Use of Intrapleural Alteplase in the Treatment of Parapneumonic Effusion in Children: A Report of a 10-year Experience

Introduction

Pneumonia is associated with significant morbidity and mortality worldwide, particularly among children younger than 5 years of age.¹ While patients typically recover with the use of antimicrobials and supportive care, some patients develop complications.² While the incidence of parapneumonic effusion (PPE) and empyema in children in the United States has decreased after the introduction of the pneumococcal vaccines,³ the overall incidence appears to be increasing globally over the past decade.^4–8 Approximately 40% to 50% of children admitted with pneumonia develop a PPE, and many of them require additional therapy, including surgical intervention.^9,10

Current practice guidelines recommend 2 strategies for the initial management of complicated PPE as follows: chest tube drainage with intrapleural fibrinolytic therapy and video-assisted thoracoscopic surgery (VATS).^11–13 Two systematic reviews of randomized trials demonstrated similar rates of treatment failure and mortality between the 2 strategies.^14,15 However, there were inconsistent findings regarding the differences in hospital length of stay (LOS) and cost.^14–17 An economic analysis found that chest tube drainage with fibrinolytic therapy was the more cost-effective strategy for children with PPE, based on limited outdated data.¹⁶ Furthermore, a recent report that included nearly 3500 children with PPE showed that patients treated with primary VATS had a shorter hospital and pediatric intensive care unit (PICU) LOS and reduced use of health care resources, including radiographic studies and mechanical ventilation, which could reduce overall hospitalization costs.¹⁷

Older fibrinolytic agents, such as streptokinase and urokinase, were initially evaluated for the treatment of patients with PPE yielding positive outcomes.¹⁸ However, their use has been replaced by alteplase (tissue plasminogen activator) for safety reasons. Alteplase has been used frequently with variable dosing strategies for children with PPE.¹² The 2011 Pediatric Infectious Diseases Society and the Infectious Diseases Society of America pediatric pneumonia guidelines recommend 2 dosing regimens based on the results of 2 prospective studies: a fixed dose (4 mg) daily for 3 days and a weight-based dose (0.1 mg/kg, maximum 3 mg) every 8 hours for 3 days.^11,19,20 However, observational studies have reported various dosing strategies, ranging from 0.5 to 10 mg, given as a fixed,^21–24 weight-based,^25–27 or ultrasound-grade-based^28,29 regimen, with positive overall outcomes.

Given the variability in alteplase dosing among children with PPE in the available literature, more evidence is needed to help define an optimal dosing regimen. This study reports outcomes associated with a 10-year experience of children treated with intrapleural alteplase for PPE, aiming to evaluate the clinical outcomes of lower alteplase doses (≤2 mg) compared with higher doses (>2 mg).

Materials and Methods

Results

Seventy-six patients were screened; 72 were included in the final analysis. Four patients were excluded because they received alteplase for effusions associated with intra-abdominal infections through a peritoneal tube or abdominal drainage device.

Baseline Characteristics.

Table 1 summarizes the baseline characteristics of the included patients. The median age was 5 years (IQR, 1–8 years), with a similar proportion of males and females (50% each). All the included patients had variable degrees of PPE secondary to various etiologies, with pneumonia being the most common etiology (75%); 2 patients with pericardial effusion had an associated PPE. Alteplase was administered as intrapleural for all included patients. There were considerable differences between the 2 dose groups. The lower dose group was younger (2.2 [IQR, 0.7–6] years vs 8 [IQR, 5–14] years), had fewer obese patients (18% vs 37%), and had lower supplemental oxygen requirements (40% vs 63%).

Table 1.Baseline Characteristics

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Approximately 50% of patients had a positive culture result at some time during their hospitalization. The most common isolate was methicillin-resistant Staphylococcus aureus (n = 10). The median duration of antibiotic therapy was 22 days (IQR, 18–26 days). Table 2 summarizes infectious disease characteristics.

Table 2.Infectious Diseases Characteristics

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Intrapleural Alteplase Therapy.

Overall, the median alteplase dose was 2 mg (IQR, 2–4 mg); most patients (n = 19; 26%) received three doses. Most patients received no more than 1 dose per day (n = 51; 71%). A concentration of 1 mg/10 mL was used in most patients (n = 68; 94%). The lower-dose group received a median dose of 2 mg (IQR, 2–2 mg), whereas the higher-dose group received a median dose of 4 mg (IQR, 4–4 mg). The majority received alteplase as initial therapy (69%), defined as treatment given within the first 2 days after chest tube insertion. Seventeen patients received alteplase with primary VATS, and 2 received intrapleural dornase alfa therapy. The treatment-failure group (n = 10) received a higher median alteplase dose (4 vs 2 mg) compared with the treatment-success group (n = 62). The characteristics of alteplase therapy are outlined in Table 3. Alteplase dose per age and dose per weight per age of alteplase are illustrated in Figure 1.

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Table 3.Alteplase Treatment Characteristics

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Treatment Outcomes.

Treatment failure occurred in 10 (14%) patients; 7 required VATS and 3 had recurrent PPE. There was no significant difference in treatment failure rate between patients who received an alteplase dose of 2 mg or less compared with those who received a higher dose of more than 2 mg (9% vs 22%; p = 0.161). The median time to rescue VATS was 4 days (IQR, 4–8 days) after chest tube insertion and 3 days (IQR, 3–7 days) after alteplase initiation. The median chest tube output following alteplase instillation was 279 mL/24h (IQR, 120–432 mL/24h). The median duration of chest tube placement was 5 days (IQR, 4–9 days) (Table 4). A higher chest tube output (346 vs 175 mL/24h; p = 0.002) and a longer duration of chest tube placement (8 vs 5 days; p = 0.004) were observed in the higher dose group. However, after adjusting for weight, both groups showed a similar chest tube output (12 mL/kg/24h). There were no significant differences in hospital LOS, PICU LOS, or mortality rate.

Table 4.Treatment Outcomes According to Alteplase Dose

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Four patients died during the 6-month interval from the first alteplase dose. The causes of death were reported as cardiac arrest secondary to COVID-19 respiratory failure, cor pulmonale, right atrial perforation, and septic shock.

Figure 2 illustrates the differences between the median chest tube output 24 hours before and after the first alteplase dose. There was a higher rate of increment after the first alteplase dose in the lower dose group compared with the higher dose group (378% vs 118%). After adjusting for weight, both groups showed a comparable increment rate (333% vs 329%). Supplemental Table S1 shows treatment outcomes between treatment success and failure groups. Supplemental Table S2 shows laboratory values before and after alteplase therapy.

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Post-hoc Analyses.

In patients receiving alteplase with primary VATS, a chest tube was inserted immediately following the VATS, and alteplase was initiated in a median of 2 days (IQR, 1–2 days) after the VATS. Patients who received this combined therapy (n = 17) had a lower treatment failure rate (6% vs 17%; p = 0.434) compared with those who received alteplase alone (n = 54); however, this difference was not statistically significant (Table 5). Patients who received alteplase alone had a higher chest tube output (322 vs 166 mL/24h; p = 0.005). This was consistent after adjusting for weight (14 vs 10 mL/kg/24h; p = 0.046). Additionally, combination therapy was associated with a shorter duration of chest tube placement (4 vs 6 days; p = 0.001), hospital LOS (7 vs 13 days; p = 0.001), and PICU LOS (2 vs 11 days; p = 0.01).

Table 5.Treatment Outcomes According to Initial Therapy

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In patients with pneumonia (n = 54), there were similar outcomes compared with the total study population (n = 72): treatment failure rate (13% vs 14%); median chest tube output (12 mL/kg/24h both groups); median duration of chest tube placement (5 days both groups); median hospital LOS (9 vs 10 days); and median PICU LOS (6 vs 7 days). Similarly, a higher dose was not associated with better outcomes (Supplemental Table S3).

Eight children younger than 3 months of age (median age, 23 days; range, 10–83 days) were included in a separate analysis (Supplemental Table S4). The indication for chest tube placement in these patients was PPE associated with pneumonia (n = 3), chylothorax (n = 3), pericardial effusion (n = 1), and intra-abdominal surgery (n = 1). All patients were treated with the lower dose strategy and achieved a 100% treatment success rate. The median duration of chest tube placement was 6 days (IQR, 4–11 days); the median hospital LOS was 57 days (IQR, 36–85 days); and the median PICU LOS was 57 days (IQR, 34–85 days).

Discussion

In this retrospective analysis, we report a 10-year experience with intrapleural alteplase for the management of PPE in children (N = 72). There was an overall treatment failure rate of 14%, which is comparable to results from previous studies that have reported various rates, including <10%,^17,23,28,29 10–16.6%,^{16,19,26,32,33} and >20%.²² These studies used various fibrinolytic agents with different dosing strategies, and treatment failure was defined differently across studies. The median hospital LOS after chest tube placement was 10 days, slightly higher than LOS reported in both prospective (median, 6–6.9 days;^19,33 mean, 7.7–9 days^34,35) and retrospective (median, 6.2–9 days^21,32,36) studies.

There are 3 key findings from our study. First, lower intrapleural alteplase doses (≤2 mg) were associated with comparable clinical outcomes compared with higher alteplase doses (>2 mg). Our findings may have been influenced by disease severity, which we were unable to assess, and the number of patients who received primary VATS, which was higher in the ≤2 mg group (26.6% vs 18.5%). However, other studies using similar lower doses (1–2 mg) have reported positive overall outcomes.^21,28,29 In a retrospective study of 32 children (mean age, 6.8 years) treated for PPE with intrapleural alteplase, 81% received 1 mg doses, and 19% received 2 mg doses. Treatment success was achieved in 97% of patients.²⁸

Our analysis showed that younger children (≤6 years) received a higher weight-based dose (≥0.1 mg/kg) compared with older children (>6 years) (Figure 2B). However, this difference is less likely to affect the outcomes because patients with treatment failure of all ages received a comparable median weight-based dose compared with the treatment-success group (n = 10; 0.14 mg/kg vs n = 62; 0.12 mg/kg).

In this study, most patients (64%) received only 1 to 3 alteplase doses, a finding consistent across both the treatment success (63%) and failure (70%) groups. While 2011 guidelines recommend 3 and 9 doses for the 4 mg fixed and the weight-based dosing regimens, respectively,¹¹ fewer doses might be sufficient for most patients. Thus, the decision to give repeated alteplase doses should be individualized based on patient response rather than an arbitrary number of doses. Our findings are consistent with those of Baram and colleagues,²³ who reported a 10-year prospective study evaluating outcomes associated with intrapleural alteplase (0.1 mg/kg) in children with PPE; the mean number of alteplase doses administered was 2.1 doses (range, 1–3 doses). In the 95 patients assessed, the treatment success rate was approximately 98%.²³

Although administration of fewer total alteplase doses appears to be effective, the optimal frequency of alteplase instillation remains unclear. Published studies have reported frequencies of daily,¹⁹ twice daily,²⁹ three times daily,²⁰ and four times daily.²⁶ A randomized trial demonstrated higher than expected chest tube output the day following twice-daily dosing, suggesting potential benefit compared with once-daily dosing.²⁷ Another study that evaluated twice-daily dosing showed a significant reduction in the mean days of alteplase therapy from 4.1 to 2.8 days while eliminating the need for surgical intervention, leading to an insignificant reduction in the mean LOS.²⁹ In our analysis, we did not evaluate the frequency of alteplase instillation due to the lack of a standardized protocol, but most patients received once-daily dosing.

A second important finding is that alteplase therapy following primary VATS as combination therapy for children with PPE might be associated with better outcomes compared with alteplase therapy alone. While previous studies showed similar outcomes between VATS and fibrinolytic therapy when used alone,^14–17 little evidence is available for the combination. Gates and colleagues²¹ reported that surgery (with or without fibrinolytic therapy) in children with PPE was associated with a significant increase in hospital and PICU LOS. In contrast, we found that the combination of primary VATS and alteplase was associated with a clinically and statistically significant reduction in the duration of chest tube placement, as well as hospital and PICU LOS, which could result in a reduction in overall cost. Variation between the 2 studies could be related to the fact that we only included primary VATS with alteplase, whereas Gates et al²¹ included patients who received VATS at all stages of therapy with or without fibrinolytic therapy. Furthermore, owing to the lack of a control group of patients treated with VATS alone, it is possible that the positive impact was primarily driven by the VATS procedure. However, previous studies suggest that primary VATS and fibrinolytic therapy alone are associated with similar outcomes.^14–17

A total of 24 patients underwent VATS at various intervals in our analysis: 17 underwent primary VATS, and 7 underwent rescue VATS after initial alteplase (treatment failure). The timing of therapies and how they differ between the 2 groups might raise a concern. The difference in days between VATS and alteplase initiation was 2 days (IQR, 1–2 days) for the combination group (primary VATS) and 3 days (IQR, 3–7 days) for the treatment failure group (rescue VATS). While this could affect the validity of treatment failure as an outcome, secondary outcomes were better in the combination therapy (Table 5) compared with the treatment failure group (Supplementary Table S1). One possible explanation is that VATS early in the disease course might be associated with better outcomes than VATS performed as rescue therapy. A recent retrospective study conducted by Di Mitri et al³⁷ found that early VATS performed within 5 days from admission was associated with a shorter duration of PICU and hospital LOS compared with VATS performed later in the hospital admission. The PICU and hospital LOS were numerically lower in our patients who received combination therapy compared with the early VATS therapy reported by Di Mitri et al³⁷ (2 vs 7 days for PICU LOS; 7 vs 22 days for hospital LOS). Additional studies are needed to confirm whether the improved outcomes in our study were related to the timing of VATS or the use of combination therapy.

A third key finding is that intrapleural alteplase appears to be effective among children younger than 3 months of age with various thoracic effusions. A recent review suggested that the youngest patient reported in the literature to receive intrapleural alteplase was 3 months.³⁸ Our study included 8 children younger than 3 months of age (median age, 23 days; range, 10–83 days) who were treated with alteplase doses ranging from 0.5 to 2 mg, achieving a 100% treatment success rate. The median duration of chest tube placement was similar to that of the total population (6 vs 5 days), but the hospital and PICU LOS were higher in this group, likely due to their underlying conditions.

Chest tube output is one of the parameters used to evaluate the effectiveness of alteplase therapy in children with PPE.^12,13 Despite the lack of evidence to guide therapy based on drainage volume in children and its uncertainty as a surrogate marker for treatment success,¹² it has generally been used as the sole primary outcome.^26,27 In our analysis, chest tube output did not correlate with clinical outcomes. Similarly, in a retrospective study evaluating alteplase compared with urokinase in children with PPE, the significantly higher chest tube output seen after alteplase instillation did not translate to superior clinical outcomes compared with the urokinase group.³⁶ In another prospective study, a significantly shorter hospital LOS was achieved in the fibrinolysis group despite a lower total drainage volume compared with patients who did not receive fibrinolytic therapy.³⁵

Limitations of Study

This study has several limitations. First, given the retrospective design, we were unable to assess several crucial factors, including disease severity, all adverse events, and the need for additional procedures (e.g., thoracentesis, additional chest tube insertions). Second, our study included a relatively small sample size, which led to considerable baseline differences between the dosing groups that may have affected the findings. Third, our analysis included patients with thoracic effusions caused by various etiologies, whereas most previous studies included only pneumonia-related etiologies. However, most patients had pneumonia as their primary etiology for PPE, and post-hoc analysis showed similar outcomes when the analysis was restricted to patients with pneumonia. This is one of the few studies describing the use of intrapleural alteplase in children with PPE secondary to the other noninfectious etiologies. Finally, owing to the lack of a standardized protocol, the optimal timing of alteplase instillation following primary VATS (n = 17) cannot be determined; however, most patients received alteplase on postoperative day 1 or 2. Similarly, because treatment failure was defined differently among providers, defining a specific time to treatment failure was challenging (rescue VATS; n = 7). Different practice guidelines recommend different timing for surgical evaluation (2–3 vs 7 days after initial therapy). Therefore, in all our patients who were initially treated with chest tube placement and alteplase, the need for VATS at any time was considered a treatment failure.

There are several opportunities for future research to improve outcomes in children with PPE. Additional prospective studies are needed to determine the optimal alteplase dosing strategy and to evaluate the cost-effectiveness of various treatment approaches. Although, randomized trials may not be feasible for various reasons, the design and implementation of institutional protocols and pathways can significantly contribute to the literature.²⁹ Although predictors of treatment failure have been evaluated previously in children with PPE,^22,35 additional studies are needed to identify populations at risk that could potentially benefit from primary VATS with alteplase to improve clinical and economic outcomes. While several studies have reported the effectiveness of alteplase therapy at various doses, future research should focus on safety parameters. Even with the use of relatively low alteplase doses, bleeding has been reported.³⁹ Additionally, weight-based dosing should be further investigated in various age groups. Only 2 weight-based alteplase doses have been evaluated in children with PPE. The current standard dose of 0.1 mg/kg has been evaluated in several studies;^20,25,27 however, studies use different maximum alteplase doses. A larger alteplase dose of 0.4 mg/kg extrapolated from adult data was evaluated in 1 study.²⁶ Of note, none of the aforementioned studies evaluated weight-based dosing across different age groups. Prolonged dwell time after alteplase instillation has been reported to reduce the required dose in adults,^40,41 but this has not been evaluated in children. Last, in clinical practice, many providers use fibrinolytic therapy only when there is inadequate chest tube output. In our study, only 31% of patients received alteplase as a rescue therapy. Currently, it is unclear whether the timing of alteplase administration affects outcomes, as previous studies have shown conflicting results.^21,27,42

Conclusions

Lower alteplase doses (≤2 mg) resulted in successful treatment of PPE in most patients, including patients younger than 3 months. Higher alteplase doses were not associated with better clinical outcomes. While intrapleural fibrinolytic therapy alone appears to be effective in resolving PPE, alteplase combined with primary VATS may be associated with better clinical and economic outcomes in some patients. Larger studies are required to confirm these results and estimate the cost-effectiveness of various treatment strategies.