Pediatric Pulmonology

Intrapleural Alteplase Decreases Parapneumonic Effusion Volume in Children More Than Saline Irrigation Sheila J. Hanson, MS, MD,* Peter L. Havens, MS, MD, Pippa M. Simpson, PhD, Melodee L. Nugent, MA, and Robert G. Wells, MD Summary. Objective: In this prospective, double-blind, randomized crossover trial, we determined the effect of intrapleural fibrinolysis with alteplase compared to that of normal saline irrigation on the thoracostomy tube output and pleural effusion volume in children with complicated parapneumonic effusion. Methods: Twenty seven children, median age 3.5 years, referred to the interventional radiology service for thoracostomy tube drainage of a parapneumonic effusion were studied. Seventeen patients with pleural fluid thickness greater than 2 cm or >20% ipsilateral chest volume after 8 hr of thoracostomy tube drainage entered the treatment arm. They were randomized to receive alteplase 0.1 mg/kg twice a day on days 1 and 3, or on days 2 and 4, with normal saline irrigation on the alternate days. Daily pleural fluid volume measured by low dose chest computed tomography (CT) and thoracostomy tube output was compared between the saline and alteplase groups. Results: Compared to normal saline irrigation, alteplase irrigation resulted in increased thoracostomy tube drainage and to a greater decline in pleural fluid volume. Earlier alteplase administration resulted in increased fluid mobilization compared to administration later in the hospital course. There were no bleeding complications. Conclusions: Intrapleural fibrinolysis with alteplase safely increases pleural drainage and decreases the volume of pleural inflammatory debris compared to intrapleural administration of normal saline. The benefit of intrapleural alteplase on decreasing the volume of pleural inflammatory debris occurs for up to 72 hr with repeated twice daily dosing. Pediatr Pulmonol. 2015; 9999:XX–XX. ß 2015 Wiley Periodicals, Inc.

Key words: fibrinolysis; empyema; pleural effusion; pediatric. Funding source: none reported.

INTRODUCTION

Parapneumonic pleural inflammation may progress from the exudative or “simple” stage of clear, free-flowing pleural fluid to the fibro-purulent or “complicated” stage with intrapleural fibrin deposition forming fibrin strands and septations to the “organized” stage with a thick pleural peel.1,2 Simple thoracostomy tube placement may be adequate to fully drain an early exudative effusion, but at later stages either intrapleural fibrinolysis3,4 or surgical intervention5,6 may be needed to clear the complicated effusion with empyema or a pleural peel. Three randomized trials in children compared intrapleural fibrinolysis to surgical intervention and showed equivalent effectiveness of surgical intervention and either urokinase7,8 or alteplase.9 Based on cost considerations, current recommendations favor initial treatment with intrapleural fibrinolysis followed by surgical intervention for failure of initial therapy,10 although primary surgical intervention is still considered an acceptable option.11 A case series of initial alteplase once daily for three doses reported 15.7% of patients were treated with subsequent surgical intervention for failure of fibrinolysis.12 ß 2015 Wiley Periodicals, Inc.

Intrapleural fibrinolysis in adults produces greater thoracostomy tube output than normal saline irrigation.13 Animal models using direct measurement of intrapleural fluid volumes and thoracostomy tube output in experimentally produced empyemas in rabbits suggest that this

Medical College of Wisconsin, Children’s Hospital of Wisconsin, Milwaukee, Wisconsin. Preliminary data presented at American Thoracic Society annual meeting, Toronto, 2008. Conflict of interest: None.


Correspondence to: Sheila Hanson MS, MD, Children’s Hospital of Wisconsin MS 681, 9000 W. Wisconsin Ave, Milwaukee, WI 53201. E-mail: [email protected] Received 24 June 2014; Revised 16 January 2015; Accepted 21 January 2015. DOI 10.1002/ppul.23184 Published online in Wiley Online Library (wileyonlinelibrary.com).

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increased pleural fluid output may not be completely from fibrin degradation and clearing of pleural inflammatory debris, but rather from inflammation caused by the fibrinolytic agent itself.14 Computed tomography (CT) allows visualization of the entire chest cavity, and can be utilized for objective measurements of pleural volume.15 By measuring both thoracostomy tube output and the change in volume of pleural fluid/inflammatory debris in children with parapneumonic effusion treated with thoracostomy tube drainage, it should be possible to show that fibrinolysis either stimulates increased pleural fluid production (an increase in pleural fluid volume greater than the thoracostomy tube output) or mobilizes existing pleural fluid (a decrease in pleural fluid volume and increased thoracostomy tube output). We hypothesized that in children with complicated parapneumonic effusion, intrapleural irrigation with alteplase would increase thoracostomy tube drainage from the mobilization of existing pleural inflammatory debris rather than by stimulation of additional pleural fluid formation, determined by volumetric CT measurements showing a greater decrease in pleural volume following alteplase compared to normal saline irrigation. We report a prospective, double-blind, randomized, crossover trial to compare the effects of alteplase versus normal saline thoracostomy tube irrigation on pleural volume and thoracostomy tube output. The design of the study allowed evaluation of the effects of alteplase versus saline, and the timing of the intervention on the change in pleural volume. PATIENTS AND METHODS Patients

This study was a prospective, randomized, doubleblinded, crossover trial performed at Children’s Hospital of Wisconsin (CHW) and approved by the Children’s Hospital Institutional Review Board. The study was performed under an Investigation New Drug (IND) application from the Food and Drug Administration (IND#11487) for which the author PLH acted as the sponsor. All patients less than 18 years of age with a clinical diagnosis of acute pneumonia referred to the interventional radiology service at CHW for thoracostomy tube drainage of a parapneumonic effusion between October 1, 2005 and March 1, 2007 were eligible for initial approach by the study team. The study team was notified by the radiology department when an order for an interventional chest tube was placed. Patients who had bedside or intra-operative chest tube placement were not included. The decision to place a chest tube for parapneumonic effusion was under the direction of the primary team and not under the control of study personnel. Consent and assent were obtained from all patients prior to study enrolment. The primary medical Pediatric Pulmonology

team managed all treatments except for thoracostomy tube irrigations. Patients with any known contraindication to the intravascular administration of alteplase (Activase; Genentech, South San Francisco, CA) were excluded: active internal bleeding, a history of cerebrovascular accident, recent (within 2 months) intracranial or intraspinal surgery or trauma, intracranial neoplasm, arteriovenous malformation or aneurysm, known bleeding diathesis, severe uncontrolled hypertension, intracranial hemorrhage, or history of intracranial hemorrhage. Study patients had coagulation studies prior to beginning treatment and were excluded for a PTT greater than 1.5  normal or an INR > 1.5. Patients receiving concurrent therapy with warfarin, heparin, or high dose aspirin were excluded. Pregnant patients were excluded. Design Study Group Assignment

After 8–12 hr of drainage via a patent thoracostomy tube, each patient was imaged with a low dose protocol chest CT. For entry criteria to the treatment arm, the pleural fluid thickness was measured by upright chest radiograph and ultrasound and pleural fluid volume by low-dose chest CT. If any of the imaging met study criteria of pleural fluid occupying >20% of the ipsilateral chest cavity volume or the pleura was >2 cm in thickness then the patient was randomized into one of the treatment arms. Monitoring group. If the pleural fluid occupied < 20% of the ipsilateral chest cavity volume or the pleura was 20% of the ipsilateral chest cavity volume or was >2 cm in thickness, the patients were randomized to receive alteplase thoracostomy tube irrigation twice daily on days 1 and 3 or days 2 and 4, with normal saline irrigation alone on the alternating days. Randomization and Blinding

Upon entry into the treatment arm, patients were randomized to receive either alteplase or normal saline thoracostomy tube irrigation on intervention day 1. Study group treatment was alternated on days 1 through 4 of the study, so that both groups received 2 days of alteplase and 2 days of normal saline irrigation. The study period ended after 4 days of fibrinolysis and saline irrigation, with all further interventions managed by the primary team. Patients had their chest tube removed and exited the study

Intrapleural Alteplase for Pediatric Empyema

early if they had low thoracostomy tube output (20% and pleural thickness >2 cm; 13 qualified based on pleural volume >20% alone, and one patient based on pleural thickness alone. Clinical characteristics of patients in the treatment and monitoring arms are summarized in Table 1. Patients in treatment groups 1 and 2 showed no statistically significant differences in disease severity as reflected in the variables presented in Table 1. Pathogens were identified in 10 of 28 (36%) children in the study, either by direct culture of blood (N ¼ 4/27),

Intrapleural Alteplase for Pediatric Empyema TABLE 1— Patient Demographics

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1

Treatment group 1

Treatment group 2

Monitor group

N eval Median (range) or N (%) N eval Median (range) or N (%) N Eval Median (range) or N (%) Age, years Sex, male Weight, kg Duration of symptoms prior to thoracotomy, days Antibiotic prior to chest tube, days Duration of fever after admission, days Antibiotic duration, days Length of hospital stay, days Chest tube duration, days Positive blood culture Positive pleural fluid culture Positive pleural fluid latex agglutination panel Pleural fluid pH Glucose, mg/dl LDH, IU/L WBC, k/ml Loculations on initial CT, N (%)

9 9 9 9

3.4 (0.7–5.8) 4 (45) 15.3 (8.6–23.0) 7 (4–12)

8 8 8 8

3.5 (0.7–5.5) 4 (50) 14.8 (8.0–16.7) 11 (6–21)

11 11 11 11

5.8 (1.1–10.1) 7 (64) 21.8 (10.1–33.6) 7 (2–17)

9 9 8 9 9 8 8 5

1 (0–8) 2 (0–3) 14 (5–21) 8 (7–19) 6 (4–16) 2 (25) 1 (13) 2 (40)

8 8 8 8 8 8 8 3

3 (1–7) 1 (0–2) 16 (8–22) 9 (7–13) 6 (4–9) 1 (13) 0 (0) 1 (33)

11 11 11 11 11 11 11 4

1 (0–7) 2 (0–4) 18 (10–28) 13 (6–20) 8 (1–16) 1 (9) 2 (18) 3 (75)

4 7 7 7 9

7 (7–8) 32 (20–82) 27489 (3777–148871) 4500 (1500-80000) 2 (22)

6 4 4 6 8

7.6 (7–8) 54 (20–101) 7571 (741–24245) 6278 (450–25000) 2 (25)

7 9 7 10 11

8 (7–9) 20 (20–88) 39945 (820–90237) 20500 (2350–247500) 1 (9)

1 There were no statistically significant differences among the three groups for all of these variables and no differences between Treatment 1 and Treatment 2.

pleural fluid (N ¼ 3/27), or latex agglutination testing of pleural fluid (N ¼ 6/12). Forty-six percent had >48 hr of antibiotic therapy prior to thoracostomy drainage. In the treatment arms, streptococcus pneumoniae was identified in four patients and Group A streptococcus in one patient. In the monitoring arm, 4 patients also had streptococcus pneumoniae identified and Group A streptococcus identified in one patient. Treatment Arm

On treatment days 1 through 3, thoracostomy tube output was higher in the alteplase treated subjects compared to those treated with saline. This was statistically significant on treatment days 1 and 3 (Table 2 and Fig. 3). Pleural fluid declined most on each day with alteplase irrigation compared to the days with saline. This was statistically significant on study days 1 and 3 (Table 3).

Alteplase administration occurring on day 1 versus day 2 resulted in increased thoracostomy tube drainage volume (P < 0.0001) (Table 2). There were no bleeding complications and no pneumothoraces associated with alteplase administration. One patient was referred for surgical intervention on study day 2, and had thoracostomy tube duration of 7 days, and hospital length of stay of 8 days. After unblinding at study conclusion, it was found that this patient did not receive alteplase prior to the thoracotomy. One patient developed pneumatoceles. Monitoring Arm

Patients in the monitoring arm showed a trend toward shorter duration of symptoms prior to thoracostomy tube insertion, compared to those who entered the treatment groups (Table 1). Patients in the monitoring arm who did

TABLE 2— Thoracostomy Tube Output Between Treatment Groups by Study Day

Treatment group 1 (alteplase days 1 and 3) Drain output, ml; median (range) N Treatment group 2 (alteplase days 2 and 4) Drain output, ml; median (range) N P-value between groups for that day

Day 1

Day 2

Day 3

Day 4

360 (71, 704) 9

142(4, 634) 9

216(68, 710) 9

56(34, 324) 9

33 (24, 44) 8 0.001

216 (27,438) 6 0.139

46 (10, 135) 6 0.002

20(0, 138) 6 0.815

Bold indicates patients received alteplase on that day.

Pediatric Pulmonology

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Fig. 3. Thoracostomy tube output by treatment group by time.

not receive alteplase showed an increase in pleural volume on 2 of the first 3 study days (Table 4). Five patients in this arm (45%) received intrapleural fibrinolysis directed by the primary team outside of the randomized study protocol. Alteplase administration occurred at variable times throughout the hospital course (day 1–4); dosing frequency ranged from daily to once every 2 days. Increased thoracostomy tube output and greater decline in pleural fluid volume were seen in those who received alteplase compared to saline. This effect was statistically significant only on study day 2. One patient in this group, who did not receive fibrinolysis, developed a bronchopleural fistula. DISCUSSION

In this prospective, double-blinded, randomized crossover trial, intrapleural fibrinolysis with alteplase resulted in improved mobilization of complicated parapneumonic effusions in children compared to saline irrigation. The increase in thoracostomy tube output on days of alteplase

irrigation was not associated with a corresponding increase in pleural fluid volume as might be expected if the increased drainage was secondary to an inflammatory effect of the alteplase as previously postulated14; rather the increased thoracostomy drainage was associated with a decrease in pleural fluid volume as objectively measured by volumetric chest CT reflecting improved evacuation of the pleural effusion. Earlier intrapleural fibrinolysis may be more efficacious, as alteplase initiation on day 1 resulted in increased thoracostomy drainage and decreased pleural volume compared to alteplase initiation on day 2. However, administration of alteplase on any day results in greater thoracostomy drainage and decreased pleural fluid volume compared to saline, an effect that was seen both in the randomized treatment arm of the study and in the observational (monitoring) arm. Patients were assigned to the monitoring group if the initial pleural fluid volume was