Intrapleural Fibrinolytics in the Management of Empyema

Abstract

Children with empyema are managed differently depending on local practice. There are 2 main approaches: a primary surgical debridement using either a video-assisted thoracoscopic surgical (VATS) approach or an open procedure and primary medical treatment using a chest drain plus intrapleural fibrinolytic drugs. This difference in approach has engendered sufficient passion to produce 2 head-to-head randomized controlled trials (VATS versus fibrinolytics), and neither trial could demonstrate a difference in length of stay or other outcome measure. Other evidence shows that fibrinolytics are successful in between 85% and 95% of cases and that a primary medical management strategy is less costly than surgery.

Introduction

The pleural circulation is a dynamic process. In health, the parietal pleura filters 0.02–0.1 mL/kg/h of pleural fluid; this is then reabsorbed through parietal pleural lymphatics at the lung base and cardiac surfaces. At any time the pleural space contains ∼0.3 mL/kg fluid. These pleural lymphatics have a substantial reserve capacity, so accumulation of pleural fluid only occurs when there is a severe mismatch between fluid production and resorption.

Infection affecting the adjacent lung results in increased permeability of local capillaries, and locally released inflammatory mediators diffuse into the pleural fluid, in turn, activating pleural mesothelial cells. This sets off an inflammatory cascade with activated pleural mesothelial cells, releasing a number of cytokines, including interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor alpha, and platelet-activating factor. As bacteria enter the pleural space, there is activation of the coagulation cascade leading to a procoagulant activity and decreased fibrinolysis, encouraging deposition of fibrin in the pleural space.¹ Thus, infection in the pleural space results in hugely increased fluid production and fibrinous blockage of parietal lymphatic pores (Fig. 1). How should this problem best be managed?

FIG. 1.

Schemata of cascade in the pleural space leading to empyema.

The aim of empyema management is to treat the infection and thus shut down the inflammatory drivers, restoring the normal pleural circulation, and ultimately restoring the normal lung function. This is achieved with antibiotic therapy, directed to the likely causal organism, either alone or in combination with drainage of the pleural space. Drainage can be achieved by using a simple chest drain, a drain plus fibrinolytic, or by surgical drainage commonly performed as video-assisted thoracoscopic surgical (VATS). This article will present the arguments and evidence supporting chest drain plus intrapleural fibrinolytic for the management of empyema.

Evidence Supporting Fibrinolysis

Intrapleural fibrinolytics have been used in empyema since the 1950s. Initially, naturally derived streptokinase (bacterial derived) was used. This was followed by urokinase (human) and a more recently manufactured tissue plasminogen activator (alteplase). In theory, fibrinolytics disrupt fibrin production, leading to more effective drainage of the pleural space. This occurs both through the pleural drain and by re-establishing effective lymphatic drainage. In rabbit models with tetracycline-induced pleural injury, both proenzyme single-chain urokinase and tissue plasminogen activator reversed loculations at 96 h after injury.² In children, fibrinolytics can be instilled and drainage can be achieved through soft small-bore (6–12 FG) chest drains. There have been no formal studies comparing small- and large-bore drains in children.

There have been 2 randomized controlled trials in children comparing intrapleural fibrinolytics to placebo. Thomson et al.³ compared intrapleural urokinase to intrapleural placebo (normal saline). Fifty-eight patients with empyema aged 6 months to 18 years (median age, 3.3 years) underwent drainage if they had a persistent fever (>38°C) 24 h into treatment with parenteral antibiotics, or if they had a collection causing respiratory distress. Patients were randomized to receive either urokinase, 40,000 units in 40 mL twice daily, or placebo. The primary outcome measure was the length of hospital stay post-intervention. Study results showed a statistically significant shorter length of stay in the treatment group (7.4 days versus 9.5 days; P=0.027). Ninety-three percent (27/29) of children who received urokinase did not need surgery.

Singh et al.⁴ compared intrapleural streptokinase (15,000 units/kg/day) to intrapleural placebo (normal saline) in a prospective randomized controlled trial. They included 40 children, aged 1 month to 12 years, with loculated effusions (Light's classification; 5 and above) Stage 5 being a multiloculated effusion, culture or Gram stain positive; stage 6, an empyema with frank pus and a single locule; and stage 7, a complex empyema with multiple locules. The first dose of placebo or streptokinase was given 24 h after drain insertion with 2 further daily doses. There was no significant difference in outcome measures (duration of persistence of symptoms, fever, and respiratory distress; volume and duration of pleural fluid drainage). However, of those with multiple loculations at onset (Light's stage 7), 0/9 in the streptokinase group and 5/7 in the placebo group had residual pleural thickening on ultrasonography examination performed 30 days after diagnosis and required surgery. The length of hospital stay was not used as an outcome measure.

Between 2001 and 2011, there were 28 reported studies^3–30 of fibrinolysis in children, including the randomized controlled trials mentioned above. In total, 979 children were treated with an overall success rate (discharge without surgery) of 85.3%.

What Does Surgery Do?

Managing empyema with surgery dates back to Hippocrates (∼500 B.C). Modern-day practice usually entails a debridement procedure to remove pus and fluid from the pleural space. This is most commonly by VATS or with a limited open procedure (mini-thoracotomy). Is the VATS procedure a real advance from the Hippocrates' time? After surgery, the patient will still have a chest drain in situ to drain any further fluid that is likely to accumulate in the pleural space. Some surgeons will also use fibrinolytics postoperatively. Surgery does not contribute to re-establishing the pleural circulation, nor does it spare the need for a chest drain. It is, however, more invasive and always requires a general anesthetic.

Evidence for VATS Versus Fibrinolytics

There have been 2 well-conducted randomized controlled trials in children comparing chest drain plus intrapleural fibrinolytics to thoracoscopic surgery. Sonnappa et al.⁵ compared chest drain plus intrapleural urokinase to primary VATS procedure. Sixty children aged 0–16 years with empyema on chest radiograph and ultrasonography were randomized into either a urokinase group or a VATS group. The urokinase group received 12 hourly doses of intrapleural urokinase for 3 days. Failure of treatment was defined as persistent fever after 4 days with persistent fluid on ultrasonography. These patients went on to have secondary VATS. The VATS group underwent primary VATS (or mini-thoracotomy if VATS inappropriate) and had 1 or 2 chest drains left in situ post-operatively. In both groups, drains were removed when drainage fell to 40–60 mL/24 h. There was no difference in length of hospital stay in either group (6 days in each), and failure rates were similar (5/30 in the urokinase group and 4/30 in the VATS group).

St. Peter et al.⁶ compared VATS to fibrinolysis. They randomized 36 children, aged up to 18 years, with empyema to VATS or fibrinolysis (alteplase). The VATS group had a drain left in post-procedure. The fibrinolysis group had their first dose of alteplase given at chest-drain insertion and a further 2 doses given 24 hourly. Drains in both groups were removed if <1 mL/kg/day fluid was drained. Results were remarkably similar to the Sonnappa trial. There was no difference in length of stay or in any other outcome measures between the groups. Two patients required ventilator support in the VATS group post-procedure.

In addition to these randomized controlled trials, there have been a number of retrospective reviews. For example, Gates et al.¹¹ retrospectively compared outcomes of 53 patients treated in 4 different ways (chest drain alone; chest drain plus fibrinolytic; chest drain plus fibrinolytic and surgery; and surgery alone). They found that the length of hospital stay and critical care stay to be shorter and hospital charges to be lower in the nonsurgical groups than in the surgical groups.

Morbidity Associated with Surgery

There is no convincing evidence that the method of primary management of empyema has an effect on critical-care admission rates. St. Peter et al.⁶ had 2 patients from the VATS group admitted to intensive care for ventilator support post-procedure. One in each group was admitted to critical care in the study of Kurt et al.³¹ Gates et al.¹¹ showed a longer length of stay in intensive care in patients undergoing surgery than in the nonsurgical group. The size and type of the chest drain left in post-procedure and the adequacy of pain relief are important determinants of post-operative morbidity. There can also be blood loss at debridement that is sufficient to need blood replacement.

Morbidity Associated with Fibrinolytics

When using fibrinolytics versus chest drain alone, there does not seem to be any difference in admissions to critical care. Thomson et al.³ had 3 patients admitted from each group. Wells and Havens²⁰ retrospectively investigated the safety and efficacy of urokinase and alteplase in children with parapneumonic effusions or empyema. There were no major complications in patients treated with either agent. Fibrinolytic instillation can cause discomfort, so intrapleural local anesthetic such as Marcaine can be given to combat this. Streptokinase is known to cause more bleeding and chest wall pain than other fibrinolytics. It can also cause a febrile reaction and rarely can result in an anaphylactoid reaction on repeated exposure.¹⁴ Streptokinase is no longer routinely used in the United Kingdom or the United States for the treatment of empyema in children.

Failure Rates

It is important to consider the failure rates of both of these management options. Six percent of patients receiving urokinase required surgical pleural decortication in the study of Thomson et al.³ Sonnappa et al.⁵ had similar failure rates in both groups; 4 patients in the VATS group had to convert to mini-thoracotomy, and 1 had VATS twice. Five patients in the urokinase group went on to have surgery. Sixteen percent of patients in the fibrinolysis group in the study of St. Peter et al.⁶ had to undergo secondary VATS. Single-center data⁸ with consistent management showed fibrinolytic failure rates, that is, requiring surgery due to the persistence of symptoms and an inadequate response to medical management, of well under 5%.

Long-Term Outcomes

At 3-month follow-up, 92% of patients who received urokinase had a chest radiograph, which was normal or showed minimal pleural thickening.³ Singh et al.⁴ did not have any abnormal chest X-rays at follow-up in those treated with Streptokinase. At 6-month follow-up, Sonnappa et al.⁵ had similar results in both groups, with 21/30 in the VATS group and 18/30 in the urokinase group having abnormal chest radiographs. They did not state what they classified as abnormal, and it is likely that they included minimal pleural thickening as abnormal. There is no comparative long-term lung function data reported.

Costs

Where 2 treatments are equally efficacious, costs are of great importance in considering management options. Four studies have specifically considered the costs of treatment.

Sonnappa et al.⁵ found the cost in the VATS group to be significantly higher, by 25% (P<0.001). St. Peter et al.⁶ also found there to be a significantly higher procedure charge in the VATS group than in the fibrinolytic group. Cohen et al.³² compared the projected costs and clinical outcomes associated with 5 competing strategies for the management of pediatric empyema. These were antibiotics±chest drain, chest drain without intrapleural fibrinolytics, repeated thoracocentesis, and chest drain with fibrinolytics and VATS. They found chest drain with fibrinolytics to be least costly ($7,787) and VATS to be most expensive ($2,235 more than chest drain plus fibrinolytic). In their retrospective study, Gates et al.¹¹ again had lower costs in the nonsurgical groups, but total costs were much higher in all groups (Table 1).

Table 1.

Summary of Main Trials

Author	Management	Number in group	Length of stay (days)	Complications	Follow-up status	Costs (U.S. $)
Thomson et al.³	Urokinase	29	7.4	2 Required surgery 3 PICU 3 Blood transfusion	28 Normal CXR	—
	Placebo	29	9.4	3 Required surgery3 PICU2 Blood transfusion	28 Normal CXR	—
Singh et al.⁴	Streptokinase	19	—	—	0 Surgical drainage at 30 days	—
	Placebo	21	—	—	5 Surgical drainage at 30 days	—
Sonnappa et al.⁵	VATS	30	6	4 Failures	21 Abnormal CXR	Mean=$11,379Median=$10,146
	Urokinase	30	6	5 Failures	18 Abnormal CXR	Mean=$9,127Median=$6,914
St. Peter et al.⁶	VATS	18	6.9	2 Ventilatory support1 Temporary dialysis	—	$11,700
	Alteplase	18	6.8	3 Failures requiring VATS	—	$7,600
Gates et al.¹¹	TPA	24	8.4	ICU stay 0.1 days	—	$23,473
	Surgery	6	12.4	ICU stay 3.5 days	—	$42,650
Cohen et al.³²	Fibrinolytic	—	6.7	Failure probability 0.09	—	$7,787
	VATS	—	6.0	Failure probability 0.1	—	$10,632

VATS, video-assisted thoracoscopic surgical; CXR, chest X-ray; PICU, Paediatric Intensive Care Unit; ICU, Intensive Care Unit; TPA, tissue plasminogen activator.

Conclusions

It is clear that there is a choice in how to manage a child with an empyema. Insertion of a small soft-chest drain under either procedural sedation or general anesthetic, followed by instillation of fibrinolytics through the chest drain, is a safe and effective treatment in up to 95% of cases (Table 2). This management strategy results in a short duration of hospital stay and a normal long-term outcome. The alternative surgical approach is also effective, but is more invasive, always involves general anesthesia, and has significantly higher costs for no reduction in hospital stay or improvement in either short- or long-term morbidity. It is likely that with further understanding of the inflammatory processes involved in the pleural space that the next generation of fibrinolytic drugs will be able to clear the pleural space and re-establish the pleural circulation more rapidly and effectively.

Table 2.

Management of Empyema (Oxford Protocol)

1. Antibiotic choice should reflect local practice and the hospital policy.

2. Consider drainage in a child with pneumonia and a pleural collection who remains unwell after 48 h of antibiotic treatment, or who has a massive collection at presentation.

3. Insertion of drain should be ultrasound directed or under ultrasound control.

4. Use procedural sedation (eg, midazolam and fentanyl).

5. Instil lignocaine to skin, subcutaneous tissues, and down to pleural space with aspiration of pleural fluid to confirm location of empyema.

6. Insert small soft drain (eg, pigtail catheter size 6–12 FG) using seldinger technique.

7. Attach to drain bottle and suction (−20 cm H₂O).

8. Instil 40,000 units urokinase (1,000 units per mL) in 40 mL normal saline through drain (12 hourly). In children under 10 kg, this volume can be reduced to 20,000 units in 20 mL.

9. Clamp for 4 h after instillation and encourage mobilization.

10. After 4 h return drain to suction.

11. Repeat for a usual minimum of 3 days, and adjust total duration according to the response.

12. A good analgesia is important to encourage mobilization. Use intrapleural marcaine 0.25% (0.5–1.0 mL/kg) instilled at same time as urokinase. For oral analgesia use diclofenac or ibuprofen.

13. If the fever persists at day 5, repeat the chest radiograph and ultrasonography, and at this stage consider adding clindamycin for the theoretical advantage of improved tissue penetration. If there is a large collection not being reached by the drain, the drain may need to be repositioned.

14. If the fever persists at day 10, repeat investigations, possibly including computed tomography scan, and consider surgical debridement.

15. The aim of treatment is resolution of active infection, not clearance of the pleural space. Remove the drain when temperature has settled (<38°C) for 24 h, and the volume drained per 24 h is 100 mL or less (take the urokinase volume into account). At this point, change the antibiotics from i.v. to oral. Often, the child can go home the same day. Do not expect the CXR to look normal. There is often a significant amount of pleural thickening, which may be difficult to differentiate from the residual fluid. This has always nearly completely resolved by 6 weeks.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Kroegel

, Anthony

. Immunobiology of pleural inflammation: potential implications for pathogenesis, diagnosis and therapy. Eur Respir J, 1997; 10:2411–2418.

Idell

, Azghani

, Chen

, Koenig

, Mazar

, Kodandapani

, Bdeir

, Cines

, Kulikovskaya

, Allen

. Intrapleural low-molecular-weight urokinase or tissue plasminogen activator versus single-chain urokinase in tetracycline-induced pleural loculation in rabbits. Exp Lung Res, 2007; 33:419–440.

Thomson

, Hull

, Kumar

, Wallis

, Balfour-Lynn

. Randomised trial of intrapleural urokinase in the treatment of childhood empyema. Thorax, 2002; 57:343–347.

Singh

, Mathew

, Chandra

, Katariya

, Kumar

. Randomized controlled trial of intrapleural streptokinase in empyema thoracis in children. Acta Paediatr, 2004; 93:1443–1445.

Sonnappa

, Cohen

, Owens

, van Doorn

, Cairns

, Stanojevic

, Elliott

, Jaffé

. Comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema. Am J Respir Crit Care Med, 2006; 174:221–227.

St. Peter

, Tsao

, Spilde

, Keckler

, Harrison

, Jackson

, Sharp

, Andrews

, Rivard

, Morello

, Holcomb

3rd , Ostlie

. Thoracoscopic decortication vs tube thoracostomy with fibrinolysis for empyema in children: a prospective, randomized trial. J Pediatr Surg, 2009; 44:106–111.

Khalil

, Corbett

, Jones

et al. Less is best? The impact of urokinase as the first line of management of empyema thoracis. Pediatr Surg Int, 2006; 23:129–133.

Barnes

, Hull

, Thomson

. Medical management of parapneumonic pleural disease. Pediatr Pulmonol, 2005; 39:127–134.

Tasci

, Burghard

, Schafer

, Rabe

, Ewig

, Luderitz

. Long term outcome of intrapleural fibrinolytic therapy via small-bore catheter drainage in the management of complicated parapneumonic effusion and empyema: a case series. Med Klin (Munich), 2005; 100:181–185.

10.

Ekingen

, Guvenc

, Sozubir

, Tuzlaci

, Senel

. Fibrinolytic treatment of complicated pediatric thoracic empyemas with intrapleural streptokinase. Eur J Cardiothorac Surg, 2004; 26:503–507.

11.

Gates

, Hogan

, Weinstein

, Arca

. Drainage, fibrinolytics, or surgery: a comparison of treatment options in pediatric empyema. J Pediatr Surg, 2004; 39:1638–1642.

12.

Ulku

, Onen

, Onat

, Kilinc

, Ozcelik

. Intrapleural fibrinolytic treatment of multiloculated pediatric empyemas. Pediatr Surg Int, 2004; 20:520–524.

13.

Weinstein

, Restrepo

, Chait

, Connolly

, Temple

, Macarthur

. Effectiveness and safety of tissue plasminogen activator in the management of complicated parapneumonic effusions. Pediatrics, 2004; 113:e182–e185.

14.

Yao

, Wu

, Liu

, Wu

, Chuang

, Wang

. Treatment of complicated parapneumonic pleural effusion with intrapleural streptokinase in children. Chest, 2004; 125:566–571.

15.

Hawkins

, Scaife

, Hillman

, Feola

. Current treatment of pediatric empyema. Semin Thorac Cardiovasc Surg, 2004; 16:196–200.

16.

Barbato

, Panizzolo

, Monciotti

, Marcucci

, Stefanutti

, Gamba

. Use of urokinase in childhood pleural empyema. Pediatr Pulmonol, 2003; 35:50–55.

17.

Hilliard

, Henderson

, Langton Hewer

. Management of parapneumonic effusion and empyema. Arch Dis Child, 2003; 88:915–917.

18.

Cochran

, Tecklenburg

, Turner

. Intrapleural instillation of fibrinolytic agents for treatment of pleural empyema. Pediatr Crit Care Med, 2003; 4:39–43.

19.

Ozcelik

, Inci

, Nizam

, Onat

. Intrapleural fibrinolytic treatment of multiloculated postpneumonic pediatric empyemas. Ann Thorac Surg, 2003; 76:1849–1853.

20.

Wells

, Havens

. Intrapleural fibrinolysis for parapneumonic effusion and empyema in children. Radiology, 2003; 228:370–378.

21.

Pierrepoint

, Evans

, Morris

, Harrison

, Doull

. Pigtail catheter drain in the treatment of empyema thoracis. Arch Dis Child, 2002; 87:331–332.

22.

Kilic

, Celebi

, Gurpinar

et al. Management of thoracic empyema in children. Pediatr Surg Int, 2002; 18:21–23.

23.

Dass

, Deka

, Barman

, Duwarah

, Khyriem

, Saikia

, Hoque

, Mili

. Empyema thoracis: analysis of 150 cases from a tertiary care centre in North East India. Indian J Pediatr, 2011; 78:1371–1377.

24.

van Loo

, van Loo

, Selvadurai

, Cooper

, Van Asperen

, Fitzgerald

. Intrapleural urokinase versus surgical management of childhood empyema. J Paediatr Child Health, 2010[Epub ahead of print]10.1111/j.1440–1754.

25.

Stefanutti

, Ghirardo

, Barbato

, Gamba

. Evaluation of a pediatric protocol of intrapleural urokinase for pleural empyema: a prospective study. Surgery, 2010; 148:589–594.

26.

Kobr

, Pizingerova

, Sasek

, Fremuth

, Siala

, Racek

. Treatment of encapsulated pleural effusions in children: a prospective trial. Pediatr Int, 2010; 52:453–458.

27.

Diéguez

, Alapont

, San Román

, Micó

, Viguer

. [Drug treatment with fibrinolytics (corrected) of secondary empyema secondary to complicated parapneumonic effusion] Cir Pediatr, 2009; 22:162–167.

28.

Demirhan

, Kosar

, Sancakli

, Kiral

, Orki

, Arman

. Management of postpneumonic empyemas in children. Acta Chir Belg, 2008; 108:208–211.

29.

Aydoğan

, Aydoğan

, Ozcan

, Tugay

, Gokalp

, Arisoy

. Intrapleural streptokinase treatment in children with empyema. Eur J Pediatr, 2008; 167:739–744.

30.

, Chen

, Yen

, Yang

, Lien

. Intrapleural streptokinase for the treatment of childhood empyema. Acta Paediatr Taiwan, 2007; 48:251–256.

31.

Kurt

, Winterhalter

, Connors

, Betz

, Winters

. Therapy of parapneumonic effusions in children: video-assisted thoracoscopic surgery versus conventional thoracostomy drainage. Pediatrics, 2006; 118:e547–e553.

32.

Cohen

, Weinstein

, Fisman

. Cost-effectiveness of competing strategies for the treatment of pediatric empyema. Pediatrics, 2008; 121:e1250–e1257.