Bronchoscopic Delivery of Aminocaproic Acid as a Treatment for Pulmonary Bleeding: A Case Series

Abstract

Objective:

Bronchoscopy is an essential therapeutic modality in the treatment of pulmonary bleeding. Although numerous endoscopic treatments exist, topical ε-aminocaproic acid has not been described in the literature. This study documents the use of this novel treatment for pulmonary bleeding and compares it to available evidence for tranexamic acid, a similar anti-fibrinolytic agent.

Design:

Case-series study.

Setting:

ICU and general inpatient floors of a tertiary medical center.

Patients:

Forty-six patients receiving endobronchial ε-aminocaproic acid for the treatment or prevention of pulmonary bleeding.

Measurements and Main Results:

Of the 46 patients included in the study, 41.6% and 13% presented with non-massive and massive hemoptysis, respectively. In patients with active pulmonary bleeding, endobronchial application of ε-aminocaproic acid and accompanying therapies resulted in cessation of bleeding in 94.7% of cases. A total of six patients received ε-aminocaproic acid monotherapy; in three patients with active bleeding, 100% achieved hemostasis after treatment. Of the 36 patients successfully treated for active pulmonary bleeding, 27.8% had recurrent bleeding within 30 days. Thirty-day adverse events were as follows: death (10 patients), deep vein thrombosis (2 patients), renal failure (2 patients), and stroke (2 patients).

Conclusions:

Endobronchial administration of ε-aminocaproic acid during bronchoscopy may be a safe and efficacious option in the treatment and prevention of pulmonary bleeding. Further studies are necessary to better define ε-aminocaproic acid’s safety profile, optimal routes of administration, and comparative effectiveness to tranexamic acid.

Introduction:

Hemoptysis is a frequently encountered symptom in clinical practice (1). There is a broad range of etiologies for hemoptysis which vary based on geography and clinical setting (2). The diagnostic approach to hemoptysis generally includes a chest radiograph followed by chest computed tomography or bronchoscopy depending on clinical circumstances (2, 3). In addition to being diagnostically useful, bronchoscopy has the additional benefit of being the most effective initial therapeutic procedure in hemodynamically unstable patients (1). Numerous bronchoscopic treatment modalities exist including local coagulation therapy (e.g. argon plasma coagulation, electrocautery, cryotherapy), topical vasoconstrictive agents (e.g. epinephrine, vasopressin), cold saline lavage, and balloon tamponade (1).

Tranexamic acid (TXA) is an antifibrinolytic that has predominately been used topically and intravenously to reduce bleeding in surgical patients, trauma, and menorrhagia (4). However, it has been less extensively used as a treatment for hemoptysis. Endobronchial administration of TXA during bronchoscopy was first described in 2009 (5) and has since been investigated in prospective observational studies (6–7) and a randomized controlled trial (8). ε-aminocaproic acid (EACA), like TXA, is a synthetic lysine analogue that competitively blocks the lysine bind site on plasminogen, thereby preventing its conversion to plasmin and subsequent fibrinolysis (4). Differences between the medications include greater potency (9) and cost (10) of TXA relative to EACA. A Cochrane review in 2011 analyzed eight RCTs directly comparing intravenous EACA and TXA in perioperative patients and found no significant difference in blood loss, transfusion requirements, or adverse events between the groups (11). Despite the similar pharmacologic mechanism and clinical outcomes there is a paucity of studies using EACA (11). The reason for this is not well documented, however familiarity (12), available data (13), and potency (14) are suggested reasons surgeons choose TXA over EACA in clinical practice. The financial advantage of EACA has led to continued interest in its use (10, 15–16). To the best of our knowledge, topical administration of EACA during bronchoscopy has not been described. The purpose of this study was to describe this therapeutic modality in the treatment and prevention of pulmonary bleeding.

Patients and Methods:

Patients and Study Design

This study was a retrospective chart review of patients who underwent bronchoscopy and in whom endobronchial EACA was administered to control or prevent pulmonary bleeding at New York-Presbyterian/Weill Cornell Medical Center from March 2015 to December 2017. Approval was obtained from the Weill Cornell Medical Center Institutional Review Board (#1507016369). Inclusion criteria included age 18–99 years old, hospital admission, and documentation of EACA administration during bronchoscopy. Data was extracted from the original patient charts and entered on a standardized data collection form using REDCap tools hosted at the Weill Cornell Medicine Clinical and Translational Science Center (17). Study data included patient demographics, past medical history, anti-platelet and anti-coagulant medication use, coagulation profiles, the presence of hemoptysis, pulmonary bleeding causes and risk factors, and bronchoscopy information including procedure location, type of anesthesia, ventilatory support, hemostatic medication details, and the use of other hemostatic maneuvers. Hemoptysis was categorized as massive in instances of blood loss greater than 100mL in 24 hours, abnormal gas exchange or airway obstruction, and hemodynamic instability (18). Outcomes of interest included frequency of hemostasis during index bronchoscopy, 30-day adverse events, and 30-day recurrent bleeding events.

Index Bronchoscopy

Indications for index bronchoscopy included diagnosis of suspected infection or malignancy, investigation of unexplained respiratory compromise, and treatment of hemoptysis. EACA in a 1 gram/10mL concentration was instilled through the bronchoscope followed by a 10mL air flush for the treatment of active bleeding or as prophylaxis. Indications for prophylactic treatment included prevention of post-biopsy bleeding, treatment of clot overlying a previously active site of bleeding, and treatment over a successfully cauterized bleeding lesion. In cases of active bleeding, EACA was applied directly to the site of bleeding when visualized. When the site of bleeding could not be visualized, EACA was delivered proximal to the presumed site of bleeding. In patients who had multiple bronchoscopies with EACA administration the chronologically first was selected as the index. The decision regarding utilization of additional hemostatic medications and maneuvers was made at the time of bronchoscopy by the bronchoscopist. Bronchoscopy was terminated when visual evidence of active bleeding had ceased, hemostasis could not be achieved, or when the intended diagnostic procedure was completed. In patients with active bleeding, index bronchoscopy was categorized as effective or ineffective depending on if hemostasis was achieved by end of procedure. A subgroup analysis of bronchoscopy effectiveness was performed in patients treated solely with EACA. The management of anti-platelet and anti-coagulant medication use surrounding index bronchoscopy was recorded and compared to current recommendations (19).

Recurrent bleeding

Recurrent bleeding was defined as evidence of pulmonary bleeding up to 30 days after effective index bronchoscopy. Patients with ineffective or prophylactic index bronchoscopies were excluded. Evidence of pulmonary bleeding was defined as visual evidence of bleeding on repeat bronchoscopy or angiography, hemoptysis requiring blood product administration or intervention, or death assumed to be related to uncontrolled pulmonary hemorrhage in which diagnostic confirmation of bleeding was not obtained. Patients with self-resolving small volume hemoptysis were recorded but not considered recurrent bleeding. The necessity of adjunctive hemostatic procedures to control recurrent bleeding such as repeat bronchoscopy or bronchial artery embolization were also recorded. For patients discharged from the hospital in less than 30 days from index bronchoscopy, medical records within the Weill Cornell Medical Center system were screened for bleeding events.

Adverse Events

Adverse events were recorded in all patients for 30 days after index bronchoscopy. Included events were deep vein thrombosis (DVT), pulmonary embolism, stroke, myocardial infarction, renal failure, and death. Death was categorized by relationship to pulmonary bleeding. In patients who left the hospital prior to 30 days, medical records within the Weill Cornell Medical Center system were reviewed for additional events in the relevant timeframe. Clinical circumstances surrounding adverse events were described to elucidate possible contributing factors other than EACA administration.

Statistical Analysis

Patients were summarized by clinical categories with counts and percentages. Patient age, hospital length of stay, coagulation profiles, and hemostatic agent dosages are presented as medians with interquartile ranges.

Results:

Baseline characteristics of the 46 patients included in the study are provided in Table 1. During bronchoscopy, 38 patients were treated for active bleeding, and eight patients were treated prophylactically. Of the eight patients who received prophylactic treatment, three received treatment to prevent post-biopsy bleeding, three received treatment to clot overlying a previously bleeding lesion, and two received treatment to a bleeding area successfully controlled with electrocautery. Indications for EACA administration in actively bleeding and prophylactically treated patients are provided in Table 2. Regarding topical hemostatic agents, 25 patients received a combination of EACA, phenylephrine, and cold saline, 11 patients received EACA alone, 10 patients received a combination of EACA and phenylephrine, and one person received a combination of EACA, epinephrine, and cold saline (Table 3). Among the patients with active bleeding, 36 achieved hemostasis during index bronchoscopy. Anti-coagulant and anti-platelet medications were managed in accordance with guidelines outlined by Youness et al (19) in all but two patients; one patient was continued on clopidogrel prior to and after index bronchoscopy due to percutaneous coronary intervention occurring five days prior, and one patient was continued on a heparin drip during bronchoscopy due to ongoing respiratory failure from a pulmonary embolism.

Table 1.

Patient Characteristics

Patient Characteristics
Characteristic	No. of Patients (%)
Total patients	46
Age (years), median (IQR)	62.5 (49.8–74)
Sex (male)	32 (69.6)
Smoking status
Current or former	24 (52.2)
Never	21 (45.7)
Unknown	1 (2.2)
Hospital length of stay (days), median (IQR)	17.5 (11–39)
Coagulation profile, median (IQR)
Platelet count (K/μL)a	186 (115–286)
Prothrombin time (sec)b	12.6 (11.6–14)
Activated partial thromboplastin time (sec)b	28.8 (26.8–32.9)
International normalization ratioc	1.1 (1–1.2)
Past medical history
Malignancy	33 (71.7)
Lung cancer	7 (15.2)
Hypertension	23 (50)
Hyperlipidemia	19 (41.3)
COPD	11 (23.9)
Type 2 diabetes	8 (17.4)
DVT/Pulmonary embolism	8 (17.4)
Coronary artery disease	5 (10.9)
Bone marrow translant	4 (8.7)
HIV/AIDS	3 (6.5)
Chronic kidney disease	3 (6.5)
End stage renal disease	3 (6.5)
Myocardial infarction	2 (4.3)
Stroke	2 (4.3)
Hemoptysis
Massive	6 (13)
Non-massive	13 (28.3)

IQR = Interquartile range, DLBCL = Diffuse large B-cell lymphoma, COPD = Chronic obstructive pulmonary disease, DVT = Deep vein thrombosis, HIV = Human immunodeficiency virus, AIDS = Acquired immune deficiency syndrome

^aData not available for one subject

^bData not available for six subjects

^cData not available for nine subjects

Table 2.

Indications for Aminocaproic Acid Administration

	No. of Patients (%)
Variable	Active bleeding	Prophylaxis
Iatrogenic
Transbronchial biopsy	11 (23.9)	2 (4.3)
Endobronchial biopsy	4 (8.7)	1 (2.2)
Bronchoalveolar lavage	1 (2.2)
CT guided lung biopsy	1 (2.2)
Non-iatrogenic
Tumor	8 (17.4)	2 (4.3)
Diffuse alveolar hemorrhage	4 (8.7)
Cryptogenic	4 (8.7)
Infection	2 (4.3)	3 (6.5)
Bronchiectasis	2 (4.3)
Pulmonary embolism	1 (2.2)

Table 3.

Index bronchoscopy characteristics.

Variable	No. of Patients (%)
Location
ICU	35 (76.1)
Operating room	7 (15.2)
Endoscopy suite	4 (8.7)
Anesthesia type
General	27 (58.7)
Moderate	19 (41.3)
Intubation
Before bronchoscopy	30 (65.2)
During or after bronchoscopy	5 (10.9)
No intubation	11 (23.9)
Hemostatic agent frequency of use
EACA + phenylephrine + cold saline	25 (54.3)
EACAa	11 (23.9)
EACA + phenylephrine	10 (21.7)
EACA + cold saline + epinephrine	1 (2.2)
Hemostatic agent amount, median (IQR)
EACA (g)a	3 (2–4)
Phenylephrine (mcg)b	400 (290–475)
Cold saline (mL)c	20 (12.5–35)
Hemostatic maneuver frequency of use
Cautery	8 (17.4)
Cautery + APC	4 (8.7)
Cryotherapy + APC	2 (4.3)
APC	2 (4.3)
Bronchial blocker	2 (4.3)
Cryotherapy	1 (2.2)

IQR = interquartile range, APC = argon plasma coagulation, g = gram, mcg = microgram, mL = milliliter

^aIncludes subjects receiving hemostatic maneuvers

^bData not available for 16 subjects

^cData not available for 21 subjects

^dData not available for 20 subjects

Of the 36 patients with effective index bronchoscopies, 26 had no evidence of recurrent pulmonary bleeding within 30 days of index bronchoscopy. In this group, six patients had small volume hemoptysis which resolved spontaneously without the need for transfusion or intervention. Ten patients had recurrent bleeding within 30 days after index bronchoscopy. The initial cause of bleeding, subsequent procedures to control bleeding, and mortality in these patients can be seen in Table 4.

Table 4.

Thirty Day Recurrent Bleeding Characteristics

Patient #	Cause of Bleeding	Additional Hemostatic Procedures	Death (Y/N)
1	Bronchiectasis	Bronchoscopy, Bronchial Artery Embolization	N
2	Cryptogenic	Bronchoscopy	N
3	CT guided lung biopsy	Bronchoscopy	N
4	Diffuse alveolar hemorrhage		Y
5	Diffuse alveolar hemorrhage	Bronchoscopy	N
6	Pulmonary embolism	Bronchoscopy, Bronchial Artery Embolization	Y
7	Transbronchial biopsy	Bronchoscopy	Y
8	Tumor		Y
9	Tumor	Bronchoscopy	N
10	Tumor		N

Six patients received EACA without accompanying hemostatic agents or maneuvers during index bronchoscopy. Of these patients, three were treated for active bleeding and three were treated prophylactically. All three patients with active bleeding achieved hemostasis after treatment.

In regard to adverse events, 10 patients died within 30 days of index bronchoscopy. One death was related to uncontrolled pulmonary bleeding, two were multifactorial in etiology including pulmonary bleeding, and seven were unrelated to pulmonary bleeding. Two patients developed a stroke. One was caused by hemorrhagic brain tumors from metastatic thyroid cancer, and the other was attributed to atrial fibrillation in which anticoagulation was discontinued to prevent worsening hemoptysis. Renal failure developed in two patients. One patient with diffuse large B cell lymphoma developed renal failure related to tumor lysis syndrome, multiple chemotherapeutic agents, and amphotericin B administration. The other patient was hospitalized for hemophagocytic lymphohistiocytosis from which disseminated intravascular coagulation and subsequent renal failure developed. Lastly, two patients developed a DVT. One patient with metastatic lung cancer developed a lower extremity DVT after heparin DVT prophylaxis was discontinued to prevent worsening hemoptysis. The other patient developed a right upper extremity DVT as a surgical complication of a right pneumonectomy two weeks prior. There was no patient overlap regarding non-death adverse events.

Discussion:

In the developed world the most common etiologies of hemoptysis include bronchiectasis, lung cancer, and bronchitis. Patients with hemoptysis are more likely to be male, in the 5^th to 6^th decade of life, and have a history of smoking (3, 20–22). Mortality in this patient population can range from 8.7–10% with an average hospital admission length of 8–10 days (3, 22). Although there is no consensus definition of massive hemoptysis, it is estimated to account for 5–15% of hemoptysis cases (3, 20). Among the diagnostic and treatment options for pulmonary bleeding, bronchoscopy remains an essential procedure. Topical administration of hemostatic agents is one therapeutic application of bronchoscopy. Cold saline and vasoconstrictive medications such as epinephrine are among the most frequently used agents for this purpose despite limited supporting evidence (1).

Studies investigating the use of EACA in pulmonary bleeding are limited and predominately use intravenous therapy (22–26). However, Shapiro et al (27) and Fernandez (28) each describe a patient with massive hemoptysis due to pulmonary aspergilloma who received percutaneous intracavitary EACA with good effect. Although EACA is generally thought to be well tolerated, the theoretical risk of thrombosis is an active area of investigation. Current safety data are derived from studies that were not designed or powered to detect these events (16, 29). In pulmonary bleeding, endobronchial administration of EACA could minimize thrombosis risk by decreasing systemic exposure.

The precedent for using bronchoscopically administered endobronchial EACA for pulmonary bleeding is set by limited data supporting the use of TXA for this purpose. Solomonov et al (5) in 2009 were the first to describe this treatment modality in two patients with iatrogenic pulmonary bleeding. Both patients achieved immediate hemostasis after treatment. In 2010 Marquez-Martin et al (6) treated 48 patients with TXA who had moderate hemoptysis refractory to cold saline and epinephrine. Hemostasis was achieved in 100% of patients with iatrogenic causes of bleeding and 39.2% of patients with non-iatrogenic causes; a three-month recurrent bleeding rate of 16.6% was observed. In 2017 Korraa et al (7) compared cold saline with or without epinephrine to TXA in 40 patients with bronchopulmonary bleeding. They found no statistically significant difference between the 95% hemostasis rate of the TXA group and the 100% hemostasis rate of the control group; no two-week recurrent bleeding events were noted. Lastly, Fekri et al (8) in 2017 performed a randomized control trial comparing TXA to epinephrine in 50 patients with hemoptysis refractory to cold saline. Both treatment groups achieved hemostasis in 100% of cases with no three-month recurrent bleeding events. All three studies were performed in the bronchoscopy suite of a university hospital and observed no adverse events related to TXA administration. Patients with massive hemoptysis were excluded from two studies (6–7).

In the present study, patient age, sex, and smoking history were similar to those studies using TXA. However, our patient population predominately consisted of ICU patients with higher rates of massive hemoptysis. Despite this, our effective index bronchoscopy rate of 94.7% is comparable to those recorded for endobronchial TXA (6–8). Furthermore, all 3 actively bleeding patients treated with EACA alone achieved hemostasis. This suggests EACA may be utilized for the treatment of pulmonary bleeding without accompanying hemostatic agents or maneuvers. Rebleeding rates in our study were higher than those studies using TXA. However, differences in illness severity, patient heterogeneity, and recurrent bleeding surveillance methods may contribute to this disparity. Mortality rates in our study were congruent with general estimates of ICU patients (30–32). This is consistent with our finding that most patient deaths were unrelated to pulmonary bleeding. Although 6 non-death adverse events were noted, inciting factors other than EACA use were documented by the treating physician in each case.

To the best of our knowledge, this study is the first to describe the use of topically applied EACA during bronchoscopy for pulmonary bleeding. However, our study had multiple limitations. Due to the retrospective nature of the study, data was not consistently available regarding severity of hemoptysis, coagulation panels, and specific doses of hemostatic agents administered. The high frequency and variation of co-administered hemostatic agents and maneuvers with EACA makes assessment of individual efficacy difficult. Thirty-day recurrent bleeding and adverse event monitoring post-discharge from the hospital was limited to events within the Weill Cornell Medical Center system, potentially underestimating these events. Although the severity of disease in our patient population reduces generalizability, our results provide insight into the potential benefit and safety of endobronchial EACA for the increasingly complex and co-morbid patients with pulmonary bleeding seen in tertiary care centers.

Conclusion:

Endobronchial administration of EACA during bronchoscopy may be a safe and efficacious option in the treatment and prevention of pulmonary bleeding. Further studies are necessary to better define EACA’s safety profile, optimal routes of administration, and comparative effectiveness to TXA.