Abstract
OBJECTIVES:
The objective of this study was to evaluate the efficacy and safety of tranexamic acid (TXA) nebulization to control bleeding in hemoptysis.
MATERIALS AND METHODS:
In this randomized controlled clinical trial, 27 participants with hemoptysis received nebulization with TXA (500 mg/5 mL, q 8 hourly for 2 days), and 29 participants with hemoptysis received nebulization with 0.9% normal saline (5 mL, q 8 hourly for 2 days) along with the standard therapy and followed up for 8 weeks.
RESULTS:
The mean percentage decrease in the frequency (63.9% vs. 39.8%, P = 0.012) and quantity (73.4% vs. 51.7%, P = 0.024) of hemoptysis was significantly higher in the TXA group compared to the control group at day 1 but was insignificant at day 2. However, after excluding participants who underwent intervention (N = 11), the improvement in frequency (76.2% vs. 50.3%, P = 0.049) and quantity (85.2% vs. 58.6%, P = 0.021) of hemoptysis was significantly better in the TXA group even at day 2. Out of 56 participants, 24 participants achieved resolution of hemoptysis, which was also significantly (P = 0.003) better in the TXA group (63.0%) compared to the control group (24.1%). No serious adverse drug reaction was observed. Minor cough (37.5%) and throat irritation (33.9%) were observed, which were comparable (P = 0.432) between the groups.
CONCLUSION:
TXA nebulization, an alternative route of administration, was found to be safe. Prompt nebulization with TXA was effective as bridging therapy in hemoptysis to achieve the immediate goal of bleeding control before definitive intervention planned or performed. Further studies are encouraged to evaluate this novel approach of TXA nebulization. Trial registration: clinicaltrials.gov PRS ID: NCT05648656.
Keywords: Hemoptysis, nebulization, tranexamic acid
Introduction
Hemoptysis is the expectoration of blood from lung parenchyma or airways and is frequently encountered in a medical emergency.[1] Mortality associated with hemoptysis varies to the extent of 7%–30% in submassive hemoptysis and 50%–100% in massive hemoptysis.[2] Prompt medical therapy and bronchoscopic or endovascular intervention are therapeutic as well as diagnostic for the management of hemoptysis. Medical management is executed on priority for achieving hemostasis at the earliest and prevention of aspiration before the treatment of the underlying etiology through performing any definitive bronchoscopic or endovascular intervention. While the majority of the cases can be managed successfully with prompt medical therapy, only the refractory cases and life-threatening hemoptysis are required definitive procedures, like digital subtraction angiography (DSA)-guided embolization of the bleeding vessel and bronchoscopic procedures such as endobronchial glue, endobronchial embolization using silicone spigots, endobronchial stents, and laser photocoagulation. Tranexamic acid (TXA), a synthetic derivative of the amino acid lysine, acts by blocking lysine-binding sites of plasminogen, inhibiting fibrinolysis and preventing breakdown of the fibrin clots. Thus, TXA enhances clot stabilization, facilitating bleeding control and hemostasis.[3] As a medical therapy, TXA is used to control bleeding in hemoptysis and in other surgical/traumatic/visceral causes of bleeding before definitive intervention is performed to achieve hemostasis. Previously conducted institutional study found that intravenous (IV) TXA infusion was superior to placebo to decrease frequency and quantity of hemoptysis, duration of hospital stay, and need for endovascular or bronchoscopic or surgical intervention and blood transfusion.[4] Apart from the commonly studied and widely practiced routes of administration, i.e. IV and oral, novel routes such as aerosolized and endobronchial TXA also showed potential for achieving hemostasis in hemoptysis.[5] A recently conducted randomized controlled trial (RCT), assessing the efficacy of TXA nebulization in submassive hemoptysis, concluded that nebulized TXA was efficient in the reduction of frequency and quantity of hemoptysis.[6] As per previous RCT and multiple case reports, nebulized TXA was also found to be safe, as no severe adverse drug reaction (ADR) was reported during use.[7] However, because of the limited number of research with small sample size and barring some case reports, evidence for using nebulized TXA in hemoptysis is limited. Similarly, data regarding ADR related to TXA nebulization are also limited. The advantage of the nebulized form of TXA is that it is supposed to reach the local site of bleeding (lung/airway) promptly and at a higher concentration, facilitating the rapid control of bleeding to achieve hemostasis. The present study was planned to evaluate the novel approach of TXA nebulization for the management of hemoptysis, further to generate additional information regarding the safety and efficacy of the nebulized TXA.
Materials and Methods
Aim
The aim of the study was to evaluate the safety and efficacy of TXA nebulization for the treatment of hemoptysis.
Site of the study
The study was conducted at the emergency medical outpatient department of the Post Graduate Institute of Medical Education and Research (PGIMER), a tertiary care center in Northern India under collaboration with the department of Internal Medicine, Pulmonary Medicine, Radio diagnosis and Imaging, and Pharmacology.
Study design
In this randomized controlled, double-blind clinical trial, individuals presented with hemoptysis were screened for enrollment and randomized into the TXA and control groups as per the inclusion and exclusion criteria, receiving nebulization with TXA and 0.9% normal saline (NS) for 2 days, respectively. Both the groups received standard care of therapy, underwent endovascular or bronchoscopic intervention as per indication, and followed up for 8 weeks physically or telephonically as and when required. The institutional ethics committee reviewed and approved the protocol, and the study was registered with clinicalTrials.gov (clinicaltrials.gov PRS ID: NCT05648656).
Study duration
The study was executed during the period of July 2021 to December 2022.
Inclusion and exclusion criteria
Irrespective of gender, with age ≥18 years, all the patients presenting with hemoptysis were screened for enrollment in the study. Patients presented with massive hemoptysis with expectorated blood >600 mL/24 h or hypoxemia or shock and requiring O2 or ionotropic support were excluded from the study. Patients with a history of allergy to TXA, pregnancy, renal failure (serum creatinine >1.5 mg/dL), patients who were already receiving oral contraceptive pill, antiplatelet, or anticoagulant, and not willing to consent were excluded from the study.
Method and intervention
All patients presenting with hemoptysis and requiring hospitalization were screened for enrollment in the study. The diagnosis of hemoptysis was based on the patient’s history of coughing out fresh or altered blood and physical examination. Subsequently, patients with hemoptysis were recruited in the study as per the inclusion and exclusion criteria after receiving written informed consent from the patient or his/her legal heirs. The participants were randomized into treatment and control groups. Randomization was executed with the help of computer-generated random numbers in a block randomization pattern with variable-size blocks (4 and 6). Randomization and treatment allocation concealment were performed by the pharmacologist in the Department of Clinical Pharmacology, PGIMER, Chandigarh. The treatment group received nebulization with TXA (500 mg/5 mL) q8 hourly for 2 days, and the control group received nebulization with 0.9% NS (5 mL) q8 hourly for 2 days. In addition, both the group received standard care of therapy, and endovascular or bronchoscopic intervention was performed by the expert clinicians in the field of intervention radiology and pulmonary medicine as per indications. Nebulization was done by breath-actuated nebulizer (LUPINEB) using a standard nebulizer machine. The TXA or matched 0.9% NS was administered under direct observation (DOT) for the first dose to inspect for any ADR. The investigator administering the drug and the participants were unaware of the study arms. ADR incurred in the patients during the study were notified to the PGIMER ADR Monitoring Center, Regional Center for North Zone, under the Pharmacovigilance Program of India, Indian Pharmacopeia Commission, Ministry of Health and Family Welfare, Government of India.
For all participants, clinical details were recorded, and baseline blood investigations (complete blood count, electrolytes, renal function, coagulation profile, and liver function test) were performed for risk stratification and to systematize further plan of management. The initial prime concern was to secure the airway, breathing, and circulation. Crystalloid infusion was administered to ensure hemodynamic stability as and when required. Blood transfusion was initiated at a hemoglobin (Hb) threshold of 7 g/dl to maintain a target Hb of 7–9 g/dl or in the presence of hemodynamic instability despite fluid resuscitation. Patients with massive hemoptysis, with hemodynamic instability, and who were intubated were excluded from the study because of the prompt need for definitive procedures like endovascular or bronchoscopic intervention. The treating physician could choose additional evaluation and therapy. The cause of hemoptysis was determined based on the clinical history, examination, laboratory, and radiology imaging data. If any patient developed hemodynamic compromise and needed intervention during the study, the indicated interventions were executed as guided by the pulmonologist, interventional radiologist, and the treating physician. All the participants were kept under observation. The participants were instructed to measure the frequency of hemoptysis and collect the expectorated blood in a measuring cup daily during hospitalization to quantify the volume of bleeding. Patients were discharged after stabilization when hemostasis was achieved, as guided by the treating physician, and subsequently were followed up for 8 weeks physically or telephonically as and when required.
Primary outcome
Frequency of hemoptysis: The number of episodes of hemoptysis per day was compared between the study groups at day 0, day 1 (24 h), and day 2 (48 h)
Quantity of hemoptysis: The volume (mL) of expectorated blood per day was compared between the study groups at day 0, day 1 (24 h), and day 2 (48 h)
The Visual Analog Scale (VAS) score: Visual subjective assessment by the participant was used to compare the amount of hemoptysis at day 0, day 1 (24 h), and day 2 (48 h). VAS was presented to the participants as a 10-cm line anchored by description with “no hemoptysis” at one end and “worst imaginable hemoptysis” at the other. Participants were asked to mark a point on the 10-cm line to indicate the severity.
Secondary outcomes
Resolution of hemoptysis: Resolution of hemoptysis was defined as no episode of hemoptysis, sustained for at least 48 h following cessation of hemoptysis
Adverse drug events: Participants were monitored and inquired about any adverse drug events
Need for intervention: The overall need for therapeutic interventions like endovascular, bronchoscopic, or surgical procedure to achieve hemostasis was compared between the study groups
Need for blood transfusion: The total number of participants requiring blood transfusion, as well as the number of units of packed red blood cells transfused, was recorded and compared between the study groups
Duration of hospital stay: The total duration of hospital stays (from the day of admission to the day of discharge or death) was recorded
Mortality: All the participants were followed up for 4 weeks, physically or telephonically, to assess well-being, recurrence, and mortality
Recurrence of hemoptysis: Recurrence was defined as a fresh episode of hemoptysis after resolution during 28 days of follow-up.
Sample size and statistical analysis
At the initiation of our study, there were not many clinical trials available to determine the efficiency of nebulized TXA in the treatment of hemoptysis. As per one RCT published to assess the effectiveness of inhaled TXA for the treatment of hemoptysis, 96% bleeding resolution was achieved in the TXA group compared to 50% in the control group.[6] Anticipating at least 80% response rate to therapy with a difference of 40% between the groups, the calculated sample size was 44, when there was an 80% chance (power) of detecting a significant difference between the groups at a one-sided 0.05 significance level (alpha error of 5%). Anticipating a 10% dropout, around 50 patients were planned to be recruited in the study. Randomization was executed with the help of a computer-generated random number in a block randomization pattern with variable-size blocks (4 and 6). Randomization and treatment concealment were performed by the pharmacologist in the Department of Clinical Pharmacology, PGIMER, Chandigarh. A total of 84 patients with hemoptysis were screened for enrollment in the study, out of which 28 patients were excluded as per exclusion criteria [Figure 1]. Subsequently, a total of 56 patients were recruited in the study and randomly assigned into the TXA group (N = 27) and the control group (N = 29) who received intervention as per the study protocol [Figure 1]. The data were managed in the database system through Microsoft Excel (Microsoft Corporation, USA), and statistical analysis was performed by SPSS 22.0 version (IBM, USA). The parametric data were analyzed by paired or unpaired “t” test; however, the categorical endpoints were analyzed with the nonparametric Chi-square test. P < 0.05 was considered statistically significant.
Figure 1.
Study design, screening, and enrollment. TXA = Tranexamic acid, NS = Normal saline
Results
Baseline characteristics of the study population
The mean (±standard deviation [SD]) age of the participants was 43.2 (15.4) years, ranging from 18 to 75 years, and majority of the participants were males (76.8%) compared to females (23.2%). The most frequently associated comorbidities were previously treated pulmonary tuberculosis (53.6%), followed by prior history of hemoptysis (32.1%), diabetes (17.9%), and hypertension (5.4%). Out of 56 participants, 23 (41.1%) participants had a history of smoking, and 22 (39.3%) participants had history of alcohol abuse. The distribution of age, gender, and comorbidity was similar between the groups [Table 1].
Table 1.
Baseline characteristics of the study population
| Parameters | TXA (n=27), n (%) | Control (n=29), n (%) | P |
|---|---|---|---|
| Age (years), mean±SD | 42.9±15.4 | 43.6±15.6 | 0.867 |
| Male (n=43) | 22 (81.5) | 21 (72.4) | 0.645 |
| Female (n=13) | 5 (18.5) | 8 (27.6) | 0.645 |
| Old PTB (n=30) | 11 (40.7) | 19 (65.5) | 0.06 |
| Past history of hemoptysis (n=18) | 8 (29.6) | 10 (34.5) | 0.698 |
| Diabetes (n=10) | 4 (14.8) | 6 (20.7) | 0.566 |
| Hypertension (n=3) | 2 (7.4) | 1 (3.4) | 0.511 |
| Smoking (n=23) | 10 (37.0) | 13 (44.8) | 0.554 |
| Alcohol (n=22) | 8 (29.6) | 14 (48.3) | 0.153 |
| Shortness of breath (n=25) | 12 (44.0) | 13 (44.8) | 0.977 |
| Fever (n=16) | 8 (29.4) | 8 (27.6) | 0.866 |
| Postural symptoms (n=6) | 4 (14.8) | 2 (6.9) | 0.338 |
| Pallor (n=24) | 11 (40.7) | 13 (44.8) | 0.757 |
| Tachycardia (n=19) | 9 (33.3) | 10 (34.5) | 0.928 |
| Tachypnea (n=19) | 11 (40.7) | 8 (27.6) | 0.299 |
| Clubbing (n=6) | 2 (7.4) | 4 (13.8) | 0.440 |
SD=Standard deviation, PTB=Posttuberculosis, TXA=Tranexamic acid
Clinical features
The most common associated symptoms in participants presenting with hemoptysis were shortness of breath (44.6%), followed by fever (28.6%) and postural symptoms (10.7%). One participant in the TXA group had associated upper gastrointestinal bleed. The most common clinical examination findings were pallor (42.9%), followed by tachycardia (33.9%), tachypnea (33.9%), and clubbing (10.7%). The clinical features were comparable between the groups [Table 1].
Investigations
The mean (±SD) Hb, total leukocyte count (TLC), and platelet counts of the study participants were 10.7 (2.2) g/dL, 8.6 (3.5) ×109/L, and 226 (114) ×109/L, respectively. Anemia (Hb <12 g/dL in males and <11 g/dL in females) was present in 48.2% of participants, and 12.5% of participants each had leukocytosis (TLC ≥12 × 109/L) and leukopenia (TLC ≤4.5 × 109/L). Thrombocytopenia (platelet count <150 × 109/L) was present in 23.2% of participants. As per liver function test results, the mean (±SD) serum bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and albumin were 0.96 (3.01) mg/dL, 30.66 (18.6) IU/L, 31.84 (28.7) IU/L, and 3.48 (0.55) g/dL, respectively. Jaundice (total serum bilirubin ≥2 mg/dL), transaminitis (SGOT/SGPT >40 IU/L), and hypoalbuminemia (serum albumin <3.5 g/dL) were present in 1.8%, 21.4%, and 37.5% of participants, respectively. The mean (±SD) serum creatinine level was 0.69 (0.21) mg/dL, and no participants with renal dysfunction (creatinine ≥1.5 mg/dL) were included in the study.
In the coagulation profile, the mean (±SD) prothrombin time (PT), international normalized ratio (INR), PT index, and activated partial thromboplastin time were 15.7 (3.03) s, 1.12 (0.13), 88.30 (8.69) %, and 29.7 (4.1) s, respectively. Coagulopathy (INR >1.5) was present in 3.6% of participants. Blood investigations finding were comparable between the study groups [Table 2].
Table 2.
Investigation finding and etiology of hemoptysis
| Parameters | TXA (n=27), n (%) | Control (n=29), n (%) | P |
|---|---|---|---|
| Anemia (n=27) | 14 (51.9) | 13 (44.8) | 0.599 |
| Leukocytosis (n=7) | 3 (11.1) | 4 (13.8) | 1.000 |
| Leukopenia (n=7) | 4 (14.8) | 3 (10.3) | 0.700 |
| Thrombocytopenia (n=13) | 4 (14.8) | 9 (31.0) | 0.151 |
| Transaminitis (n=12) | 6 (22.2) | 6 (20.7) | 0.889 |
| Jaundice (n=1) | 1 (3.7) | 0 | 0.482 |
| Hypoalbuminemia (n=21) | 7 (25.9) | 14 (48.3) | 0.084 |
| Coagulopathy (n=2) | 1 (3.7) | 1 (3.4) | 1.000 |
| Pulmonary cavity (n=33) | 14 (51.9) | 19 (65.5) | 0.299 |
| Fibrotic lung lesion (n=23) | 10 (37.0) | 13 (44.8) | 0.554 |
| Lung consolidation (n=19) | 10 (37.0) | 9 (31.0) | 0.635 |
| Fungal ball (n=13) | 5 (18.5) | 8 (27.6) | 0.422 |
| Bronchiectasis (n=7) | 4 (14.8) | 3 (10.3) | 0.700 |
| Bronchial artery hypertrophy (n=23) | 12 (44.4) | 11 (37.9) | 0.621 |
| Pulmonary artery abnormalities (n=6) | 2 (7.4) | 4 (13.8) | 0.671 |
| Active PTB (n=21) | 10 (37) | 11 (37.9) | 0.945 |
| PTB sequelae (n=7) | 4 (14.8) | 3 (10.3) | 0.700 |
| Bronchiectasis (n=3) | 2 (7.4) | 1 (33.3) | 0.605 |
| CPA (n=11) | 3 (11.1) | 8 (27.5) | 0.172 |
| Pulmonary mucormycosis (n=2) | 1 (3.7) | 1 (3.4) | 0.982 |
| ABPA (n=2) | 2 (7.1) | 0 | 0.229 |
| Malignancy (n=2) | 0 | 2 (6.7) | 0.492 |
| Undifferentiated (n=8) | 5 (18.5) | 3 (10.0) | 0.457 |
PTB=Posttuberculosis, TXA=Tranexamic acid, CPA=Chronic pulmonary aspergillosis, ABPA=Allergic bronchopulmonary aspergillosis
The most common computed tomography (CT) abnormalities were pulmonary cavity (58.9%), followed by fibrotic lesion (41.1%), consolidation (33.9%), fungal ball (23.2%), and bronchiectasis (12.5%). Bronchial artery hypertrophy was present in 41.1% (N = 23) of participants, and pulmonary artery abnormalities were present in 10.7% (N = 6) of participants. A total of 48.2% (N = 27) participants had bilateral, and 51.8% (N = 29) of participants had unilateral lung involvement. Two or more CT findings were present in 67.8% (N = 38) of participants. CT finding were comparable between the study groups [Table 2].
Etiology of hemoptysis
Among the 56 participants, most frequent underlying etiology for hemoptysis was tuberculosis (50%, N = 28), followed by fungal cavitary disease (23.2%, N = 13), bronchiectasis (5.4%, N = 3), and allergic bronchopulmonary aspergillosis and malignancy in 3.6% (N = 2) of participants each. Etiology of hemoptysis could not be established in 8 (14.3%) participants. The pattern of etiologic distribution of hemoptysis was comparable between the groups [Table 2].
Outcome
Primary outcome
Frequency of hemoptysis
The mean (±SD) frequency of hemoptysis at presentation was 8.0 (6.7) episodes/day and was comparable (P = 0.635) between the groups [Table 3]. The mean percentage decrease (improvement) in the frequency of hemoptysis was higher in the TXA group as compared to the control group at both day 1 (63.9% vs. 39.8%) and day 2 (70.9% vs. 51.6%). The difference was statistically significant at day 1 (P = 0.012) but was insignificant at day 2 [Table 3]. However, after excluding participants (N = 11) who underwent either DSA or surgical intervention to control hemoptysis, the percentage decrease (improvement) of hemoptysis was significantly higher in the TXA group at day 1 (68.0% vs. 41.7%, P = 0.014) as well as day 2 (76.2% vs. 50.3%, P = 0.049) as compared to the control group [Table 4].
Table 3.
Primary and secondary outcomes
| Outcome variable | TXA (n=27) | Control (n=29) | P |
|---|---|---|---|
| Frequency of hemoptysis at presentation (episodes/day) | 7.6±6.2 | 8.4±7.2 | 0.635 |
| Percentage decrease in frequency at day 1 | 63.9±29.5 | 39.8±39.3 | 0.012 |
| Percentage decrease in frequency at day 2 | 70.9±40.0 | 51.6±43.0 | 0.088 |
| Quantity of hemoptysis at presentation (mL) | 135.2±73.5 | 136.9±139.4 | 0.954 |
| Percentage decrease in quantity at day 1 | 73.4±27.6 | 51.7±40.4 | 0.024 |
| Percentage decrease in quantity at day 2 | 80.5±28.0 | 62.6±43.9 | 0.076 |
| VAS score of hemoptysis at presentation | 7.6±1.9 | 7.0±1.7 | 0.248 |
| Percentage decrease of VAS at D1 | 67.0±28.6 | 45.8±32.9 | 0.013 |
| Percentage decrease of VAS at D2 | 74.6±33.3 | 58.0±38.4 | 0.089 |
| Resolution of hemoptysis (n=24), n (%) | 17.0 (63.0) | 7.0 (24.1) | 0.003 |
| Adverse drug reaction (n=26), n (%) | 14 (51.8) | 12 (41.4) | 0.432 |
| Cough (n=21), n (%) | 13 (48.1) | 8 (27.6) | 0.112 |
| Throat irritation (n=19), n (%) | 12 (44.4) | 7 (24.1) | 0.109 |
| Duration of hospital stay (days) | 5.4±4.7 | 6.7±6.1 | 0.384 |
| Need for intervention (n=11), n (%) | 4 (14.8) | 7 (24.1) | 0.380 |
| Digital subtraction angiography (n=9), n (%) | 4 (14.8) | 5 (17.2) | 1.00 |
| Surgical intervention (n=2), n (%) | 0 | 2 (6.9) | 0.492 |
| Need for blood transfusion (n=9), n (%) | 4 (14.8) | 5 (17.2) | 0.805 |
| Recurrence of hemoptysis (n=3), n (%) | 2 (7.4) | 1 (3.4) | 0.510 |
TXA=Tranexamic acid, VAS=Visual Analog Scale
Table 4.
Primary and secondary outcomes after excluding participants who underwent intervention
| Outcome variable | TXA (n=23) | Control (n=22) | P |
|---|---|---|---|
| Frequency of hemoptysis at presentation (episodes/day) | 7.0±5.8 | 8.2±7.6 | 0.544 |
| Percentage decrease in frequency at day 1 | 68.0±29.5 | 41.7±38.2 | 0.014 |
| Percentage decrease in frequency at day 2 | 76.2±38.7 | 50.3±46.6 | 0.049 |
| Quantity of hemoptysis at presentation (mL/day) | 134.8±77.9 | 95.5±64.4 | 0.073 |
| Percentage decrease in quantity at day 1 | 78.6±21.1 | 50.9±43.3 | 0.009 |
| Percentage decrease in quantity at day 2 | 85.2±24.0 | 58.6±47.1 | 0.021 |
| VAS score of hemoptysis at presentation | 7.43±1.9 | 7.0±1.8 | 0.391 |
| Percentage decrease of VAS at day 1 | 72.4±25.6 | 47.1±36.2 | 0.009 |
| Percentage decrease of VAS at day 2 | 81.0±29.7 | 56.6±41.0 | 0.026 |
| Resolution of hemoptysis (n=24), n (%) | 17 (73.9) | 7 (31.8) | 0.005 |
TXA=Tranexamic acid, VAS=Visual Analog Scale
Quantity of hemoptysis
The mean (±SD) quantity of hemoptysis at presentation was 136.1 (111.6) mL/day and was comparable (P = 0.954) between the groups [Table 3]. The mean percentage decrease (improvement) in quantity of hemoptysis was more in the TXA group than the control group at both day 1 (73.4% vs. 51.7%) and day 2 (80.5% vs. 62.6%). The difference was statistically significant at day 1 (P = 0.024) but insignificant at day 2 [Table 3]. However, after excluding the participants (N = 11) who underwent either DSA or surgical intervention to control hemoptysis, the percentage decrease (improvement) was significantly higher in the TXA group at day 1 (78.6% vs. 50.9%, P = 0.009), as well as at day 2 (85.2% vs. 58.6%, P = 0.021) as compared to the control group [Table 4].
Visual Analog Scale score of hemoptysis
The mean (±SD) VAS score of hemoptysis at presentation was 7.27 (±1.78), which was comparable (P = 0.248) between the groups [Table 3]. The mean percentage decrease (improvement) in VAS score of hemoptysis was more in the TXA group as compared to the control group at both day 1 (67.0% vs. 45.8%) and day 2 (74.6% 58.0%). Similar to the previous outcome parameters, the difference was statistically significant at day 1 (P = 0.013) but insignificant at day 2 [Table 3]. Again, after excluding participants (N = 11) who underwent either DSA or surgical intervention to control hemoptysis, the percentage decrease (improvement) was significantly more in the TXA group at day 1 (72.4% vs. 47.1%, P = 0.009), as well as at day 2 (81.0% vs. 56.6%, P = 0.026) as compared to the control group [Table 4].
Resolution of hemoptysis
Resolution of hemoptysis was defined as no episode of hemoptysis sustained for at least 48 h following cessation of hemoptysis. Out of 56 participants, 24 participants achieved resolution without requiring DSA or surgical intervention [Table 3]. Resolution of hemoptysis was significantly (P = 0.003) higher in the TXA group (63.0% vs. 24.1%) as compared to the control group [Table 3].
Secondary outcomes
No serious ADR was observed during the study. Out of 56 participants, 26 (46.4%) participants reported minor cough or throat irritation or both. Minor cough and throat irritation was observed in 37.5% (N = 21) participants and in 33.9% (N = 19) participants respectively, which were comparable between the groups [Table 3].
The mean (±SD) duration of hospital stay was 5.4 (4.7) days in the TXA group which was lower than 6.7 (6.1) days in the control group, but the difference was statistically insignificant (P = 0.384) [Table 3].
A total of 11 (19.6%) participants required DSA or surgical intervention to control bleeding, out of which 9 (16.1%) participants underwent DSA, and 2 (3.6%) participants underwent surgical resection of lung [Table 3]. The need for intervention was lesser in the TXA group as compared to the control group (14.8% vs. 24.1%), but the difference was statistically insignificant (P = 0.380) [Table 3].
A total of 9 (16.1%) participants required blood transfusion which was comparable (P = 0.805) between the groups [Table 3]. Only 3 (5.3%) participants had a recurrence of hemoptysis, which was comparable (P = 0.510) between the groups [Table 3]. No death was reported in either group during the hospital stay and within 28-day follow-up of participants.
Discussion
Hemoptysis is a common presentation in medical emergencies with significantly higher mortality, varying from submassive to massive hemoptysis. Etiological workup and definitive management are time consuming; thus, prompt measure to achieve hemostasis is required to be performed. Medical management followed by endovascular and bronchoscopic intervention have been the mainstay for managing hemoptysis.
TXA is a lysine derivative that inhibits fibrinolysis, preventing the breakdown of fibrin clots and helping in clot stabilization.[3] As a medical therapy, TXA is used for bleeding control in hemoptysis. Oral and IV are the most commonly used routes of administration for TXA, but novel approaches like nebulized-TXA had shown potential role in the management of hemoptysis. However, because of limited research and some case reports, evidence for the use of nebulized-TXA in hemoptysis is limited. The index study was a double-blinded randomized control clinical trial to evaluate the efficacy and safety of nebulized-TXA for the management of hemoptysis.
According to the index study, the most common etiology of hemoptysis was tuberculosis (50%), followed by secondary fungal infections (23.2%), and only 3.4% of participants had malignancy. As per the previous institutional study also, tuberculosis was the most common etiology of hemoptysis, but fungal etiology was very low (1.56%) as compared to the present study.[8] This might be because of the recent widespread availability and use of investigations required to make diagnosis of fungal infection due to higher level of suspicion following coronavirus disease 2019 (COVID-19) pandemic. In the middle east, malignancy (36.2%), followed by bronchiectasis (34.04%), was the most common etiology, which was in accordance with the contemporary studies on the etiology of hemoptysis in areas with a low prevalence of TB.[6]
Primary outcome
The mean percentage decrease (improvement) in frequency of hemoptysis at day 1 in the TXA group was significantly (P = 0.012) more than the control group (63.9% vs. 39.8%). Similarly, improvement in quantity of hemoptysis was also significantly (P = 0.024) higher in the TXA group compared to the control group (73.4% vs. 51.7%) at day 1. In addition, VAS score too showed similar improvement at day 1, with a higher mean percentage decrease (67.0% vs. 45.8%) in the TXA group compared to the control group (P = 0.013). At day 2, the improvement in frequency, quantity, and VAS score of hemoptysis was higher in the TXA group as compared to the control group; however, the difference was statistically insignificant. Majority of the participants with persisting hemoptysis underwent endovascular or surgical intervention by day 2, after which hemoptysis was controlled. Thus, after excluding these participants who underwent intervention, the improvement in frequency, quantity, and VAS score of hemoptysis was significantly better in the TXA group as compared to the control group both at day 1 as well as day 2. Similar RCT also found a decrease in the amount of hemoptysis with TXA nebulization, starting from day 2.[6] The present study, however, indicated significant improvement in frequency and quantity of hemoptysis at day 1 itself, thus demonstrating a prompter action of nebulized-TXA in hemoptysis. According to the present study, the participants were nebulized for a shorter duration of 2 days compared to 5 days in the previous study leading to lesser amount of exposure to the drug. Gopinath et al. also demonstrated significant reduction in the amount of hemoptysis at 6 h, 12 h, and 24 h, with TXA nebulization (P < 0.05). However, this was an open-label study and compared nebulized-TXA with IV-TXA.[9] The resolution of hemoptysis was significantly (P = 0.003) more in the TXA group (63%) as compared to the control group (24.1%) which was in accordance to the previously published studies. One of them observed resolution on day 5, and another interpreted at 30 min postintervention, both showed a significant resolution of hemoptysis with nebulized-TXA.[6,9] Contrary to the present study two meta-analyses though showed significant reduction in the amount of hemoptysis but failed to demonstrate significant resolution of hemoptysis with TXA irrespective of route of administration.[10,11]
Secondary outcome
The mean (±) duration of hospital stay was shorter in the TXA group (5.4 ± 4.7 days) compared to the control group (6.7 ± 6.1 days), but the difference was statistically insignificant (P = 0.384). However, previously published meta-analysis as well as RCTs on TXA nebulization demonstrated a significant reduction in duration of hospital stays with TXA in hemoptysis.[6,9,10,11] In the present study, the participants were kept admitted even after cessation of hemoptysis for diagnostic evaluation leading to prolongation of hospital stay lacking statistical significance. The need for intervention was also less for the TXA group (14%) compared to the control group (24.1%), but again, this difference was not statistically significant (P = 0.380). However, contrary to the present study, previously published meta-analysis as well as RCTs on nebulized-TXA demonstrated a significantly reduced need for intervention with TXA in hemoptysis.[6,9,10,11] The need for blood transfusion was comparable in both the groups. No other study with nebulized-TXA evaluated the need for blood transfusion. Study with IV TXA also showed no significant impact with respect to the need for blood transfusion as the blood transfusion was relied on baseline Hb and associated comorbidities, along with the severity of hemoptysis.[4] Only three participants had recurrence of hemoptysis which was comparable between the groups (P = 0.510). However, Wand et al. demonstrated significantly lower recurrence rates with TXA nebulization at 28 days and 1-year follow-up.[6] In other RCTs, patients were not followed up to evaluate incidence of recurrence.[9] In the present study, no incident of death was reported during 28 days of follow-up of the participants. Although meta-analysis showed reduction in short-term mortality in with TXA, RCT could not demonstrate any mortality benefit with the use of TXA nebulization in hemoptysis.[6,11]
Adverse drug reaction
Minor side effects associated with TXA are nausea, vomiting, diarrhea and major side effect of thromboembolic events, and allergic reactions were also reported.[12,13] No major ADR was reported during the present study. Minor cough and throat irritation after nebulization were reported and comparable between both the groups. These symptoms were self-limiting and did not require any additional pharmacological intervention. Previous studies also reported no serious ADR with TXA nebulization.[4,6] However, Gopinath et al. reported bronchospasm with nebulized-TXA in two participants which was reversible after bronchodilator nebulization.[9] A meta-analysis showed minor adverse events such as mild headache, slight chest discomfort, and nausea with TXA. However, most of the studies included in the met analysis used IV TXA.[10] Thus, it can be interpreted that the nebulized form of TXA might reduce the risk of adverse events associated with IV or oral administration.
Overall, the index study demonstrated that nebulization with TXA resulted in improvement of severity of hemoptysis in terms of frequency, quantity, VAS score of hemoptysis, and achieved faster resolution of hemoptysis. The nebulized TXA may have multiple advantages over the use of IV TXA. Local administration ensures a more rapid and targeted drug administration leading to faster onset of action. In respiratory diseases such as chronic obstructive pulmonary disease and bronchial asthma, the aerosolized route of drug administration is favored over the systemic route. Similarly, nebulized TXA is likely to act promptly in active hemoptysis compared to the IV route of administration. IV TXA can also lead to serious thrombotic adverse events, and local administration in the form of nebulization is unlikely to produce such effects, as demonstrated in the present study.[12,13] IV drug administration requires expertise; however, nebulization does not require much expertise and can be administered at home or first point of care with the simple portable nebulizer machine. In resource-constraint settings with limited availability of tertiary care center equipped with DSA and surgery facilities, TXA nebulization can be used as a prompt therapy for controlling bleeding before definitive management can be sought after referral to the higher center. The present study was one of the first kinds in the national setting to evaluate the efficacy and safety of TXA in the form of nebulization to control bleeding of hemoptysis.
The limitation of the study was a small sample size (n = 56) due to the slow recruitment because of ongoing COVID-19 pandemic. RCTs with a larger sample size would be appreciated to evaluate the efficacy and safety of nebulized-TXA further. The present study only included patients with submassive hemoptysis. Future studies in patients with massive hemoptysis are encouraged. However, these patients may require prompt definitive therapy such as endobronchial/endovascular or surgical intervention, and TXA nebulization can be initiated as a bridging therapy in these patients. As per protocol, all the participants received standard therapy of IV TXA as advised by the treating physician in addition to the TXA nebulization. Hence, the role of TXA nebulization alone in hemoptysis is still debatable.
Conclusion
TXA nebulization, an alternative route of administration was found to be safe for the treatment of hemoptysis. Prompt nebulization with TXA is effective as bridging therapy in hemoptysis to achieve the immediate goal of hemostasis and stabilization before definitive endovascular/endobronchial or surgical intervention is planned or performed. Route of administration of TXA should be individualized as per presence or absence of side effects and response to the therapy. Further studies with larger sample size are encouraged to evaluate the efficacy and safety of this novel approach of TXA nebulization for the treatment of hemoptysis.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
We thank and acknowledge all the participants for their voluntary participation in this study to generate better knowledge regarding TXA nebulization for the treatment of hemoptysis
Funding Statement
Nil.
References
- 1.Earwood JS, Thompson TD. Hemoptysis: Evaluation and management. Am Fam Physician. 2015;91:243–9. [PubMed] [Google Scholar]
- 2.Shigemura N, Wan IY, Yu SC, Wong RH, Hsin MK, Thung HK, et al. Multidisciplinary management of life-threatening massive hemoptysis: A 10-year experience. Ann Thorac Surg. 2009;87:849–53. doi: 10.1016/j.athoracsur.2008.11.010. [DOI] [PubMed] [Google Scholar]
- 3.Dunn CJ, Goa KL. Tranexamic acid: A review of its use in surgery and other indications. Drugs. 1999;57:1005–32. doi: 10.2165/00003495-199957060-00017. [DOI] [PubMed] [Google Scholar]
- 4.Bellam BL, Dhibar DP, Suri V, Sharma N, Varma SC, Malhotra S, et al. Efficacy of tranexamic acid in haemoptysis: A randomized, controlled pilot study. Pulm Pharmacol Ther. 2016;40:80–3. doi: 10.1016/j.pupt.2016.07.006. [DOI] [PubMed] [Google Scholar]
- 5.Márquez-Martín E, Vergara DG, Martín-Juan J, Flacón AR, Lopez-Campos JL, Rodríguez-Panadero F. Endobronchial administration of tranexamic acid for controlling pulmonary bleeding: A pilot study. J Bronchology Interv Pulmonol. 2010;17:122–5. doi: 10.1097/LBR.0b013e3181dc8c17. [DOI] [PubMed] [Google Scholar]
- 6.Wand O, Guber E, Guber A, Epstein Shochet G, Israeli-Shani L, Shitrit D. Inhaled tranexamic acid for hemoptysis treatment: A randomized controlled trial. Chest. 2018;154:1379–84. doi: 10.1016/j.chest.2018.09.026. [DOI] [PubMed] [Google Scholar]
- 7.Alabdrabalnabi F, Alshahrani M, Ismail N. Nebulized tranexamic acid for recurring hemoptysis in critically ill patients: Case series. Int J Emerg Med. 2020;13:45. doi: 10.1186/s12245-020-00304-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Bhalla A, Pannu AK, Suri V. Etiology and outcome of moderate-to-massive hemoptysis: Experience from a tertiary care center of North India. Int J Mycobacteriol. 2017;6:307–10. doi: 10.4103/ijmy.ijmy_54_17. [DOI] [PubMed] [Google Scholar]
- 9.Gopinath B, Mishra PR, Aggarwal P, Nayaka R, Naik SR, Kappagantu V, et al. Nebulized versus IV tranexamic acid for hemoptysis: A pilot randomized controlled trial. Chest. 2023;163:1176–84. doi: 10.1016/j.chest.2022.11.021. [DOI] [PubMed] [Google Scholar]
- 10.Tsai YS, Hsu LW, Wu MS, Chen KH, Kang YN. Effects of tranexamic acid on hemoptysis: A systematic review and meta-analysis of randomized controlled trials. Clin Drug Investig. 2020;40:789–97. doi: 10.1007/s40261-020-00946-y. [DOI] [PubMed] [Google Scholar]
- 11.Chen LF, Wang TC, Lin TY, Pao PJ, Chu KC, Yang CH, et al. Does tranexamic acid reduce risk of mortality on patients with hemoptysis?A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021;100:e25898. doi: 10.1097/MD.0000000000025898. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90:446–55. doi: 10.1160/TH03-03-0152. [DOI] [PubMed] [Google Scholar]
- 13.Ijaopo EO, Ijaopo RO, Adjei S. Bilateral pulmonary embolism while receiving tranexamic acid: A case report. J Med Case Rep. 2020;14:212. doi: 10.1186/s13256-020-02545-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
