proper venous access and infusion monitoring to prevent extravasation and complications.
		Alternative routes: Investigational studies on novel administration routes (such as intraosseous) for specific clinical scenarios.

[i] rtPA, recombinant tissue plasminogen activator; IV, intravenous; IA, intra-arterial.

Contraindications and potential risks associated with thrombolytic therapy in CPR

Thrombolytic therapy during CPR carries significant risks, which necessitate careful consideration of contraindications (51). Absolute contraindications include active internal bleeding, a history of intracranial hemorrhage, recent major surgery or trauma, known bleeding disorders and severe uncontrolled hypertension (83–85). Relative contraindications, which require a risk-benefit analysis, include recent gastrointestinal bleeding, peptic ulcer disease and pregnancy (86). The most significant potential risk of thrombolytic therapy is hemorrhage, including intracranial hemorrhage, which can lead to devastating outcomes (87). Other risks include reperfusion arrhythmias, allergic reactions and an increased risk of further thrombotic events in certain conditions (88).

The decision to use rtPA during CPR must balance these risks against the potential for improved survival and neurological outcomes, particularly in patients with a high likelihood of thrombotic cardiac arrest etiology. This decision-making process often depends not only on patient-specific factors but also on the availability of institutional protocols, access to rapid diagnostic imaging and multidisciplinary team input (89,90). In emergency settings, bedside tools such as focused cardiac ultrasound can assist in identifying possible thrombotic causes (such as massive PE), providing a rationale for thrombolytic administration even when formal imaging is not feasible (91). Furthermore, institutions with predefined algorithms for cardiac arrest management that include thrombolytic therapy in select cases help streamline decision-making and reduce hesitation during critical moments (92,93). Comprehensive patient assessment and adherence to established guidelines are essential to optimizing the benefits of thrombolytic therapy while minimizing its risks (29). Ultimately, a tailored approach that integrates clinical judgment, real-time diagnostics and institutional capabilities is crucial in determining the appropriateness of rtPA during CPR.

Challenges and limitations of thrombolytic therapy in CPR

While promising in specific scenarios, thrombolytic therapy poses medical and logistical challenges when used during CPR. These issues encompass medical and logistical aspects, which must be carefully addressed to utilize thrombolytic agents such as rtPA effectively. This section outlines key limitations, including bleeding risks, inconsistent efficacy and difficulties with timely administration in diverse settings (94,95).

Bleeding complications

A primary concern with thrombolytic therapy in CPR is the increased risk of bleeding, particularly intracranial hemorrhage (96). While the goal is to dissolve obstructive coronary clots and restore myocardial blood flow, this benefit comes with a higher risk of bleeding, especially in critical areas such as the brain (49,97). The delicate balance between thrombolysis and hemorrhage must be meticulously managed, as any imbalance can lead to catastrophic outcomes (49). Moreover, CPR patients often have impaired clotting due to pre-existing conditions or prior treatments, further heightening bleeding risks (98).

Variable response rates and effectiveness

Response to thrombolytic therapy during CPR varies markedly among patients (99). While some patients may exhibit a robust response to thrombolytic agents, experiencing rapid clot dissolution and successful resuscitation, others may demonstrate limited or no response despite timely administration (69,100). This variability stems from multiple factors, including the cause of cardiac arrest, the degree of vessel occlusion and individual patient characteristics such as age, comorbidities and coagulation status. As a result, identifying patients most likely to benefit remains a challenge and calls for more personalized and evidence-based approaches (67).

Logistic challenges in administering thrombolytic therapy

Besides clinical concerns, logistical barriers hinder effective thrombolytic administration during CPR, particularly in pre-hospital and in-hospital environments (101,102). Unlike standard CPR interventions, thrombolytic therapy requires trained personnel, specialized equipment and infrastructure (103,104). In pre-hospital care, EMS teams must be trained in thrombolysis and the required drugs and monitoring tools must be readily available en route. In hospitals, issues such as drug storage, preparation and protocol adherence can delay timely administration (64,73). Addressing these challenges demands standardized protocols, cross-disciplinary teamwork and ongoing system improvements.

Future directions and research perspectives

Optimization of thrombolytic therapy protocols in CPR

As CPR methods evolve, research is focusing on refining thrombolytic therapy, especially regarding timing, dosage and delivery of agents such as rtPA. Ongoing studies explore how patient-specific factors, including comorbidities and arrest etiology, can inform protocol adjustments (78,105). There is also growing interest in personalized medicine approaches that tailor thrombolytic regimens to individual biomarker profiles. This could maximize therapeutic efficacy while minimizing adverse outcomes such as bleeding. Collaborative research across clinical and industry sectors aims to integrate thrombolysis more effectively into ACLS frameworks.

Exploration of novel thrombolytic agents and delivery methods

In parallel with efforts to optimize existing thrombolytic agents, researchers are exploring novel agents and delivery methods to enhance the efficacy and safety of thrombolytic therapy in CPR. Novel thrombolytic agents, such as modified variants of rtPA or entirely new classes of thrombolytic drugs, are being investigated for their potential to improve clot dissolution kinetics and reduce the risk of reperfusion injury (106). Furthermore, advancements in drug delivery technologies enable targeted and controlled delivery of thrombolytic agents to the site of vascular occlusion, thereby minimizing systemic exposure and off-target effects. Nanoparticle-based drug delivery systems, microneedle patches and catheter-based delivery platforms are among the innovative approaches being explored to optimize the delivery of thrombolytic therapy during CPR (107).

Integration of thrombolytic therapy with other resuscitative interventions

As the complexity of resuscitative interventions continues to expand, there is growing interest in integrating thrombolytic therapy with other advanced techniques, such as extracorporeal membrane oxygenation (ECMO), to improve outcomes in refractory cardiac arrest cases. ECMO provides temporary cardiopulmonary support by oxygenating blood outside the body, allowing for prolonged resuscitative efforts and stabilization of patients with profound hemodynamic instability (108). Research endeavors are underway to elucidate the optimal strategies for combining thrombolytic therapy with ECMO in the management of cardiac arrest patients with suspected or confirmed pulmonary embolism or massive myocardial infarction (109). By synergistically addressing both the underlying cause of cardiac arrest (such as acute coronary syndrome and pulmonary embolism) and the resultant hemodynamic collapse, the integration of thrombolytic therapy with ECMO holds promise for improving survival and neurological outcomes in select patient populations (110). Moreover, ongoing studies are investigating the potential synergistic effects of combining thrombolytic therapy with other advanced resuscitative interventions, such as targeted temperature management and mechanical circulatory support devices, to optimize outcomes in refractory cardiac arrest cases further (111). Through interdisciplinary collaboration and rigorous clinical research, these integrated approaches aim to redefine the standard of care for patients in cardiac arrest, ultimately improving survival rates and neurological recovery.

Ethical and legal considerations

Ethical implications of administering thrombolytic therapy

Using thrombolytics during CPR involves complex ethical issues related to autonomy, benefit, harm and resource fairness. In emergencies, informed consent is often not feasible, raising concerns about respecting patient autonomy while aiming to save lives (112). The risk of adverse effects, especially bleeding, must be weighed against the potential benefit of restoring circulation. Additionally, the uneven availability of thrombolytic therapy across healthcare settings raises questions of equity and access. Clinicians must carefully navigate these ethical concerns within resource-constrained environments (113).

Legal issues surrounding informed consent, liability and documentation

Legally, thrombolytic use during CPR touches on informed consent, liability and documentation. Given the urgency of CPR, formal consent may not always be possible, but providers should communicate risks and alternatives whenever feasible (114). Failing to inform or document appropriately could result in legal consequences, including malpractice claims. Comprehensive documentation of treatment rationale, consent discussions (if possible) and patient responses is vital to protect both patients and clinicians (115).

Clear guidelines and protocols for the use of thrombolytic therapy in CPR

Clear guidelines and protocols are paramount for the safe and effective use of thrombolytic therapy in CPR. These guidelines offer healthcare providers with standardized procedures for patient assessment, medication administration and monitoring during resuscitative efforts (65). Guidelines help ensure practice consistency, reduce care variability and promote patient safety. They outline criteria for patient selection, dosing regimens and monitoring parameters to minimize the risk of adverse events associated with thrombolytic therapy. Additionally, clear protocols aid in informed decision-making and facilitate communication among healthcare team members (116). They provide a framework for addressing ethical dilemmas, such as determining futility or prioritizing resources in resource-limited settings. Regular review and updates of guidelines and protocols are essential to incorporate new evidence and best practices. This iterative process helps healthcare institutions adapt to advancements in medical knowledge and technology, ultimately improving patient outcomes in the challenging context of CPR.

Conclusion

The present review provided compelling evidence supporting the efficacy of thrombolytic therapy, specifically rtPA, in improving outcomes for patients undergoing CPR. The administration of rtPA has been shown to increase the likelihood of ROSC and favorable neurological outcomes. However, it is imperative to carefully consider the potential risks, including hemorrhagic complications. Future research should focus on refining patient selection criteria, optimizing dosing regimens and identifying ideal timing for rtPA administration to maximize benefit and minimize adverse events. Additionally, large-scale randomized controlled trials are needed to further elucidate the role of thrombolytic therapy in specific patient populations, such as those with acute myocardial infarction or stroke. By integrating evidence-based guidelines and protocols, healthcare providers can harness the potential of thrombolytic therapy to markedly improve patient survival and quality of life following cardiac arrest.

Acknowledgements

Not applicable.

Funding

The present study was supported by Jilin Provincial Health and Health Commission (grant no. 2022LC038).

Availability of data and materials

Not applicable.

Authors' contributions

All authors contributed to the study conception and design. Original draft preparation was conducted by WZ, YP and JD. Writing, reviewing and editing of the draft manuscript was completed by WZ, YP, DX and WW. In addition, WW supervised the writing, analyses and revision of the manuscript. All authors commented on previous versions of the manuscript. Data authentication is not applicable. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Authors' information

Professor Wenhai Wang

ORCID: 0009-0002-3879-4259

References