Management and prognosis of parapneumonic effusion and empyema in children

INTRODUCTION — Parapneumonic effusion is defined as pleural effusion associated with lung infection (ie, pneumonia). These effusions result from the spread of inflammation and infection to the pleura. Much less commonly, infections in other areas adjacent to the pleura, such as the retropharyngeal, vertebral, abdominal, and retroperitoneal spaces, may spread to the pleura, resulting in the development of effusion.

Early in the course of parapneumonic effusion, the pleura becomes inflamed; subsequent leakage of proteins, fluid, and leukocytes into the pleural space forms the effusion. At the time of formation, the pleural effusion is usually sterile with a low leukocyte count. With time, bacteria invade the fluid, resulting in empyema, which is defined as the presence of grossly purulent fluid in the pleural cavity. The development of pleural empyema is determined by a balance between host resistance, bacterial virulence, and timing of presentation for medical treatment [1]. (See "Epidemiology, clinical presentation, and evaluation of parapneumonic effusion and empyema in children", section on 'Pathophysiology'.)

The management of parapneumonic effusion and empyema in children will be reviewed here. The epidemiology, etiology, pathophysiology, clinical presentation, and evaluation of parapneumonic effusion and empyema in children are discussed separately. (See "Epidemiology, clinical presentation, and evaluation of parapneumonic effusion and empyema in children".)

The evaluation and management of parapneumonic effusion in adults also are discussed separately. (See "Pleural fluid analysis in adults with a pleural effusion" and "Imaging of pleural effusions in adults" and "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)

DEFINITIONS

●Parapneumonic effusion is defined as pleural effusion associated with lung infection (ie, pneumonia). Early in the disease course, the effusion usually is free-flowing (also known as a "simple" effusion) and sterile.

●Loculated parapneumonic effusion refers to the presence of septations (separate compartments) within the effusion, which interfere with free flow of fluid. Loculation usually is detected by imaging (ultrasonography or computed tomography [CT]). Loculation is caused by accumulation of proteinaceous debris in the fluid as the disease progresses.

●Empyema is defined as the presence of bacterial organisms on Gram stain and/or grossly purulent fluid in the pleural cavity.

●Complicated parapneumonic effusion refers to changes in the pleural fluid due to bacterial invasion into the pleural space. Because bacteria are cleared rapidly after antibiotic therapy, cultures of fluid from complicated parapneumonic effusions are often negative. In clinical practice, the term is often used to refer to either loculated effusion or empyema.

●Complicated pneumonia refers to pneumonia with any complication, including loculated parapneumonic effusion, empyema, or (more rarely) pneumothorax, necrotizing pneumonia, or lung abscess.

OVERVIEW — Both medical and surgical interventions have a role in the management of parapneumonic effusion in children [2,3]. The goals of therapy include sterilization of the pleural cavity, resolution of pleural fluid, and reexpansion of the lung. Selection of treatment depends upon factors including the patient's respiratory status and the size and loculation of the fluid collection, as well as the response to initial interventions. With appropriate treatment, outcomes are generally excellent.

Clinical experience and data from studies of parapneumonic effusion in adults cannot be extrapolated to children, because underlying lung disorders are more common in adults and the morbidity and mortality of parapneumonic effusion in adults are higher than in children.

Hospitalization — The majority of patients with pneumonia complicated by parapneumonic effusions will require hospitalization. Transfer to a facility with specialists in pediatric pulmonology, pediatric surgery, and pediatric anesthesia should be considered early in the care of children who may require video-assisted thoracoscopic surgery (VATS) or fibrinolytic therapy [2].

Occasionally, patients with small parapneumonic effusions who are clinically well and are responding to outpatient therapy can be managed without hospitalization, providing that they are followed closely to monitor progress. Indications for hospitalization include ages younger than six months, evidence of bacteremia or respiratory compromise, and failure of outpatient management [4]. (See "Pneumonia in children: Inpatient treatment", section on 'Hospitalization'.)

Clinical course — Parapneumonic effusion and empyema is a disease process that evolves over time, and different management strategies are appropriate at different stages [3].

●In early stages, children tend to have small effusions and are in no respiratory distress; such patients usually can be managed as outpatients, with broad-spectrum oral antibiotics and close observation with chest radiographs on an outpatient basis. (See 'Small parapneumonic effusion' below.)

●Later in the evolution of the process, the effusion may become larger and may compromise respiratory function, requiring hospitalization, intravenous (IV) antibiotics, ultrasound assessment, and drainage of pleural effusion [2,5]. (See 'Moderate or large simple effusion (not loculated)' below.)

●Subsequently, the effusion may become loculated or organized, and/or frankly infected (empyema). This stage usually requires more aggressive therapy, including fibrinolytic therapy or surgical debridement/drainage of the pleural space [6]. Expert opinion on the optimal type and timing of drainage and surgical intervention continues to evolve, and management remains somewhat controversial [2]. (See 'Loculated effusion or empyema' below.)

Children with pneumonia-associated pleural disease can present initially with an effusion that is in any one of these stages of evolution. Management depends on the stage of evolution of the parapneumonic process and what therapy has already been provided. In some cases, oral antibiotics may have already been initiated in the outpatient setting before the effusion became apparent.

SUPPORTIVE CARE — Supportive care for children with parapneumonic effusion may include antipyretics, analgesia, and early ambulation [2]. Children with empyema are invariably febrile; antipyretics should be used for comfort as needed, with the caveat that their use may mask the resolution of fever, which is one of the indicators of clinical progress. Analgesia should be used to treat pleuritic pain, which may interfere with breathing and affect the child's willingness to cough. Adequate analgesia will also help with early ambulation and other measures to encourage lung expansion. However, analgesia should be tailored to the patient's symptoms rather than regularly scheduled to permit monitoring of clinical improvement. Sedatives may cause central respiratory depression and should be used sparingly and cautiously, with close monitoring of respiratory status.

Children with parapneumonic effusions may become dehydrated as a result of poor intake and increased losses from fever and tachypnea. IV fluids should be administered if the child refuses oral intake or is unable to drink. However, close attention must be paid to fluid balance since these children also are at risk for developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)

Bronchodilator therapy has no role in treatment of children with parapneumonic effusions and may potentially worsen their ventilation-perfusion (V/Q) mismatch, exacerbating hypoxemia. Chest physiotherapy is not recommended [2].

ANTIBIOTIC THERAPY

Choice of agent — All children with parapneumonic effusion should be treated with antibiotic therapy. In children with a small effusion, this may include broad-spectrum oral antibiotics and close observation on an outpatient basis [5].

Children with moderate to large effusions or empyema require hospitalization and treatment with intravenous (IV) antibiotics in doses adequate to ensure pleural penetration [2]. If drainage of pleural fluid is indicated, pleural fluid should be sent for bacterial cultures and Gram stain to help direct antibiotic therapy. Additional techniques may be used to increase the yield of microbiologic diagnosis, especially in children who have received antibiotics. These include direct and enrichment culture for aerobic and anaerobic organisms, pneumococcal antigen detection (latex agglutination), and specific or broad-range polymerase chain reaction (PCR) testing. Preferably, the culture should be sent prior to beginning antibiotics if this does not delay treatment. However, cultures can still be helpful even if the patient has been on antibiotics prior to the sampling of pleural fluid. (See 'Overview of management' below.)

The initial choice of antibiotic(s) should be empiric, informed by considerations of the most common organisms causing community-acquired or nosocomial pneumonia in the patient's age group in his/her community or hospital, respectively. Antibiotic therapy should be modified based upon the sensitivity results if and when they are available.

Community-acquired infection

●For outpatients (ie, those with a small effusion who are clinically well), empiric antibiotic regimens are the same as for pediatric community-acquired pneumonia. The considerations are summarized in the table (table 1) and detailed in a separate topic review. (See "Community-acquired pneumonia in children: Outpatient treatment".)

●For inpatients, suggested empiric therapy is IV ceftriaxone or cefotaxime (where available), plus clindamycin or vancomycin if Staphylococcus aureus or anaerobes are a consideration. The choice of first-line antibiotics is mainly determined by the most common bacteriologic etiology causing community-acquired pneumonia in a given area. Antibiotic selection is summarized in the table (table 2A-B) and detailed in a separate topic review. (See "Pneumonia in children: Inpatient treatment", section on 'Complicated CAP'.)

For ill-appearing children, it is particularly important to include vancomycin or clindamycin in the regimen because of the increasing frequency of parapneumonic effusions caused by community-associated methicillin-resistant S. aureus (CA-MRSA) [7-9]. Vancomycin remains the drug of choice to treat MRSA. However, other antibacterial agents, such as clindamycin, can be used if the organism is sensitive to them. The use of newer anti-MRSA antibiotics should be reserved for the most resistant cases. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'MRSA infections'.)

Hospital-acquired infection — Empiric antibiotic therapy for children with hospital-acquired (nosocomial) parapneumonic effusion should include coverage for Gram-negative organisms. If aspiration is suspected (ie, in children with underlying neuromuscular disease or neurologic impairment), coverage for oral anaerobes is recommended. (See "Pneumonia in children: Inpatient treatment".)

Duration — The duration of antibiotic therapy should be individualized, depending on the adequacy of fluid drainage and the clinical response of the patient [5]. Common practice is to continue antibiotics for at least 10 days after resolution of fever; antibiotics may be changed from the IV to oral route when the child has been afebrile and without a chest drain for two to five days, or possibly sooner if close clinical follow-up is assured [2]. For community-acquired pneumonia associated with a parapneumonic effusion or empyema, oral antibiotics appear to be as effective as IV antibiotics after hospital discharge [10-12]. Moreover, oral antibiotics avoid potential complications that can be associated with IV catheters. For most cases of parapneumonic effusion or empyema, a total antibiotic course of two to four weeks is adequate [5,13]. Infections caused by certain pathogens, including CA-MRSA, may require a longer course of treatment.

FREE-FLOWING PLEURAL FLUID

Small parapneumonic effusion — A small pleural effusion is generally defined by its appearance on chest radiograph as fluid occupying <1 cm on lateral decubitus radiograph or opacifying less than one-fourth of the hemithorax [5]. Children with effusions of this size who are well-appearing and in no respiratory distress can be managed as outpatients, with broad-spectrum oral antibiotics and close observation with chest radiographs (algorithm 1) [5]. (See 'Antibiotic therapy' above.)

Even if the effusion is small, hospital admission and intravenous (IV) antibiotics are appropriate for patients who are ill-appearing, in respiratory distress, under six months of age, have evidence of bacteremia/sepsis, or have failed outpatient management. (See 'Hospitalization' above.)

Moderate or large simple effusion (not loculated) — A moderate or large pleural effusion is typically defined as fluid occupying >1 cm on lateral decubitus radiograph or opacifying more than one-fourth of the hemithorax [5]. Such patients should be further evaluated with ultrasonography to determine whether the fluid is free-flowing (simple effusion) or loculated.

Overview of management — Recommendations for management of parapneumonic effusion and empyema have been developed by the British Thoracic Society (BTS), the American Pediatric Surgical Association (APSA), and the Pediatric Infectious Diseases Society (PIDS) [2,5,14]. These approaches are similar, as summarized in the algorithm (algorithm 2):

Patients with simple effusions (free-flowing fluid) can be treated with drainage and empirically selected IV antibiotics, which are subsequently adjusted based on polymerase chain reaction (PCR) or culture and sensitivity results. In our practice, we insert a pigtail catheter (small-bore catheter), which allows for continuous drainage. Continuous drainage (rather than antibiotics alone or simple thoracentesis) is particularly important if the patient has significant respiratory compromise or if the effusion is very large (eg, occupying more than one-half of the hemithorax), as determined by thoracic ultrasound. Patients who do not have a good clinical or radiologic response within 24 to 48 hours are likely progressed to loculated fluid or empyema and will need to be treated accordingly.

Whenever drainage is done, a fluid sample should be sent for cultures and Gram stain to help direct antibiotic therapy. Additional techniques may be used to increase the yield of microbiologic diagnosis in children who have received antibiotics. These include direct and enrichment culture for aerobic and anaerobic organisms, pneumococcal antigen detection (latex agglutination), and specific or broad-range PCR. Measurement of other characteristics of the pleural fluid, such as pH, glucose, and lactate dehydrogenase (LDH), may be helpful if the diagnosis of empyema is in doubt or in the setting of an underlying condition that might be responsible for the effusion, such as collagen vascular disease. Routine measurement of these characteristics is not recommended. Although they have been used to predict a need for drainage procedures, the results rarely change management of a patient with community-acquired pneumonia [5]. (See "Epidemiology, clinical presentation, and evaluation of parapneumonic effusion and empyema in children", section on 'Microbial analysis'.)

As an alternative, a trial of antibiotics without drainage has been suggested for clinically stable patients with moderate and, occasionally in selected patients, large effusions. This approach was evaluated in hospitalized children who were stable and clinically well with no need for oxygen supplementation and no signs of severe respiratory distress. These children were treated with a trial of empirically selected antibiotics for a 24- to 72-hour period without undergoing a drainage procedure; patients who did not respond clinically proceeded to chest tube placement or surgical drainage [15]. Antibiotics alone were successful in approximately one-half of these children.

Thoracentesis — Simple thoracentesis is rarely used for management of parapneumonic effusion in children. However, it is occasionally used to obtain pleural fluid for diagnostic purposes, in cases where continuous drainage via pigtail catheter is not anticipated and if empiric selection of antibiotics is not considered sufficient.

Thoracentesis has also been used therapeutically to drain moderate or large simple effusions in clinically stable patients, but in most institutions, the procedure has been replaced by continuous drainage via a pigtail catheter (see 'Chest tubes' below). When thoracentesis is used therapeutically, as much fluid as possible is slowly removed (up to 10 to 20 mL/kg). Insertion of a pigtail catheter or chest tube is warranted if reaccumulation of fluid occurs after the initial thoracentesis or if the effusion is very large (eg, occupying more than one-half of the hemithorax). Repeated thoracentesis is not recommended [2].

Chest tubes — Large amounts of pleural fluid can be slowly drained using chest tubes (typically pigtail catheter) with underwater seal systems. The chest tube is left in place until fluid drainage becomes minimal. Details of placement and management of chest tubes are discussed separately. (See "Thoracostomy tubes and catheters: Indications and tube selection in adults and children".)

●Indications – Indications for chest tube placement include:

•Large amounts of free-flowing pleural fluid – We generally insert a small-bore chest tube (pigtail catheter) for large effusions (eg, occupying more than one-half of the hemithorax), even in the absence of respiratory compromise.

•Compromised pulmonary function – eg, respiratory distress, hypoxemia.

•Loculated effusion – Loculation of fluid on initial or follow-up imaging or other evidence of fibrinopurulent effusions (eg, positive Gram stain, frank pus, or pH <7.0, glucose <40 mg/dL [2.22 mmol/L], LDH >1000 international units [16.67 kat/L], if these characteristics were measured) [16]. If these features are present, we suggest adjunctive fibrinolytic therapy or proceeding to video-assisted thoracoscopic surgery (VATS). (See 'Loculated effusion or empyema' below.)

•Lack of clinical improvement – For patients treated with a trial of antibiotic therapy without drainage, chest tube placement is indicated if there is no improvement (eg, fever that fails to respond to 48 to 72 hours of antibiotic therapy) or if the fluid reaccumulates or increases after thoracentesis.

●Size of tube – Smaller chest tubes (eg, <14F, including pigtail catheters) are now generally recommended over large-bore tubes to minimize patient discomfort [2,14]. In the past, smaller tubes were often avoided because they were thought to be more prone to obstruction by fibrinopurulent exudate, but clinical studies have failed to substantiate this concern, especially when fibrinolytics are used in addition to chest tube drainage [17,18]. Furthermore, when combined with fibrinolytic therapy, the use of small chest tubes may provide some advantages over large tubes [19,20]. (See "Thoracostomy tubes and catheters: Indications and tube selection in adults and children".)

●Placement – Ultrasonography can be used to guide chest tube placement. The procedure can be performed at the same time as the ultrasonography, or the skin can be marked to indicate the optimum site for drain insertion [21-24]. A fluid sample should be sent for cultures and Gram stain to help direct antibiotic therapy. (See "Thoracostomy tubes and catheters: Placement techniques and complications".)

A chest radiograph is typically obtained after insertion of the chest tube to ensure that there is no pneumothorax and to verify position [2]. However, an effectively functioning chest tube should not be repositioned solely on the basis of a radiograph [25].

●Management – All chest tubes should be connected to a unidirectional drainage system, which must be kept below the level of the patient's chest at all times [2]. The underwater seal system is frequently used. This system is comprised of a tube placed underwater at a depth of approximately 1 to 2 cm and a side vent, which either permits escape of air or is connected to a suction pump [2]. The system should be assessed daily for the amount of drainage, the presence of bubbling, and the presence of swing in the fluid with respiration (which confirms tube patency and appropriate position in the pleural cavity).

Large effusions should be drained gradually. We suggest clamping the drain for one hour after drainage of the initial 10 mL/kg of pleural fluid. In large children and adolescents, some experts suggest that no more than 1500 mL of fluid should be drained at one time and that drainage should be limited to 500 mL/hour, although there is no specific evidence on which to base this suggestion [2,26]. These precautions are suggested because very rapid drainage of pleural fluid occasionally causes pulmonary edema (known as "reexpansion pulmonary edema"). This complication has been reported after drainage of large effusions in adults [27] and in children with malignant lymphoma [28] but is otherwise rare in children.

Clamped drains must be immediately unclamped if there are any signs of clinical deterioration (eg, breathlessness, chest pain). This could be caused by tension pneumothorax in patients with air leak (which may be subclinical) [2] or by rapid accumulation of fluid.

Continuous bubbling from a chest drain suggests a continued visceral pleural air leak, which may develop into a tension pneumothorax if the chest drain is clamped. Therefore, a bubbling chest drain should not be clamped [2,26]. If continuous bubbling is present while the chest tube is connected to suction, the position of the tube should be assessed since it may be partly out of the thorax with one of its drainage holes open to the atmosphere [2]. Continuous bubbling may also be caused by a bronchopleural fistula, especially in cases of necrotizing pneumonia, a complication that sometimes requires surgical intervention.

Routine daily chest radiographs are not needed, since radiographic findings lag behind clinical status [3]. Repeat chest radiographs as indicated by changes in clinical status or after interventions (ie, removal of suction or clamping).

●Troubleshooting – Sudden cessation of fluid drainage may indicate kinking or blockage of the tube by thick exudative fluid, pus, or debris [2]. Small soft drains are prone to kinking at the exit site, particularly in young, mobile children. Obstruction of the tube by pus may be relieved by carefully flushing with normal saline (10 mL should be adequate in a small-bore drain) [2]. A drain that cannot be unblocked is to be removed and replaced if significant pleural fluid remains [2]. In addition, drainage may cease if the fluid becomes loculated or the suction holes of the tube are outside the pleural space [6].

●Removal – The chest tube can be removed once there is clinical resolution and minimal chest tube drainage (less than 10 to 15 mL per 24 hours) [2,5,6]. It is not necessary to wait for complete resolution of drainage, since the tube itself may act as a stimulus for pleural exudative reaction and increases the risk of secondary infection. There is no need to do a trial of clamping the chest tube before its removal [2]. Clinical factors indicating a response to therapy include resolution of fever, with decreasing white blood cell count and C-reactive protein (CRP), decreasing respiratory and heart rates, and improvement in appetite and sense of well-being.

Analgesia can be used for chest tube removal, and sedation may be necessary in young children [2]. Local anesthetic cream applied to the adjacent skin three hours before chest tube removal may be as effective as IV morphine for pain control [29]. The chest tube is removed with a brisk, firm movement while the child performs the Valsalva maneuver or during expiration [2]. A chest radiograph is typically performed after chest tube removal to check for pneumothorax.

●Complications – Complications of chest tubes are rare, especially with use of small tubes (pigtail catheters), and can include bleeding, wound infection at the exit site, development of bronchopleural fistula, persistent atelectasis, and laceration of the lung [24,30].

●Failure to respond – With appropriate therapy, children with symptomatic parapneumonic effusion can be expected to improve within the first few days of treatment [6,31]. If the child remains febrile or tachypneic and aeration does not improve, the chest tube may be obstructed or failing to drain because of the development of loculations, as described above [6].

For patients who do not have a good clinical response within 24 to 48 hours to management with antibiotics with chest tube drainage, we suggest advancing to the therapies used for loculated fluid or empyema (ie, either fibrinolytic therapy or VATS). At some institutions, a repeat ultrasound is performed to evaluate for loculation before advancing therapy. At other institutions, therapy is advanced empirically. (See 'Loculated effusion or empyema' below.)

LOCULATED EFFUSION OR EMPYEMA — Patients who have evidence of loculated fluid on the initial ultrasound require more aggressive intervention to drain the fluid and clear the infection. Expert opinion regarding the optimal type and timing of drainage and surgical intervention continues to evolve, and management remains somewhat controversial. The main options are fibrinolytic therapy and surgical debridement of the pleural space.

Management approaches described below are consistent with guidelines from the American Pediatric Surgical Association (APSA) and British Thoracic Society (BTS) [2,14]. Additional recommendations from the BTS guidelines are shown in the table (table 3).

Intrapleural fibrinolytics versus surgical treatment — Either intrapleural fibrinolytic therapy (pleural catheter placement with instillation of fibrinolytics) or surgical treatment (typically video-assisted thoracoscopic surgery [VATS]) is acceptable as first-line therapy for children with loculated effusions. However, we suggest a trial of fibrinolytic therapy as the initial treatment of choice, followed by VATS for those failing pleural drainage with fibrinolytics, consistent with BTS and APSA guidelines [2,14]. This suggestion is based on limited evidence, and most experts agree that either approach is reasonable. The choice may be influenced by available expertise, cost considerations, and patient preferences.

Pleural drainage with fibrinolytics is successful in approximately 83 percent of children; the remaining 17 percent who fail medical therapy will require VATS, as shown in the following randomized trials:

●A randomized trial in Europe compared VATS with medical therapy with fibrinolysis and found no difference in clinical outcome [32]. In this trial, 60 children (<16 years) with radiographic evidence of empyema and indications for drainage were randomly assigned to treatment with primary VATS or percutaneous chest tube drainage with intrapleural urokinase. The primary outcome measure was length of hospital stay after intervention, and there was no difference between groups (95% CI -2 to 1 day). The median hospital stay after intervention was six days for both groups, with a range of 3 to 16 days for those treated with VATS and 4 to 25 days for those randomized to fibrinolysis. Hospital costs were 25 percent higher for the group treated with primary VATS versus those randomized to primary fibrinolysis. Of note, the fibrinolytic used in this trial was urokinase, which is less expensive than the fibrinolytic agents commonly used in the United States and some other countries.

●Similar findings were shown in a randomized trial from the United States, in which 36 children were randomized to initial treatment with primary VATS or fibrinolysis with alteplase (recombinant human tissue plasminogen activator [tPA]) [33]. The failure rate of fibrinolysis was 16.6 percent (3 of 18 subjects), and two patients treated with primary VATS required ventilator support after surgery. There was no difference in median hospital stay after intervention, but hospital costs were substantially lower for the group treated with primary fibrinolysis (USD $11,700 versus $7,600).

Thus, long-term outcomes are excellent for all treatment plans (antibiotics alone, pleural catheters with fibrinolytics, and VATS), but surgical therapy with VATS is associated with higher treatment costs and requires special expertise. Before these randomized trials were published, many institutions preferred to use primary surgical therapy because this approach appeared to reduce duration of therapy with chest tube (10.6 versus 4.4 days), hospital stay (20 versus 10.8 days), and antibiotic therapy (21.3 versus 12.8 days) and mortality (3.3 versus 0 percent), based on a systematic review of observational studies summarized in the table (table 4) [34].

Fibrinolytic therapy — The use of fibrinolytic drugs to lyse the fibrinous strands in loculated parapneumonic effusions has been described in adults and children. These drugs include urokinase, alteplase (tPA), or streptokinase.

●Efficacy – The evidence supporting fibrinolysis as a component of medical therapy for complicated parapneumonic effusion comes from randomized trials and meta-analyses comparing various fibrinolytic therapies with normal saline, and weakly favors fibrinolytic therapy:

•A meta-analysis in adults with loculated effusions or empyema found a nonsignificant improvement in outcomes with fibrinolytic therapy compared with saline (pooled risk ratio 0.55, 95% CI 0.28-1.07) [35]. A separate meta-analysis analyzing the same trials using different methods found that fibrinolytics reduced the need for surgical intervention (pooled risk ratio 0.63, 95% CI 0.46-0.85) [36].

•A randomized study in children examined the effect of intrapleural alteplase versus normal saline on 17 children with parapneumonic effusion (>20 percent of pleural cavity or >2 cm thickness on CT scan) who underwent chest tube placement [37]. Nine subjects received alteplase on day 1 and 3 and saline on day 2 and 4, and eight patients received the alteplase on day 2 and 4 with saline on the alternate days. Pleural drainage was increased on the days that alteplase was administered compared with days when normal saline was used.

●Choice of agent – No controlled studies are available to determine whether any one of the fibrinolytic agents is more effective than the others. The choice of agent depends upon availability, with urokinase being preferred if it is available, followed by alteplase (tPA) and streptokinase. Addition of the mucolytic agent deoxyribonuclease (DNase; eg, dornase alfa) to the fibrinolytic regimen has no benefit in length of hospital stay or other outcomes, based on a randomized trial in children [38], although it appears to enhance treatment in adults [39]. (See "Management and prognosis of parapneumonic pleural effusion and empyema in adults", section on 'Intrapleural tPA +/- additional drainage'.)

Only urokinase has been studied in a placebo-controlled fashion in children and thus is recommended by the BTS [2]. In North America, urokinase is no longer available, so alteplase is usually used. This approach is supported by a retrospective case series showing similar outcomes and increased thoracostomy tube drainage with alteplase compared with urokinase [40]. Streptokinase is generally considered a third-line choice because of limited efficacy in one large trial and reports of occasional allergic reactions [2,41].

●Technique and dose – Fibrinolytic therapy is administered by instilling the drug through the chest tube, or via irrigation at the time of thoracoscopy. In most cases, we administer fibrinolytic therapy through a pigtail catheter, inserted under ultrasound guidance using light sedation. The treatment may cause discomfort, and adequate sedation and or analgesia need to be provided.

A number of different doses of these agents have been used in various studies. Two approaches for treatment with alteplase were described in the Pediatric Infectious Diseases Society (PIDS) guideline, based on clinical studies in which these regimens were shown to be safe and effective in children older than three months of age [5]:

•Alteplase 4 mg in 40 mL 0.9% saline, intrapleural, with one-hour dwell time; repeat every 24 hours for three days (total of three doses) [14,33].

•Alteplase 0.1 mg/kg (maximum 3 mg) in 10 to 30 mL 0.9% saline, intrapleural, with a 45-minute to one-hour dwell time, and repeated every eight hours for three days (total of nine doses) [42].

The following technique and dose for urokinase is recommended in the BTS guidelines [2] and is also included in the PIDS guideline [5]:

•Urokinase 40,000 units in 40 mL 0.9% saline for children one year and older, and 10,000 units in 10 mL 0.9% saline for children younger than one year. This dose should be administered twice daily (with a four-hour dwell time) for three days; additional doses can be administered if the response is incomplete after six doses. Intrapleural bupivacaine (0.5 to 1.0 mL/kg of a 0.25% solution) can be administered with urokinase if the child finds it uncomfortable [2].

●Contraindications – Fibrinolytic therapy should not be performed in patients who have bronchopleural fistula or chest tubes that are bubbling (suggestive of an air leak), since clamping of the chest tube in such a patient could result in tension pneumothorax. In addition, chest tubes that are clamped must be immediately unclamped if the child has any signs of clinical deterioration (eg, breathlessness, chest pain). (See 'Chest tubes' above.)

●Adverse effects – Adverse effects of fibrinolytic therapy include fever, discomfort, intrapleural bleeding, and anaphylaxis [19,40,43]. In the pediatric trials using urokinase and/or alteplase described above, minor side effects included discomfort during intrapleural injection and transient blood staining of the drainage fluid [19,40]. Rare immediate hypersensitivity reactions to urokinase have been reported in adults [44]. Intrapleural administration of streptokinase generates a systemic antibody response similar to that when the drug is administered intravenously (IV) [45]; fever has been reported and other immunologic responses are possible.

Surgical therapy — Surgical intervention may be used as first-line therapy for patients with loculated effusions or empyema, or a secondary therapy for those failing fibrinolytic therapy. Most experts agree that either approach is reasonable, and the choice may be influenced by available expertise, cost considerations, and patient preferences. In either case, early involvement of a surgeon in the decision-making process helps to ensure that timely surgical intervention can be performed if it is indicated [2]. (See 'Intrapleural fibrinolytics versus surgical treatment' above.)

●Indications – Situations in which surgical intervention usually is necessary include [2]:

•Lack of clinical improvement, including signs of persistent sepsis and persistent pleural collection after initial management (eg, antibiotics, chest tube drainage, and fibrinolytic therapy for three to four days)

•Complex empyema with significant lung pathology (eg, development of a thick fibrous pleural rind, sometimes termed a "peel," which may "trap" the lung and prevent lung reexpansion)

•Bronchopleural fistula with pyopneumothorax

●Video-assisted thorascopic surgery – VATS is the preferred procedure for surgical drainage in typical patients if expertise in this technique is available because it is less invasive than open thoracotomy [2]. A chest drain is left in place after the procedure for continued drainage of fluid or pus.

VATS can be used to remove the thick fibrinous septations that prevent adequate drainage of pleural fluid via chest tube. VATS permits debridement of fibrinous pyogenic material, breakdown of loculations [46-48], and drainage of pus from the pleural cavity under direct vision [2,49-51]. Contraindications to VATS include inability to develop a pleural window to access the pleural cavity, the presence of thick pyogenic material, and/or fibrotic pleural rinds [2].

Observational studies and case series suggest that VATS has good outcomes in efficacy and safety, and the procedure is commonly performed in children with empyema in centers where appropriate expertise is available [2,46,47,52-56]. Compared with open thoracotomy, VATS is less invasive and is associated with shorter duration of analgesia, chest tubes, and postoperative length of stay [16,46,47,57,58]. VATS leaves two to three small scars [2,59]. The use of VATS depends to a large extent upon the availability of the equipment and appropriately trained pediatric thoracic surgeons [2].

Compared with antibiotics and drainage, with or without fibrinolysis, VATS is more invasive and costly but has a lower failure rate. These competing considerations lead to ongoing controversy as to the relative benefits of medical therapy versus early VATS in children with parapneumonic effusion and empyema:

•Proponents of early VATS suggest that if general anesthesia is necessary for simple drain insertion, the procedure may as well be combined with VATS if an appropriately trained surgeon is available [49]. Early VATS is reported to enhance the chance of full expansion of the collapsed lung [49-51]. Some data suggest that the failure rate increases in late-presenting cases [50,57] and in patients who undergo VATS after failure of urokinase therapy [59-61].

Compared with drainage without fibrinolysis, early VATS appears to decrease the length of hospitalization. As an example, one study concluded that early VATS (<48 hours after admission) compared with late VATS (>48 hours after admission) significantly decreased the length of hospitalization (11.5 versus 15.2 days) [53]. Similar findings have been reported in other retrospective studies [54,62].

•Proponents of a trial of pleural drain/fibrinolytics point out that this approach is successful in a majority of patients, thus avoiding the need for surgery. When pleural drain placement includes fibrinolysis, it is effective in more than 80 percent of children, with similar length of stay and lower costs compared with early VATS. As a result, a trial of fibrinolysis is suggested for most patients with loculated effusion or empyema; supporting data and rationale are discussed above. (See 'Intrapleural fibrinolytics versus surgical treatment' above.)

●Other techniques – Other surgical techniques are used in selected patients but are rarely required in children.

•Minithoracotomy – Minithoracotomy achieves debridement and evacuation in a manner similar to VATS [2]. However, minithoracotomy is an open procedure that uses a conventional surgical approach but the incision length is considerably reduced compared with a typical thoracotomy incision.

•Decortication – Decortication involves an open posterolateral thoracotomy and excision of the thick fibrous pleural rind with evacuation of pyogenic material. This is a longer and more complicated procedure than minithoracotomy, leaves a larger linear scar along the rib line, and may promote subsequent development of scoliosis [2,63].

Decortication is rarely necessary in children with empyema since most, if not all, ultimately return to baseline lung function. The procedure may be necessary for children with late-presenting empyema and significant fibrous pleural rind ("peel"), complex empyema, and chronic empyema, and/or if VATS fails [2,64].

•Medical thoracoscopy – Medical thoracoscopy has been used as an alternative to VATS in adults with pleural diseases including empyema; this procedure is performed by pulmonologists rather than surgeons and is usually done under light sedation. Medical thoracoscopy is not generally used in children, because of lack of safety data and technical difficulties including trocar size. The use of this procedure in adults is discussed separately. (See "Medical thoracoscopy (pleuroscopy): Equipment, procedure, and complications".)

INVESTIGATIONAL THERAPY — Systemic glucocorticoids have been investigated as adjunctive treatment for parapneumonic effusions. We do not use this strategy, because of limited and conflicting evidence for benefit and potential adverse effects.

The use of intravenous (IV) dexamethasone as an adjunct therapy in parapneumonic pleural effusion was explored in a randomized trial in 60 children (1 month to 14 years) with parapneumonic effusion (18 with simple effusion, 12 with complicated effusion in each group) [65]. After adjustment by severity group and stratification by center, children treated with dexamethasone had shorter median time to recovery compared with placebo (109 versus 177 hours, respectively; hazard ratio 1.95, 95% CI 1.10-3.45). The benefit was primarily for children with simple rather than loculated parapneumonic effusions. Dexamethasone increased the risk for hyperglycemia, but there were no other significant differences in adverse events. Limitations of this study include some imbalance in baseline characteristics between the groups that may have influenced the outcomes and insufficient sample size to distinguish between subgroups with simple effusion versus complicated effusions. A study in adults found no benefit of systemic glucocorticoids [66].

OUTPATIENT FOLLOW-UP — After hospital discharge, children with parapneumonic effusion or empyema should be seen in follow-up to ensure full recovery and complete resolution of symptoms. We perform chest radiography (posteroanterior and lateral) at this point for patients with residual symptoms or those who had particularly severe disease at presentation. Patients should be followed until they have recovered completely and their chest radiograph has returned to near normal, which usually occurs by three to six months [2,6,67-69] but may take as long as 16 months [70]. Patients may have residual dullness to percussion and diminished breath sounds over the affected areas because of pleural thickening [2,71,72].

Evaluation for underlying predisposing conditions, such as immune disorders, should be considered in children who have a history of recurrent bacterial infections or poor growth [2,73,74]. (See "Cystic fibrosis: Clinical manifestations and diagnosis" and "Approach to the child with recurrent infections".)

PROGNOSIS AND OUTCOME — Despite the marked abnormalities at the time of presentation and the variety of treatment approaches, the majority of children with parapneumonic effusion or empyema make a complete recovery [34,75,76]. Those with empyema, particularly empyema caused by S. aureus, anaerobic bacteria, or group A Streptococcus (Streptococcus pyogenes), typically have a more delayed recovery [6]. There is no evidence that cases caused by antibiotic-resistant organisms are associated with poorer outcomes [52], although length of hospital stay may be increased [53]. If necrotizing pneumonia develops, this may be complicated by bronchopleural fistula and tension pneumothorax, or perforation through the chest wall (empyema necessitatis) [2]. These complications are rare, but if they occur, recovery is prolonged.

In a systematic review comparing primary operative and nonoperative therapy in 3418 children with empyema, the mortality rate for children treated with antibiotics and chest tubes was 3.3 percent; no deaths were reported among the 363 children treated with fibrinolytic therapy, video-assisted thoracoscopic surgery (VATS), or thoracotomy [34]. Mortality is higher for children younger than one to two years of age [71,77,78]. Mortality also is increased in patients with underlying disease (eg, aspiration, malnutrition), particularly if treatment is delayed.

Long-term follow-up studies suggest that fewer than 10 percent of children have residual symptoms [70,76,79]. The rate of residual radiologic or pulmonary function abnormalities is higher, but these abnormalities are usually mild, and most of these patients are asymptomatic and have normal exercise tolerance. As an example, among 51 children examined at least two years after recovery from parapneumonic effusion, there were small abnormalities in lung function and exercise capacity, which were of no clinical importance [80]. All of the children in this report had been managed with medical therapy alone: 73 percent with chest tube drainage and 33 percent with drainage and fibrinolysis. In another observational study of 36 children with empyema, mild spirometry abnormalities were observed soon after discharge and returned to normal within five years [81]. The study detected no differences in spirometry outcomes between the groups that had been managed with chest tube (with or without fibrinolysis) versus VATS.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric pneumonia".)

SUMMARY AND RECOMMENDATIONS

●Overview – Although approaches vary, there is a growing consensus that simple parapneumonic effusions should be treated with drainage and antibiotics, and complicated effusions with either fibrinolysis and chest tube drainage, or early surgical drainage (video-assisted thoracoscopic surgery [VATS]) (algorithm 2). (See 'Overview' above.)

●Disposition – The majority of patients with pneumonia complicated by parapneumonic effusions will require hospitalization for further management. Transfer to a facility with specialists in pediatric pulmonology, pediatric surgery, and pediatric anesthesia should be considered early in the care of children with large or loculated effusions because they may require VATS or fibrinolytic therapy. (See 'Hospitalization' above.)

●Antibiotics

•All children with parapneumonic effusion should be treated with antibiotic therapy. The choice of antibiotic initially is based upon the suspected causative organism, based on characteristics of the patient and local population, and subsequently tailored according to the results of microbiologic testing. (See 'Choice of agent' above.)

•The duration of antibiotic therapy should be individualized, depending on the adequacy of drainage and clinical response of the patient. A common approach is to continue intravenous (IV) antibiotics for two to five days after resolution of fever, followed by oral therapy to complete a total antibiotic course of two to four weeks. (See 'Duration' above.)

●Free-flowing fluid – Management of parapneumonic effusion with free-flowing fluid depends on the size of the collection and clinical course of the patient.

•Children with small pleural effusions (eg, occupying <1 cm on lateral decubitus radiograph or opacifying less than one-fourth of the hemithorax) who are in no respiratory distress usually can be managed as outpatients, with broad-spectrum oral antibiotics and close observation of clinical symptoms and with chest radiographs (algorithm 1). (See 'Small parapneumonic effusion' above.)

•We suggest that children who present with moderate or large amounts of free fluid documented by chest radiograph and ultrasonography undergo pleural drainage via small-bore chest tube (pigtail catheter) in addition to IV antibiotics, rather than antibiotic therapy alone (Grade 2C). A 24- to 48-hour trial of antibiotic therapy without chest tube placement is an acceptable alternative for hospitalized, stable patients who are not in respiratory distress and are closely monitored. Patients who respond clinically are continued on antibiotic therapy as described above. (See 'Chest tubes' above and 'Antibiotic therapy' above.)

•Chest tube removal is indicated once there is clinical resolution and minimal chest tube drainage. Clinical resolution is indicated by resolution of fever, with decreased white blood cell count, respiratory rate, and heart rate, and improved air entry and sense of well-being. (See 'Chest tubes' above.)

•For patients who do not have a good clinical and radiologic response within 24 to 48 hours to management with antibiotics with chest tube drainage, we suggest advancing to the therapies used for loculated fluid or empyema (ie, either fibrinolytic therapy or VATS) (Grade 2C). At some institutions, a repeat ultrasound is performed to evaluate for loculation before proceeding to fibrinolytic therapy or VATS. At other institutions, therapy is advanced empirically. (See 'Chest tubes' above.)

●Loculated fluid or empyema – Patients who have loculated pleural fluid documented by ultrasonography can be treated with either antibiotics alone, pleural catheter placement with fibrinolytics, or surgical therapy (VATS) (algorithm 2).

•We suggest pleural drainage via small-bore chest tube (pigtail catheter) with fibrinolysis and antibiotics as the initial treatment of choice for children with loculated effusions (Grade 2C). However, early VATS is an acceptable alternative and may be the first-line option in centers with surgeons experienced with VATS. The choice may be influenced by available expertise, cost considerations, and patient preferences. Pleural drainage with fibrinolysis is successful in approximately 80 percent of children; the remainder who fail medical therapy will require VATS. (See 'Intrapleural fibrinolytics versus surgical treatment' above and 'Fibrinolytic therapy' above.)

•Long-term outcomes are excellent for either primary medical or surgical therapy, but surgical therapy is associated with higher treatment costs and possibly greater short-term complications. (See 'Intrapleural fibrinolytics versus surgical treatment' above and 'Surgical therapy' above.)

●Follow-up – Children who have been treated for parapneumonic effusion should continue to be followed until they have recovered completely. Follow-up chest radiographs are appropriate for patients with residual symptoms or those who had particularly severe disease at presentation. (See 'Outpatient follow-up' above.)