Treatment of phase II empyema with intrapleural alteplase vs surgical debridement in children: A retrospective cohort study

doi:10.21203/rs.3.rs-4854390/v1

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Treatment of phase II empyema with intrapleural alteplase vs surgical debridement in children: A retrospective cohort study

https://doi.org/10.21203/rs.3.rs-4854390/v1

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Purpose

Describe a treatment protocol with intrapleural alteplase for phase II empyema in children and compare its efficacy and development of complications with surgical debridement.

Methods

Retrospective cohort design of children with phase II empyema treated with surgical debridement or alteplase through thoracostomy. Clinical outcomes and postoperative complications were analyzed. Efficacy was evaluated by resolution of empyema and need for re- intervention.

Results

38 patients were analyzed. Intrapleural alteplase presented less days of hospitalization (21.79 vs. 22.11 days), less blood transfusion requirement (36.84% vs. 42.11%) and less need (9 vs. 13 patients) and days of invasive mechanical ventilation (4.33 vs. 5.92 days), with no statistical difference (p = 0.68; p = 0.74; p = 0.68 respectively). Treatment failure was present in 4/19 patients treated with alteplase requiring further intervention compared to 6/19 patients treated with surgical debridement.

Conclusions

Intrapleural alteplase is as effective as surgical debridement for the treatment of phase II empyema for disease resolution and need for re-intervention. This study shows its safety and optimal clinical outcomes, minimal adverse events, less morbidity and clear clinical advantages due to its less invasive nature.

Empyema

Alteplase

Debridement

Thoracostomy

Thoracoscopy

Thoracotomy

Empyema occurs in 5–10% of children with parapneumonic effusion and 2% with pneumonia. Worldwide mortality attributable to empyema is around 15% [1]. Three phases of empyema have been recognized: (1) phase I exudative free fluid; (2) phase II fibrinopurulent fluid associated with solid portions, locules or septation; and (3) phase III an organized fluid with pleural thickening [2, 3]. The main concern of empyema is its mass effect that hinders lung mechanics, increasing morbidity, mortality and health-related costs [4].

Historically, surgery has been the treatment option for phase II empyema, either video assisted thoracic surgery (VATS) or open approach for debridement or deloculation [1]. The main goal of surgery is to allow drainage of the pleural space and complete lung re-expansion, which may also be achieved with fibrinolysis through thoracostomy. In Latin America, fibrinolysis is not generally considered as an alternative treatment of empyema, possibly due to a lack of clear indications and contraindications, doses and method of administration. Scarce case reports in Latin America have been published describing this therapy, and only one in children [5, 6]. Head-to-head comparisons between surgery and fibrinolytic therapy have shown efficacy, as well as safety [7–9]. Nonetheless, the indications and timing for treatment with fibrinolysis have not been standardized. At present, fibrinolysis is reserved for cases when patients are not eligible for surgery or at surgeon's discretion [8, 10, 11].

This study aims to compare the clinical outcomes and efficacy of treating phase II empyema with alteplase through thoracostomy versus video assisted or open debridement in a high-complexity single-center in Bogotá, Colombia. The objective of this research is to present researchers' experience and contribute to the definition of the first-line of approach in the treatment of phase II empyema, showing the clinical advantages and standardization of indications with a treatment protocol of alteplase through thoracostomy.

A retrospective cohort study was conducted with two groups at Instituto Roosevelt, a hospital that treats children with complicated health-related conditions in Colombia, an upper-middle income country where fibrinolysis for empyema is considered off-label. Data of children with phase II empyema between January 2016 and December 2023 were retrospectively retrieved. Inclusion criteria were pediatric patients with phase II empyema as a complication of pneumonia, treated either with video-assisted or open debridement or alteplase through thoracostomy. Children who had phase I (free fluid) or phase III empyema (pleural thickening), a neurological disease resulting in prolonged hospitalization, incomplete clinical records, and received a different fibrinolytic other than alteplase were excluded. Children were followed up until hospital discharge.

Phase II empyema was defined as the presence of parapneumonic effusion with solid portions, locules or septations in chest ultrasonography (US) or computed tomography (CT) [11, 12]. The clinical variables included symptoms at presentation, type of pneumonia and number of lobules affected, findings in chest x-ray, pleural effusion volume estimated by US or CT, presence of septic shock and American Society of Anesthesiologist (ASA) score [13]. Laboratories were collected before and after the initial intervention, and included pleural fluid analysis, white blood cell count, c reactive protein and platelets. Also, when pleural fluid and/or blood culture were obtained, the germ isolated was characterized. Clinical outcomes analyzed included duration of hospitalization, days in intensive care unit (ICU), days of invasive mechanical ventilation (IMV), days with tube thoracostomy, complications evaluated by Clavien Dindo classification [14] and requirement of blood transfusion. The efficacy of treatment was evaluated by two means: first, as imaging resolution of the empyema after three doses of alteplase or after initial surgical intervention, with an improved clinical course and second, as treatment failure defined as the need for further intervention.

The SPSS 24 statistical software was used for the analysis. Normality was assessed with the Shapiro-Wilk test. Student's T-test or the Mann Whitney test was used for hypothesis testing for parametric or non parametric variables, respectively. A probability value of less than 0.05 was defined as statistical significance. To assess potential source of bias due to differences in prognosis and severity, subgroup analysis according to time from onset of symptoms was conducted, grouping children in less than 8 days and more than 8 days.

All procedures performed for this study involving human participants followed the ethical standards of the Declaration of Helsinki and its amendments. This study was approved by the Instituto Roosevelt Institutional Review Board.

Forty-three children fulfilled the inclusion criteria. Two were excluded because a different fibrinolytic was used for treatment and three due to prolonged hospitalization related to neurological comorbidities (cerebral palsy). Of the remaining 38 children, 6 received video-assisted surgical debridement, 13 were treated with open debridement, and 19 received alteplase through thoracostomy. There were no patients treated with surgical debridement after 2019 since the Instituto Roosevelt adopted an institutional protocol for phase II empyema treatment. Ages ranged from 2.6 months to 17 years. Physical baseline status, measured with the ASA score, was similar in both groups. Demographics and initial characteristics at diagnosis are presented in Table 1.

Table 1

Patient demographics and baseline characteristics at diagnosis
	Alteplase by thoracostomy (n = 19)	Video assisted or open debridement (n = 19)
Gender
Male	7/19 (36.84%)	10/19 (52.63%)
Female	12/19 (63.16%)	9/19 (47.37%)
Age at the procedure (months) ⁺	40.51 [4-204]	44.67 [2.6-156.1]
Days of symptoms ⁺ ^a	9.63 [3–20]	11.63 [5–20]
Type of symptoms
Cough	(14/19) 73.68%	(16/19) 84.21%
Fever	(17/19) 89.47%	(19/19) 100%
Breathing difficulty	(19/19) 100%	(15/19) 78.95%
Dehydration	(1/19) 5.26%	(5/19) 26.32%
Ileum	(1/19) 5.26%	(4/19) 21.05%
Emesis	(5/19) 26.32%	(4/19) 21.05%
Requirement of IMV	9/19	13/19
Laboratories before initial intervention
Leukocytes⁺	19058.89	17077.89
C reactive protein⁺	74.52	89.49
Platelets⁺	432222.22	477473.68
ASA score*	3 [2–4]	3 [2–5]
Septic shock	6/19 (31.58%)	8/19 (42.11%)

⁺ Average * Median ^a Days from the start of symptoms to the initial medical consultation

IMV: invasive mechanical ventilation, ASA: American Society of Anesthesiologists

All children had chest x-ray for diagnosis, and most children had either chest US or CT for characterization of the type and extension of pneumonia and pleural effusion. Empyema was assessed by chest US in 25 patients (65.7%), thoracic CT in 12 patients (31.58%), and chest x-ray in 1 patient. Main imaging features are shown in Fig. 1. Most of the children in both groups had multilobar pneumonia. Septations were the most common radiographic criteria for final diagnosis (65.78%).

Children treated with alteplase had less days of hospitalization (21.79 vs. 22.11 days), less blood transfusion requirement (36.84% vs. 42.11%) and less need (9 vs. 13 patients) and days of IMV (4.33 vs. 5.92 days), however, no statistical significance was demonstrated (p = 0.68; p = 0.74; p = 0.68 respectively). Subgroup analysis according to onset of symptoms before the procedure showed no statistical differences. In addition, children treated with alteplase had a longer ICU stay and tube thoracostomy duration, though no statistical differences were found. These outcomes, as well as complications according to the Clavien Dindo classification, are found in Table 2.

Table 2

Clinical and efficacy outcomes
	Alteplase by thoracostomy (n = 19)	Video assisted or open debridement (n = 19)	p
Inpatient days ⁺	21.79 [10–47]	22.11 [10–46]	0.68
Days in ICU ⁺	11.58 [2–33]	11,00 [0–32]	0.95
Days on IMV ⁺ ^a	4.33 [1–13]	5.92 [1–23]	0.68
Days with tube thoracostomy ⁺	10.42 [5–22]	10.05 [3–26]	0.54
Clavien Dindo classification *	2 [1–7]	2 [1–7]	0.39
Blood transfusion requirement	7/19 (36.84%)	8/19 (42.11%)	0.74
Laboratories after initial intervention
Leucocytes ⁺	14686.47	18282.22	0.17
C reactive protein ⁺	58.21	89.88	0.02
Platelets ⁺	458941.18	465333.33	0.48
Serum LDH	312.87	452.70	0.02
Re-intervention rate	4/19 (21.05%)	6/19 (31.58%)	-
⁺ Average * Median

^a Time in days of invasive mechanical ventilation in children who required it: 9 patients in the alteplase by thoracostomy cohort and 13 patients in the video assisted or open debridement cohort.

Probability value of less than 0.05 was defined as statistical significance

ICU: intensive care unit, IMV: invasive mechanical ventilation, LDH: lactate dehydrogenase

In seven children of the alteplase group, pleural fluid cultures were positive: three with Staphylococcus aureus, three with Streptococcus pneumoniae, and one with Streptococcus pyogenes. In just two children treated with surgery, Staphylococcus aureus and Streptococcus pneumoniae were isolated. In the alteplase group, blood cultures were positive for Streptococcus pneumoniae in four children, and for Staphylococcus aureus in two children. In the debridement group, Staphylococcus aureus was cultured in two children, Streptococcus pneumoniae in two, and Klebsiella pneumoniae in one. Post-operative C reactive protein and serum lactate dehydrogenase were significantly lower in the alteplase group (p-value = 0.02). The other laboratories, namely, leucocytes, platelets, and pleural effusion cytochemistry, showed no significant differences. No mortality was reported in either group.

Four (21.05%) children treated with alteplase were regarded as treatment failure and required re-intervention. In the surgical debridement group, six (31.58%) children required further intervention, and four of them had initially been treated with VATS (Table 2). Causes of re-intervention in the alteplase group were: bronchopleural fistula in two children, and progression of the disease in the other two (one developed a residual collection and the other had persistent parapneumonic effusion with septations). Causes of re-intervention in the debridement group included bronchopleural fistula in two children, persistence of pneumothorax in two, and progression of the disease in two (persistent parapneumonic effusion with particles). Re-interventions included debridement, pleurectomy, lobectomy, and pneumorrhaphy.

Intrapleural fibrinolysis has been described for over 50 years as part of the management for complicated pleural effusion, this due to the fact that antibiotics alone cannot resolve the fibrinopurulent phase of the disease, as fibrin represents an obstacle to reach the infected fluid [3, 15]. Alteplase for the treatment of empyema is a therapy that can be safely used in children; its mechanism of action is based on the breakdown of fibrin septums, which facilitates drainage of the infected fluid [4].

There are multiple studies using fibrinolytics for the management of empyema, but mainly studying the use of urokinase and streptokinase [16–18]. However, there is no standardized dose or frequency of administration of alteplase in children, and it is usually based on limited experience with its use [3, 11, 19]. Therefore, a protocol of treatment with intrapleural alteplase applicable to all children diagnosed with phase II empyema has been implemented in our institution, and is presented in Fig. 2 [20]. Alteplase is the preferred fibrinolytic to use, due to its availability, short half-life, and high affinity to fibrin [21]. Furthermore, it is preferred because hypersensitivity reactions and antibody formation have been reported with the use of streptokinase [18, 22].

Regarding imaging diagnosis, thoracic US is the initial image of choice if pleural effusion is suspected. It is a bedside imaging study that allows adequate characterization of the fluid [23], even though it is operator-dependent. Results suggest that CT does not offer advantages over US and increases exposure to unnecessary radiation. A role for thoracic CT may be available in case of suspected complications such as abscesses or bronchopleural fistula [24].

Taking into account the role of US for the diagnosis of phase II empyema and the treatment protocol with alteplase, we have proposed an algorithm of indications for the management of empyema in children presented in Fig. 3. The diagnosis of empyema is based on clinical evolution, evidence of loculation in imaging studies, positive Gram stain or culture, evident pus, and pleural fluid with a pH < 7.2, glucose < 40, and LDH > 1000 [11, 12, 20]. Treatment with alteplase through thoracostomy should be indicated for phase II empyema at a single dose every 24 hours for 3 days. Treatment failure can be defined as clinical worsening of the patient characterized by the presence of persistent fever, increased oxygen requirement, signs of systemic inflammatory response, and imaging findings of persistent phase II empyema or development of phase III empyema. If there is no clinical or imaging improvement with alteplase, then surgery is the next option. In our institution, since 2019, all patients with phase II empyema have been initially treated with intrapleural alteplase.

VATS: Video assisted thoracic surgery

The advantages of intrapleural fibrinolysis found in this study include less days of hospitalization, less blood transfusion requirement and less days and need for IMV. Although these results did not show statistical differences, according to our experience, it offers clinical advantages due to lower morbidity associated with this intervention, as it is a less invasive approach with fewer anesthetic risk and no exposure to a surgical procedure. A key advantage of intrapleural fibrinolysis therapy is that it can be performed in the ICU under sedation, compared to surgical debridement, which is performed in the operating room under general anesthesia. Morbidity attributed to video-assisted and open decortication is 18% and 25%, respectively [22]. As for the reported success rate of intrapleural fibrinolysis for empyema, it is around 78.1–81% [21, 22], and treatment failure is reported around 16–19% [7, 21]. In our study, treatment failure for intrapleural fibrinolysis was 21%, slightly higher than previously reported.

In terms of treatment efficacy assessed as re-intervention rate, fewer patients in the alteplase group required a second procedure (21%) due to disease progression or complications, compared to the surgical decortication group (31%). This is consistent with the findings of St. Peter et al., who conducted a randomized study comparing thoracoscopic decortication and tube thoracostomy with fibrinolysis for empyema in children, finding that two patients had greater clinical deterioration after thoracoscopy. The authors justify this result because patients undergoing surgery are subjected to debridement and manipulation of the lungs at a critical moment of the disease, which conditions a release of inflammatory mediators into the circulation. More importantly, they found that patients who first underwent fibrinolysis and later required thoracoscopy did not worsen in their postoperative course, which is an argument in favor of recommending fibrinolysis as the initial treatment for empyema [7].

To date, comparisons between video-assisted thoracoscopy surgery (VATS) and intrapleural fibrinolytics via thoracostomy in children show results similar to ours. A prospective, randomized study in children, evaluating the use of alteplase compared to thoracoscopic decortication for empyema, found no statistical differences in terms of efficacy, oxygen requirements, days without fever, analgesic requirements, and length of hospitalization. However, they found significantly higher procedure costs in the video-assisted thoracic surgery group [7]. Additionally, a nationwide analysis in the United States evaluating 5424 pediatric patients with complicated pleural effusion or empyema found that percutaneous drainage with intrapleural fibrinolysis was associated with lower costs at initial admission, shorter hospital stay, and lower rates of readmission compared to surgical drainage [9]. Finally, the American Pediatric Surgery Association and Clinical Trials Committee recommend fibrinolytic intervention as the first-line therapy for empyema because it uses fewer resources and does not require surgery, reserving video-assisted thoracic surgery for patients who do not respond to non-surgical interventions [24].

Contrary to our findings, a systematic review and meta-analysis comparing VATS with thoracic drainage with fibrinolytics in children with empyema found that the re-intervention rate (p = 0.01) and hospital stay were shorter by approximately half a day (p = 0.007) in the VATS group. However, they found an effectiveness rate of 75% for fibrinolytic drainage in empyema cases, with no differences in complications compared to VATS (p = 0.2) [25].

Intrapleural fibrinolytic therapy, in addition to being effective, is safe. Ben-Or et al. evaluated complications such as bleeding and need for re-intervention associated with the use of alteplase for empyema and found a bleeding risk of 6.3%, complications of 16.7%, and need for operative interventions of 12.5%, but none of these were statistically significant [22]. Pleuritic pain is the reported discomfort most commonly associated with intrapleural fibrinolysis, often requiring premedication with analgesics to improve tolerance [26]; however, postoperative pain is significantly higher after thoracoscopy compared to fibrinolysis (p = 0.002) [21].

As for the causes of re-intervention found in this study, the development of bronchopleural fistula stands out. Therefore, we recommend avoiding the use of intrapleural fibrinolysis in patients with bronchopleural fistula, especially if they have necrotizing pneumonia, due to the increased risk of pneumothorax development or tracheal migration of the fibrinolytic through the fistula, which is also a significant cause for surgical re-intervention [27]. Other contraindications for the use of alteplase that have been described include recent cerebrovascular bleeding, coagulopathy, and known hemorrhagic diathesis [21].

The limitations of this study include the small sample size and the retrospective nature of data collection, so lack of statistical power and interpretation bias are present. Additionally, there is selection bias due to the absence of randomization. Another limitation of this study is that surgical complications were evaluated using the Clavien Dindo classification, but the Clavien Madadi classification has recently been validated as a more accurate and reliable resource for unexpected events in pediatric surgery [28]. The internal validity of the presented protocol has been demonstrated; adopting this treatment sequence allows disease resolution with optimal clinical outcomes. An increase in sample size would be required to apply this criteria and treatment approach and thus verify its external validity.

The rationale for excluding patients with prolonged hospitalization due to neurological disease, like cerebral palsy, was the nature of the pneumonia they acquired, being nosocomial and sometimes due to bronchoaspiration, which does not follow the normal clinical course of community acquired pneumonia.

To our knowledge, this is the first study conducted in Latin America on the use of alteplase as an off-label treatment for empyema in children. It is a therapy that has been carried out for many years world wide; however, it has not been systematically implemented in Latin America. Therefore, we provide a standardized management protocol for its homogeneous and orderly implementation in the treatment of phase II empyema in children. Additionally, although it has been clearly established that empyema has three phases of evolution, there has not been a comparison in children between VATS and intrapleural alteplase solely in the phase II of empyema [25]. This is relevant as it constitutes a standard of good clinical practice by selecting patients that obtain the maximum benefit from this therapy.

Intrapleural fibrinolytic therapy with alteplase via thoracostomy is as effective as surgical debridement for the treatment of phase II empyema in terms of disease resolution and need for re-intervention. This study shows our experience in the initial management of phase II empyema in children with intrapleural alteplase, suggesting its safety and optimal clinical outcomes. Clinical trials in children are needed to increase the scientific validation of this therapy.

Author Contribution

Study conception and design: I.C, L.R, G.M, M.V, M.RData acquisition: M.V, M.R, C.UAnalysis and data interpretation: L.R, M.V, I.C, G.MDrafting of the manuscript: M.V, I.C, M.R, G.MCritical revision: I.C, G.M, S.R

Acknowledgement

Evelyn Obando MD and Luz Marina Mejía MD designed and implemented the alteplase protocol in the pediatric ICU. Camilo Mendoza-Pulido MD assisted in proofreading and editing the manuscript. Manuela Quiroga MD provided editing assistance.

Data Availability

Data is provided within the manuscript and supplementary tables and figures.

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No competing interests reported.

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Treatment of phase II empyema with intrapleural alteplase vs surgical debridement in children: A retrospective cohort study

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Introduction

Methods

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Acknowledgement

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