Efficacy and safety of intrapleural administration of sodium bicarbonate in patients with acute empyema and complicated parapneumonic effusion: protocol for a prospective, single-arm, interventional study

Abstract

Background

The standard treatment for acute empyema/complicated parapneumonic effusion (CPPE) is antibiotic administration and continuous chest drainage. However, adequate drainage becomes impossible in multichambered pleural effusion and some patients may require surgery or may die. In Japan, intrapleural urokinase is frequently used to restore drainage effects; however, its supply was suspended in 2022 owing to difficulties in procuring the raw materials. In recent years, the effectiveness of intrapleural sodium bicarbonate administration for empyema/CPPE has been reported; however, complications such as hemothorax and pneumothorax occurred frequently because the research protocol involved repeated thoracentesis. Therefore, we designed an interventional study to investigate the efficacy and safety of intrapleural sodium bicarbonate administration combined with continuous chest drainage in patients with empyema/CPPE.

Methods

This study will include patients with empyema/CPPE who have been administered antibiotics and still have pleural effusion after > 12 h of continuous chest drainage. Sodium bicarbonate (50 mL) will be administered into the pleural cavity through the double-lumen catheter of the chest tube once daily for a maximum of 3 days. The primary endpoint will be treatment success rate, defined as the rate of avoiding surgery or death within 30 days of sodium bicarbonate administration. The 95% confidence interval for the treatment success rate will be calculated using the Clopper–Pearson method.

Discussion

Sodium bicarbonate can be chemically synthesized; therefore, there is little concern about supply shortages and it is inexpensive. Therefore, if it is effective against empyema/CPPE, it would prove beneficial for Japan and other countries. Once this study shows the efficacy and safety of intrapleural sodium bicarbonate administration for empyema/CPPE, we plan to conduct a prospective randomized controlled trial using a placebo.

Trial registration

This study was approved by the Yokohama City University Clinical Research Review Committee (ethics approval number: CRB24-001) on May 8, 2024, and registered with the Japan Clinical Trials Registry (jRCTs031240093) on May 17, 2024. Written informed consent will be obtained from the participants or their proxies.

Background

Acute empyema/complicated parapneumonic effusion (CPPE) is characterized by purulent effusions due to bacterial infection of the pleural cavity. The standard treatment is antibiotic administration and continuous chest drainage; however, when pleural effusion becomes multichambered owing to septal formation, drainage is inadequate, resulting in the need for surgery or death in some patients [1]. Even with the best treatment for empyema/CPPE, the 1-year mortality rate has been reported to be 10–15% [2].

Intrapleural administration of various agents has been studied to break down the septum, restore drainage efficacy, and reduce conversion to surgery and death. In 1989, a single-arm study reported the efficacy of intrapleural urokinase administration [3]. In 2011, a randomized, placebo-controlled trial reported that intrapleural administration of tissue plasminogen activator (tPA) plus deoxyribonuclease (DNase) significantly reduced conversion to surgery [4]. A retrospective study comparing intrapleural administration of urokinase with intrapleural administration of tPA + DNase showed no significant difference in the treatment success rate; however, the incidence of hemothorax tended to be higher in the tPA + DNase group than in the urokinase group [5]. Based on these reports, intrapleural administration of urokinase is frequently used in Japan for empyema/CPPE with poor drainage, although it is not covered by insurance. However, in China, which is the only source of human urine and raw material for urokinase, urine collection has decreased sharply and the supply stopped in 2022.

Recently, a prospective cohort study compared the intrapleural administration of sodium bicarbonate, which has anticoagulant [6] and antibacterial effects [7, 8], with the intrapleural administration of urokinase for empyema/CPPE with poor drainage; no significant difference in treatment efficacy was found between the two groups [9]. However, this study used a treatment protocol involving repeated thoracentesis rather than the global standard treatment of continuous chest drainage. Consequently, hemothorax and pneumothorax complications occur at a high frequency, and the results cannot be directly applied to actual clinical practice.

Therefore, we designed a prospective, single-arm, interventional study to investigate the efficacy and safety of intrapleural sodium bicarbonate administration combined with continuous chest drainage in patients with empyema/CPPE with poor drainage.

Methods/design

Aim

We aimed to evaluate the efficacy and safety of intrapleural sodium bicarbonate administration combined with continuous chest drainage in patients with empyema/CPPE.

Study design and setting

This will be a prospective, single-arm, interventional study. This study will be conducted at Yokohama City University Medical Center, and the study period is from May 17, 2024 to October 31, 2027.

Inclusion and exclusion

The inclusion criteria will be as follows: (1) ≥ 18 years of age; (2) diagnosed with empyema/CPPE (diagnostic criteria: patients with clinically apparent bacterial infection and pleural effusion and who met one or more of the following criteria: (a) imaging evidence of encapsulated pleural effusion, (b) positive Gram stain or culture of pleural fluid, (c) pleural fluid pH < 7.2, (d) pleural fluid glucose < 40 mg/dL, (e) pleural fluid lactate dehydrogenase > 1000 IU/L, and (f) pleural fluid gross findings of pus); (3) administration of antibiotics and continuous chest drainage, and the presence of residual pleural fluid on chest radiograph ≥ 12 h after the start of continuous chest drainage with − 15 cm H₂O; and (4) written consent to participate in this study. Consent from a substitute decision maker will be acceptable.

The exclusion criteria will be as follows: (1) empyema/CPPE with fistula, (2) severe renal dysfunction (estimated creatinine clearance < 30 mL/min), (3) history of serious heart disease, (4) congestive heart failure requiring treatment, (5) history of serious respiratory dysfunction, (6) abnormal coagulation function or use of anticoagulant medication, (7) alkalemia (venous blood gas pH ≥ 7.45), (8) serum Na ≥ 150 mEq/L, (9) serum K ≤ 3.0 mEq/L, (10) serum Ca ≤ 8.0 mg/dL, (11) septic shock, (12) pregnant or lactating women, (13) administered unapproved drugs within 12 weeks, and (14) judged by the physician to be unsuitable for the study.

Interventions

The following investigational treatment will be administered to patients with empyema/CPPE who meet all the inclusion and exclusion criteria. In addition to antibiotics and continuous chest drainage, 50 mL of 8.4% sodium bicarbonate (MEYLON Injection 8.4%©) will be administered intrapleurally via a double-lumen catheter. Sodium bicarbonate will be administered intrapleurally for 10 min using an infusion pump while the chest drain is clamped. Subsequently, the patient's position will be changed every 30 min to allow sodium bicarbonate to spread throughout the pleural cavity, and the chest drain will be opened after 2 h. This investigational treatment will be administered once daily for up to 3 consecutive days.

Endpoints

The primary endpoint will be the treatment success rate, defined as the rate of avoidance of surgery or death within 30 days of intrapleural administration of sodium bicarbonate. Secondary endpoints will be the duration of fever (days); duration of chest drainage (days); proportion of pleural effusion in the unilateral thorax on chest radiography on days 1 and 7; number of white blood cells, neutrophils, and C-reactive protein levels on days 1 and 7; and adverse events within 30 days.

Timeline of the study

The following information will be obtained from each patient at the time of registration: (1) clinical assessment, (2) subjective and objective symptoms, (3) vital signs, (4) pleural fluid examination, (5) hematological examination, (6) blood biochemical examination, (7) coagulation, (8) venous blood gas analysis, (9) chest radiographic findings, (10) chest computed tomographic findings, (11) electrocardiogram findings, and (12) drainage volume of the chest tube. Subsequently, information on (2), (3), (5), (6), (7), (8), (9), (12), and adverse events and concomitant medications will be obtained on day 1 (start of administration), day 2, day 3, day 4, and day 7 (± 2). On day 30 (± 7), information on (2) and adverse events and concomitant medications will be obtained (Table 1).

Table 1.

Schedule for data collection

	Screening period Baseline assessment	First administration of the investigational drug	Post-administration of the investigational drug					When canceled
		Day 1	Day 2	Day 3	Day 4	Day 7	Day 30
Allowable range (days)	− 7-registration	0	0	0	0	± 2	± 7	± 3
Informed consent, registration	X
Clinical assessmenta	X
Administration of the investigational drug		X	(X)	(X)
Subjective and objective symptomsb	X	X	X	X	X	X	X	X
Vital signsc	X	X	X	X	X	X		X
Pleural effusion examinationd	X
Hematological examinatione	X	X	X	X	X	X		X
Blood biochemical examinationf	X	X	X	X	X	X		X
Coagulation examinationg	X	X	X	X	X	X		X
Venous blood gas examinationh	X	X	X	X	X	X		X
Chest radiography	X	X	X	X	X	X		X
Chest computed tomography	X
Electrocardiography	X
Drainage volume of the chest draini	X	X	X	(X)	(X)	(X)
Adverse events		X	X	X	X	X	X	X
Concomitant medications check		X	X	X	X	X	X	X

^a Clinical assessment: age, sex, height, body weight, underlying disease, and medical history

^b Subjective and objective symptoms: fever, chest pain, cough, and sputum

^c Vital signs: blood pressure, pulse rate, body temperature, percutaneous oxygen saturation, and respiratory rate

^d Pleural fluid examination: potential hydrogen, cell count, mononuclear cell count, polynuclear cell count, total protein, lactate dehydrogenase, glucose, adenosine deaminase, Gram staining, bacterial culture

^e Hematological examination: white blood cell count, neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count, red blood cell count, hematocrit, hemoglobin, platelet count

^f Blood biochemical examination: total protein, albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, creatine kinase, lactate dehydrogenase, creatinine, blood urea nitrogen, uric acid, c-reactive protein, Na, K, Cl, Ca, Mg, P, casual blood glucose, brain natriuretic peptide

^g Coagulation: prothrombin time, activated partial thromboplastin time, D-dimer, fibrinogen/fibrin degradation products, fibrinogen

^h Venous blood gas analysis: potential hydrogen, mixed venous oxygen pressure, mixed venous carbon dioxide pressure, hydrogen carbonate, base excess, lactate

ⁱ Drainage volume of the chest tube: measure the amount of drainage daily until the chest drain is removed

Sample size

The target number of patients for this study is 25. The rationale for this is as follows: Zayed et al. reported a prospective cohort study in which sodium bicarbonate or urokinase was administered intrapleurally, in addition to antibiotic administration and repeated thoracentesis [9]. The treatment success rate of the sodium bicarbonate group was 80%. Treatment success was defined as good drainage of pleural fluid, improvement in clinical symptoms, control of systemic infection, and improvement in radiographic findings. This finding was not entirely consistent with the primary endpoint of our study; however, it was similar in terms of clinical significance. Therefore, we predicted that the primary endpoint of our study, the treatment success rate, would be 80%. In contrast, the rate of avoiding surgery or death in treatment with only the administration of antibiotics and continuous chest drainage has been reported to be 51.9–62.5% [10–12]. Therefore, if the primary outcome of this study was < 60%, it could be interpreted that intrapleural sodium bicarbonate administration had no therapeutic effect. Based on the Clopper–Pearson method, the sample size was calculated with a predicted treatment success rate of 80% and a lower limit of 95% confidence interval of 60%, and the result was 22 patients. Considering the cases that would be excluded from the analysis owing to protocol deviations, the number of patients was set at 25.

Statistical analysis

Statistical analysis will be performed for all patients who will be administered intrapleural sodium bicarbonate at least once. For the primary outcome, the treatment success rate and 95% confidence intervals will be calculated using the Clopper–Pearson method. For secondary outcomes, the median and 95% confidence intervals for the duration of fever and chest drainage will be calculated. The average and 95% confidence intervals will be calculated for the proportion of pleural effusion in the unilateral thorax on chest radiography and blood test results. All adverse effects will be described and assessed in accordance with the Common Terminology Criteria for Adverse Events, version 5.0.

Ethics

This study will be conducted in accordance with the principles of the Declaration of Helsinki and Clinical Trials Act of Japan. This study was approved by the Yokohama City University Clinical Research Review Committee (ethics approval number: CRB24 - 001) on May 8, 2024, and registered with the Japan Clinical Trials Registry (jRCTs031240093) on May 17, 2024. Written informed consent will be obtained from all participants or their proxies.

Data quality assurance

The research supervisor will monitor and ensure the appropriate implementation and management of operations. The monitoring supervisor will conduct monitoring in accordance with the procedures created before the start of the research.

Data security

Patient confidentiality will be strictly managed in accordance with medical confidentiality regulations and handled in accordance with Japan's Personal Information Protection Law.

Safety

Patients may withdraw their consent to participate in the study at any time, and the methods of confirming their intentions, such as orally and in writing, are acceptable. We will take care to ensure that no disadvantages arise from the withdrawal of consent.

Adverse event

The Yokohama City University Clinical Research Review Committee will be notified of any severe adverse events.

Discussion

To our knowledge, this is the first study to evaluate the efficacy and safety of intrapleural sodium bicarbonate administration combined with continuous chest drainage in patients with empyema/CPPE. As the supply of urokinase was suspended in Japan, surgery must be considered in patients with empyema/CPPE in whom the condition does not improve with the administration of antibiotics and continuous chest drainage. Current surgeries are less invasive than those several decades ago; however, it is better to avoid surgery, if possible, through medical treatment. In addition, surgery is difficult to perform for a considerable number of patients owing to complications or age. In Europe and America, tPA + DNase therapy is often used for empyema/CPPE [1, 13]; however, it has several complications, such as hemothorax, and is expensive. Sodium bicarbonate can be chemically synthesized without using any human-derived biological components; therefore, there is little risk of supply shortage, and it is inexpensive. Therefore, if it is effective against empyema/CPPE, it has the potential to provide benefits to Japan and other countries.

We acknowledge that this study is designed as a single-arm, exploratory trial, which limits its ability to provide strong comparative evidence. A randomized controlled trial with a placebo control group would be the ideal approach for establishing definitive evidence. Owing to limited patient enrollment within the current study period, incorporating a control group was not feasible at this stage. Instead, this study serves as an initial investigation to assess the safety and potential efficacy of sodium bicarbonate in this patient population. On the basis of our findings, we plan to conduct a future multicenter randomized controlled trial to further validate its clinical application.

To supplement the lack of comparative data, we have included clinical course data from two patients enrolled in this study, as shown in Figs. 1 and 2. By December 2024, two patients were enrolled, and both achieved the primary endpoint of treatment success. These preliminary results provide an early insight into the therapeutic effect of sodium bicarbonate administration.

Fig. 1.

Clinical course of one of the two enrolled patients. Case 1, male in his 70s

Fig. 2.

Clinical course of one of the two enrolled patients. Case 2, male in his 70s

Abbreviations

CPPE

Complicated parapneumonic effusion

DNase

Deoxyribonuclease

tPA

Tissue plasminogen activator

Authors’ contributions

All the authors have read and approved the final version of the manuscript. Conception: Y. S. and S. T.; design of the work: Y. S. and S. T.; acquisition: Y. S., S. T., R. N., S. O., A. T., S. M., T. M., T. H., C. M., K. S., and K. T.; analysis: Y. S. and S. T.; interpretation of data: Y. S. and S. T.; drafted the manuscript: Y. S. and S. T.; substantively revised it: N. K., M. Y., M. K., and T. K.

Funding

This study has not received external funding; however, it is being conducted with institutional support from the Respiratory Disease Center, Yokohama City University Medical Center.

Data availability

The datasets used and analyzed in the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study will be performed in accordance with the principles of the Declaration of Helsinki and Clinical Trials Act of Japan. This study was approved by the Yokohama City University Clinical Research Review Committee (ethics approval number: CRB24 - 001) on May 8, 2024, and registered with the Japan Clinical Trials Registry (jRCTs031240093) on May 17, 2024. Written informed consent will be obtained from all participants or their proxies.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.