Parapneumonic Pleural Effusions and Empyema Thoracis


Background

Pleural effusions are a common finding in patients with pneumonia. More than 40% of patients with bacterial pneumonia and 60% of patients with pneumococcal pneumonia develop parapneumonic effusions. While treatment with antibiotics leads to resolution in most patients, some patients develop a more fibrinous reaction, with the presence of frank pus in the most severe cases. The latter is referred to as an empyema or empyema thoracis.

Parapneumonic pleural effusions are classified into three broad groups based on fluid characteristics, which, in turn, provides a reflection on both the severity and natural history of the pleural effusion.

  • Uncomplicated parapneumonic effusions: These are exudative, predominantly neutrophilic effusions reflecting increasing passage of interstitial fluid as a result of inflammation associated with pneumonia. The fluid may be slightly cloudy or even clear, without any organisms noted on Gram stain or culture. They resolve with appropriate antibiotic treatment of the pneumonia.

  • Complicated parapneumonic effusions: These occur as a result of bacterial invasion into the pleural space that leads to an increased number of neutrophils, decreased glucose levels, pleural fluid acidosis, and an elevated lactic dehydrogenase (LDH) concentration. These effusions often are sterile because bacteria are usually cleared rapidly from the pleural space. The fluid is typically cloudy and is classified as complicated because it requires drainage for resolution.

  • Empyema thoracis: This develops as frank pus accumulates in the pleural space. Laboratory studies indicate that preexisting pleural fluid is required for the development of an empyema because empyema is not seen after direct inoculation into a "dry" pleural space. The pus is seen after thoracentesis or any drainage procedure of the pleural space and is generally characterized as thick, viscous, and opaque.

Empyema thoracis has been recognized as a serious problem for centuries. In approximately 500 BCE, Hippocrates recommended treating empyema with open drainage. The treatment of empyema remained essentially unchanged until the middle of the 19th century. In 1876, Hewitt described a method of closed drainage of the chest in which a rubber tube was placed into the empyema cavity to drain via a water seal drainage method. In the early 20th century, surgical therapies for empyema (eg, thoracoplasty, decortication) were introduced. More recently, video-assisted thoracoscopic surgery (VATS) has played a major role in the treatment of patients with empyema thoracis.

Etiology

Virtually any type of pneumonia (eg, bacterial, viral, atypical) can be associated with a parapneumonic pleural effusion. However, the relative incidence of parapneumonic pleural effusions varies with the organism. Viral pneumonia and Mycoplasma pneumonia cause small pleural effusions in 20% of patients. For thoracic empyema, bacterial pneumonia is the cause in 70%. [1Increasingly, empyema thoracis is a complication of previous surgery, which accounts for 30% of cases. Trauma may also be complicated by infection of the pleural space. In the absence of trauma or surgery, the infecting organism may spread from blood or other organs into the pleural space. These can develop into subdiaphragmatic abscesses, a ruptured esophagus, mediastinitis, osteomyelitis, pericarditis, cholangitis, and diverticulitis, among others.

Bacteriology

Bacteriologic features of culture-positive parapneumonic pleural effusions have changed over time. Prior to the antibiotic era, Streptococcus pneumoniae was the most common. S pneumoniae and Staphylococcus aureus now account for approximately 70% of aerobic Gram-positive cultures. Presently, aerobic organisms are isolated slightly more frequently than anaerobic organisms. Streptococcus milleri has also become more common. [234Klebsiella, Pseudomonas, and Haemophilus species are the three most commonly isolated aerobic Gram-negative organisms. Bacteroides and Peptostreptococcus species are the 2 most commonly isolated anaerobic organisms. Currently, empyema thoracis is most often associated with aspiration pneumonia with mixed bacterial florae containing aerobic and anaerobic bacteria. [5The usual organism isolated in empyema thoracis complicating previous surgery is S aureus.

Pathophysiology

The evolution of a parapneumonic pleural effusion, as shown in the image below, can be divided into 3 stages, including exudative, fibrinopurulent, and organization stages. [1]

Left pleural effusion developed 4 days after antibLeft pleural effusion developed 4 days after antibiotic treatment for pneumococcal pneumonia. Patient developed fever, left-sided chest pain, and increasing dyspnea. During thoracentesis, purulent pleural fluid was removed, and the Gram stain showed gram-positive diplococci. The culture confirmed this to be Streptococcus pneumoniae.

During the exudative stage, sterile pleural fluid rapidly accumulates in the pleural space. The pleural fluid originates in the interstitial spaces of the lung and in the capillaries of the visceral pleura because of increased permeability. The pleural fluid has a low white blood cell (WBC) count and a relatively low LDH level. The pleural fluid glucose and pH levels are within the reference range. These effusions resolve with antibiotic therapy, and chest tube insertion is not required. This stage takes approximately 2-5 days from the onset of pneumonia.

In the second stage, or fibrinopurulent stage, bacterial invasion of the pleural space occurs, with accumulation of polymorphonuclear leukocytes, bacteria, and cellular debris. A tendency toward loculation and septation exists, pleural fluid pH (< 7.20) and glucose levels are lower (< 60 mg/dL), and the LDH levels increase. At this stage, bacteriological stains and/or cultures of the pleural fluid can be positive for microorganisms. This stage takes approximately 5-10 days after pneumonia onset.

In the last, or organization stage, fibroblasts grow into the exudates from both the visceral and parietal pleural surfaces, and they produce an inelastic membrane called a pleural peel. Pleural fluid is thick. In an untreated patient, pleural fluid may drain spontaneously through the chest wall (ie, empyema thoracis necessitatis). Empyema thoracis may arise without an associated pneumonic process, such as from esophageal perforation, trauma, a surgical procedure in the pleural space, or septicemia. This last stage may take 2-3 weeks to develop.

Etiology

See Background for details on the etiology and bacteriology of these pleural infections.

Pneumonia is the leading cause of parapneumonic effusions and empyema thoracis.

Increasingly, empyema is also a complication of previous cardiothoracic surgery, which accounts for 30% of cases. The usual organisms are Staphylococcus species and Gram-negative bacteria.

Trauma can also lead to inoculation and superinfection of the pleural space.

In the absence of trauma or surgery, the infecting organism may have spread from blood or other organs into the pleural space. These causes include extension of infections from adjacent or distant sites (eg, ruptured esophagus, mediastinitis, osteomyelitis, pericarditis, cholangitis, diverticulitis, pericarditis) or subdiaphragmatic abscesses.

Risk factors

Risk factors for empyema thoracis include age (children and elderly persons), debilitation, pneumonia requiring hospitalization, and comorbid diseases, such as bronchiectasisrheumatoid arthritis, alcoholism, diabetes, and gastroesophageal reflux disease. [1]

A large prospective observational study in the United Kingdom, using multivariate regression analysis, identified 7 clinical factors predicting the development of complicated parapneumonic pleural effusions or empyema thoracis. They identified an albumin value of less than 30 g/L, a serum sodium value of less than 130 mmol/L, a platelet count of greater than 400 X 109/L, a C-reactive protein level of greater than 100 mg/L, and a history of alcohol abuse or intravenous drug use as independently associated with the development of complicated parapneumonic pleural effusions or empyema thoracis, while a history of chronic obstructive pulmonary disease (COPD) was associated with a decreased risk. [6]

Epidemiology

Frequency

United States

Based on hospital discharge data, approximately 1.3 million patients are hospitalized each year with pneumonia in the United States. The prevalence of parapneumonic effusions is dependent, in part, on the organism involved. Overall, pleural effusions are seen in approximately 35-40% of patients with bacterial pneumonia or anaerobic pneumonia, with a prevalence in pneumococcal pneumonia approaching 60%. Complicated pleural effusions are more commonly seen with anaerobic pleuropulmonary infections. This results in an estimated 500,000-750,000 patients with parapneumonic effusions annually. No good estimates are available regarding the fraction of these patients that proceed to complicated effusions or empyema, but in small series, approximately 5-10% require a drainage or a surgical procedure.

A study of United States hospitalization data found that in 1996, the national hospitalization rate for parapneumonic empyema-related diagnoses was 3.04 per 100,000; by 2008, it had increased to 5.98 per 100,000, a 2-fold increase. Pneumococcal empyema rates remained stable, but staphylococcal empyema rates tripled. Hospitalization rates for empyemas of other or unknown etiology (62.4% of empyema hospitalizations) doubled, as did rates for nonpneumococcal streptococcal empyemas. [7]

International

No good estimates are available on the international incidence of pneumonia. The World Health Organization has reported the burden of disease related to deaths from lower respiratory tract infections in 2004 at 4.2 million. One can extrapolate the incidence of pleural effusions and empyema using a US estimate, but caution is advised because the lack of treatment and delayed treatment in underdeveloped countries may skew the international incidence upward.

Race

No specific ethnic predisposition is recognized for empyema; however, a larger number of ethnic minorities have limited financial resources, limited access to healthcare, and more comorbidities, which, in turn, may increase their risk of pneumonia, pleural effusions, and empyema.

Sex

Empyema has no known sexual predilection.

Age

No specific age predisposition is recognized for empyema, although increasing age and associated comorbidities increase the risk for pneumonia and, subsequently, pleural effusions and empyema. Also recognized is that differences exist in empyema that occurs in children compared with adults. The most striking differences include the development of empyema in previously healthy children (as opposed to adults who usually have some underlying comorbidity) and the lower threshold for treatment with thrombolytics and surgical drainage in children compared with adults. See Empyema for more details.

Prognosis

Most patients recover, but the mortality rate remains approximately 10%. Appropriate antibiotic therapy and early drainage of pleural fluid are crucial for recovery. Approximately 15-25% of patients require surgical intervention, including decortication and/or an open drainage procedure.

Mortality/morbidity

Mortality rates from empyema have been reported to be 11-50% range. The wide difference is due in part to limited data, with mortality rates being higher (in the 50% range) at a time when current diagnostic imaging, antibiotics, and drainage options were not readily available. Other complicating factors include cardiac and respiratory comorbidities, immunosuppressive states related to medications or human immunodeficiency virus (HIV) infection, and age. Death rates related to pneumonia are higher in elderly persons and in those with the outlined underlying comorbidities. More recent reports estimate deaths in patients with pneumonia and complicated pleural effusions in the 7-10% range.

Patient Education

For patient education resources, visit the Lung Disease and Respiratory Health Center. Also, see the patient education article Bacterial Pneumonia.


CLINICAL PRESENTATION


History

Clinical manifestations of parapneumonic effusions and empyema largely depend on whether the patient has an aerobic or anaerobic infection. Aerobic infections are more acute in onset with acute febrile symptoms, while anaerobic infections can be indolent in their time course and symptoms may be nonspecific with low-grade fevers. If fever persists for more than 48 hours after the initiation of antibiotic treatment, a complicating parapneumonic effusion or empyema likely exists.

Aerobic bacterial infection

The clinical presentation in patients with aerobic bacterial pleural space infection is similar to that of patients with bacterial pneumonia. Patients present with an acute febrile illness with chest pain, sputum production, and leukocytosis. A complicated parapneumonic effusion is suggested by the presence of a fever lasting more than 48 hours after the initiation of antibiotic therapy.

Anaerobic bacterial infection

Patients with anaerobic bacterial infections involving the pleural space usually present with a subacute illness. Most of these patients have symptoms persisting for more than 7 days. Approximately 60% of patients have weight loss. Anemia is also common. Most of these patients have poor oral hygiene, many have alcoholism, or other factors that predispose them to recurrent aspiration.

Physical Examination

Most patients are febrile with tachypnea and tachycardia, often appearing toxic and fulfilling criteria for the systemic inflammatory response syndrome (SIRS). Signs of pleural effusion upon physical examination include the following:

  • Decreased or absent breath sounds

  • Dullness to percussion

  • Decreased tactile fremitus

  • Evidence of tension and contralateral tracheal shift possible with large effusions

In areas in which pneumonia and lung consolidation are adjacent and more extensive than pleural fluid, findings include (1) rales or crackles and/or (2) bronchial breath sounds or egophony.

DDx

Differential Diagnoses

TREATMENT & MANAGEMENT

Medical Care

The initial treatment of a patient with pneumonia and pleural effusion involves two major decisions. The first decision involves selection of an appropriate antibiotic that will cover likely pathogens. The second decision involves the need for drainage of pleural fluid and is be guided by the American College of Chest Physicians (ACCP) guideline recommendations for the medical and surgical treatment of parapneumonic effusions. [8]

The initial antibiotic selection is usually based on whether the pneumonia is community or hospital acquired and on the severity of the patient's illness. For a patient with community-acquired pneumonia, the recommended agents are second- or third-generation cephalosporins in addition to a macrolide. For patients hospitalized with severe community-acquired pneumonia, initiate treatment with a macrolide plus a third-generation cephalosporin with antipseudomonal activity. Enteric Gram-negative bacilli frequently cause pneumonia acquired in institutions (eg, hospitals, nursing homes). Therefore, initial antibiotic coverage should include an antibiotic effective against pseudomonads. If aspiration is evident or suspected, oral anaerobic micro-organism should also be covered.

Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) consensus guidelines on the management of community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, and healthcare-associated pneumonia in adults are published elsewhere. [2021Also see Bacterial Pneumonia.

Effusions with pleural fluid layering less than 10 mm on decubitus chest radiographs almost always resolve with appropriate systemic antibiotics. Patients with pleural effusions that have a pleural fluid layering greater than 10 mm on lateral decubitus radiographs should have a diagnostic thoracentesis unless there is a contra-indication to the procedure. If the diagnostic thoracentesis yields thick pus, the patient has an empyema thoracis and definitive pleural drainage is absolutely required. If the pleural fluid is not thick pus, then results of pleural fluid Gram stain or culture, pleural fluid pH and glucose levels, and the presence or absence of pleural fluid loculations should guide the course of action as recommended in the guidelines. [8]

Of note, the strength of recommendations by the expert panel in this guideline is somewhat limited because of the small number of randomized, controlled trials, and methodological weakness resulted in heterogeneous data. The panel urged review of these recommendations cautiously; they purposefully avoided specific recommendations or preferences on primary management approaches (ie, no drainage, therapeutic thoracentesis, tube thoracostomy, fibrinolytics, video-assisted thoracoscopic surgery [VATS], thoracotomy). Despite these limitations, consistent and possibly clinically meaningful trends formed for the pooled data and the results of the randomized, controlled trials and the historically controlled series on the primary management approach to parapneumonic pleural effusions.

Summary of the recommendations

In all patients with acute bacterial pneumonia, the presence of a parapneumonic pleural effusion should be considered (level C evidence).

In patients with parapneumonic pleural effusions, the estimated risk for poor outcome, using the panel-recommended approach based on pleural space anatomy, pleural fluid bacteriology, and pleural fluid chemistry, should be the basis for determining whether the parapneumonic pleural effusions should be drained (level D evidence). Poor outcomes could result from any or all of the following: prolonged hospitalization, prolonged evidence of systemic toxicity, increased morbidity from any drainage procedure, increased risk for residual ventilatory impairment, increased risk for local spread of the inflammatory reaction, and increased mortality. The 4 risk categories are as follows:

  • Category 1 (very low risk): The effusion is small (< 10-mm thickness on decubitus) and free flowing (A0). Because the effusion is small, no thoracentesis is performed and the bacteriology (Bx) and chemistry (Cx) of the fluid are unknown.

  • Category 2 (low risk): The effusion is small to moderate (≥10 mm and less than half the hemithorax) and free flowing (A1) with negative culture and Gram stain regardless of prior use of antibiotics (B0); pH is higher than or equal to 7.20 (C0).

  • Category 3 (moderate risk): The effusion meets one of the following criteria: large (greater than or equal to half the hemithorax), loculated effusion, thicken pleura on contrast-enhanced CT scan (A2), positive Gram stain or culture (B1), or pH less than 7.20 (C1).

  • Category 4 (high risk): This is when pleural fluid consists of pus.

Patients with category 1 or category 2 risk for poor outcome with parapneumonic pleural effusions may not require drainage (level D evidence).

Drainage is recommended for management of category 3 or 4 parapneumonic pleural effusions based on pooled data for mortality and the need for second interventions with the no-drainage approach (level C evidence).

Based on the pooled data for mortality and the need for second interventions, therapeutic thoracentesis or tube thoracostomy alone appears to be insufficient treatment for treating most patients with category 3 or 4 parapneumonic pleural effusions (level C evidence). However, the panel recognizes that in the individual patient, therapeutic thoracentesis or tube thoracostomy, as planned interim steps before a subsequent drainage procedure, may result in complete resolution of the parapneumonic pleural effusions. Careful evaluation of the patient for several hours is essential in these cases. If resolution occurs, no further intervention is necessary (level D evidence).

Fibrinolytics, VATS, and surgery are acceptable approaches for managing patients with category 3 and category 4 parapneumonic pleural effusions based on cumulative data across all studies that indicate that these interventions are associated with the lowest mortality and need for second interventions (level C evidence).

Chest tubes (tube thoracostomy)

Insert chest tubes immediately after a complicated parapneumonic pleural effusion or empyema thoracis is diagnosed (see the image below). The key to resolution involves prompt drainage of pleural fluid because delay leads to the formation of loculated pleural fluid.

Chest CT scan with intravenous contrast in a patieChest CT scan with intravenous contrast in a patient with mixed Streptococcus milleri and anaerobic empyema following aspiration pneumonia, 3 days following thoracostomy and intrapleural fibrinolysis (Reteplase).

Position the chest tube in a dependent part of the pleural effusion. Previously, large-bore (38-32F) tubes were recommended, but smaller tubes are similarly effective, and at least a 28F tube should be placed. These can be placed either using a guidewire-assisted serial dilatation technique or the more traditional cut-down approach.

Smaller pigtail catheters (8-14F) can also be placed under ultrasound or CT guidance. Consider these in smaller, difficult-to-access, multiple-loculated effusions and nonloculated, nonpurulent effusions. These catheters have also been successful in draining empyemas. The variation in success rates for these catheters (72–82%) is associated with patient selection, operator expertise, and the stage of the parapneumonic pleural effusions. The major advantage of small-bore catheters is better patient tolerance and avoidance of major complications. [1]

Continue closed-tube drainage as long as clinical and radiologic improvement are observed. The chest tube can be removed once the volume of the pleural drainage is less than 100 mL/24 h, with clearance of the pleural fluid turbidity seen in complicated pleural effusions.

If the patient does not demonstrate clinical or radiologic improvement with declining pleural fluid drainage, perform a pleural space ultrasound examination or chest CT scanning to look for pleural fluid loculations and ensure proper tube placement.

Undrained pleural fluid may respond to intrapleural thrombolytic therapy or may require placement of another tube. Closed chest tube drainage yields satisfactory results in approximately 60% of patients with aerobic infections and 25% of patients with anaerobic infections.

Intrapleural thrombolytic agents

Since the 1970s, several studies have reported success of thrombolytic therapy for loculated complicated parapneumonic pleural effusions. [222324252627282930The thrombolytic agents used in parapneumonic pleural effusions are more effective if administered in the early fibrinopurulent stage of parapneumonic pleural effusions.

With thrombolytic therapy, success rates of 70-90% have been reported. Streptokinase has been used in a dose of 250,000 IU in 100 mL of normal saline once or twice a day. Urokinase was also effective and in a randomized trial of patients with multiloculated pleural effusions. Subjects in the urokinase group drained significantly more pleural fluid, required less surgical intervention, and required fewer days in the hospital.

Important to note is that streptokinase and urokinase are no longer available in the United States.

Following instillation, the chest tube is clamped for 2-4 hours. These agents may be administered daily for as many as 14 days. Streptokinase may lead to sensitization with production of an antibody response and subsequent allergic reaction if used for systemic thrombolysis.

Streptokinase and urokinase are probably equally effective, although neither has been compared to each other in a research trial. The potential for developing antibodies to streptokinase has generally favored urokinase as a pleural thrombolytic.

While thrombolytic agents may facilitate and increase pleural fluid drainage, their effect on improving patient outcomes and avoiding surgical intervention has not been established.

A prospective randomized trial of intrapleural thrombolytic agent streptokinase (MIST1 group) was conducted on the drainage of infected pleural fluid collections. In this double-blind trial, 454 patients with pleural infection (either purulent pleural fluid or pleural fluid with a pH < 7.20 with signs of infection) received either intrapleural streptokinase (250,000 IU bid for 3 d) or placebo. Among the 427 patients who received streptokinase or placebo, no benefit was reported for streptokinase in terms of mortality, rate of surgery, radiographic outcomes, or length of hospital stay; serious adverse events (chest pain, fever, or allergy) were more common with streptokinase. [26]

Tokuda et al performed a meta-analysis of all properly randomized trials, comparing intrapleural thrombolytic agents with placebo in adult patients with empyema thoracis and complicated parapneumonic pleural effusions. The outcome of primary interest was the reduction of death and surgical intervention. Five trials totaling 575 patients were included. [27]

The MIST1 trial constituted the bulk of patients in the meta-analysis, and its non-beneficial findings contributed significantly to the final conclusion. The meta-analysis did not support the routine use of thrombolytic therapy for all patients who required chest tube drainage for empyema thoracis or complicated parapneumonic pleural effusions. Note that the meta-analysis described a nonsignificant reduction in death and surgery even despite including the MIST1 trial. Because of significant heterogeneity of the treatment effects, selected patients might benefit from thrombolytic treatment. [27]

The reason the MIST1 caused a significant heterogeneity could have been the differences in patient population studied and their study design. First, the proportion of loculated pleural effusions enrolled was low (70%). Second, unlike other studies, only plain chest radiography, and not ultrasonography or CT imaging, was used to document radiographic improvement. Third, the median size of the chest tube used was smaller, only 12F, and there was no mention whether ultrasound guidance was used for placement. Lastly, the criteria for surgical intervention were more subjective and were based on clinical judgment of the physicians, whereas other studies had more objective criteria.

Intrapleural recombinant tissue plasminogen activator (r-TPA) or alteplase has been successfully evaluated in pediatric patients with complicated parapneumonic pleural effusion and pleural empyema. Some authors have suggested that r-TPA might be a more effective therapeutic agent than streptokinase.

A small, noncomparative study of consecutive adult patients using r-TPA or alteplase administered intrapleurally in a single daily dose of 25 mg reported the treatment was well tolerated and effective. [28Another retrospective review of 22 consecutive patients also demonstrated improved drainage of pleural fluid with alteplase, with 2 mg administered into the pleural space 3 times a day for 3 days.

This has led to a prospective, randomized comparison of alteplase with placebo in the management of complicated pleural effusions and empyema. The study has been completed, and the final report of this experience is pending.

The Cochrane Database systematic review on this topic published in 2008 had identified 7 studies and 761 patients. [30A significant reduction in the need for surgical intervention was identified, but the authors also noted the discrepancy between this conclusion and results of the MIST1 trial. The authors note subgroup analysis that suggests the greatest benefit is in patients with loculated effusions, but the data are very limited and due caution is advised. No increase in adverse events was noted with thrombolytic therapy.

An r-TPA study that came out later in 2011, the MIST2 trial, included a comparison with intrapleural recombinant human DNase, a potential treatment for pleural infection that may help prevent biofilm formation and increased viscosity by destroying extracellular DNA. The blinded 2-by-2 factorial trial randomly assigned 210 patients with pleural infection to receive a 3-day study treatment using double placebo, r-TPA (alteplase) and placebo, DNase and placebo, or r-TPA and DNase. The combined intrapleural r-TPA and DNase therapy reduced hospital stay length, decreased the need for thoracic surgery, and produced a greater improvement in pleural opacity on day 7 relative to double placebo. Stay length and pleural opacity change for DNase alone and for r-TPA alone did not significantly differ from those for double placebo.

The possible explanation could be that the fibrinolytics help lyse the pleural fibrinous septation and the DNase is required to reduce the viscosity of the pus. This study suggested that DNase monotherapy should be avoided because it increases the need for thoracic surgery. [31]

After the MIST2 study, no other randomized trial has been performed in this field. The latest systematic review with meta-analysis of fairly good–quality trials was published by Janda and Swiston in 2012. This study analyzed 7 randomized controlled trials, total of 801 patients, comparing fibrinolytic therapy with placebo, including the MIST1 and MIST2 trials. The results showed significant reduction of treatment failure (surgical intervention or death) and surgical intervention alone but not for death alone or hospital length of stay. [32The MIST1 was also the one that caused significant heterogeneity in this meta-analysis. The authors also addressed potential publication bias due to missing large positive studies, as well as small and large negative studies.

Thus, the conclusion by the authors was not quite different from previous meta-analyses that although fibrinolytic therapy cannot be routinely recommended, it could be considered in patients with loculated pleural effusions because it may prevent the need for surgical intervention. More randomized controlled trials with adequate power are needed. However, pleural thickening greater than two mm on CT scan might predict failure of intrapleural fibrinolytic therapy. [33]

Surgical Care

Thoracoscopy

Thoracoscopy is an alternate therapy for multiloculated empyema thoracis. In patients with multiloculated parapneumonic pleural effusions, the loculations in the pleural space can be disrupted with a thoracoscope, and the pleural space can be drained completely. If extensive adhesions are present or thick pleural peel entraps the lung, the procedure may be converted to open thoracostomy and decortication.

Luh et al published their experience in the treatment of complicated parapneumonic pleural effusions and empyema thoracis by VATS in 234 patients (108 women, 126 men). More than 85% (200 patients) received preoperative diagnostic or therapeutic thoracentesis, tube thoracostomy, or fibrinolytics. Of 234 patients, 202 patients (86.3%) achieved satisfactory results with VATS. Only 40 patients required open decortication or repeat procedures. VATS is safe and effective for treatment; earlier intervention with VATS can produce better clinical results. [34]

Hope et al reviewed outcomes of surgical treatment for parapneumonic empyema thoracis. The use of VATS was compared with thoracotomy. Morbidity and mortality rates were similar among all groups. The conversion rate to open thoracotomy was 21%. Based on a shorter postoperative length of stay with similar morbidity and mortality in patients operated on within 11 days of admission, early aggressive surgery treatment for complicated parapneumonic effusions or empyema thoracis is recommended. [35]

Retrospective evaluation of 2 different surgical procedures (decortication vs debridement) and approaches (VATS vs thoracotomy) were analyzed by Casali and colleagues. The study included 119 patients; 51 patients had debridement (52% through VATS, 48% through thoracotomy) and 68 patients had decortications through thoracotomy. VATS debridement had a lower postoperative hospital stay and shorter duration of chest drainage and greater improvement in a subjective dyspnea score. The long-term spirometric evaluation was normal in 58 patients (56%). Age older than 70 years old was the only variable associated with poor long-term results (forced expiratory volume in 1 second [FEV1] < 60% and/or dyspnea Medical Research Council grade ≥2) at multivariate analysis. VATS is associated with less postoperative mortality and shorter postoperative hospital stay. [36]

Two other studies that support the use of VATS as a primary drainage procedure are those by Potaris et al [37and Chan et al. [38]

Wang and colleagues proposed a new technique using an electronic endoscope (bronchoscope or gastroscope) inserted through the chest tube to directly visualize, irrigate, and break down the loculation effectively in various pleural diseases, including 13 cases of empyema thoracis. [39]

In a prospective, randomized study comparing VATS and thrombolytic therapy in children with empyema, no differences in outcomes were noted between the 2 methods in a small study involving 36 patients. [40Thrombolytic therapy consisted of 4-mg doses administered 3 times over a 48-hour period. Three (16.7%) of the patients treated with thrombolytic therapy eventually required VATS for management.

Rib resection and open drainage of pleural space

Open drainage of the pleural space may be used when closed-tube drainage of the pleural infection is inadequate and the patient does not respond to intrapleural thrombolytic agents. This procedure is recommended only when the patient is too ill to tolerate decortication. The resection of one to three ribs overlying the lower part of the empyema thoracis cavity is performed, a large-bore chest tube is inserted into the empyema thoracis cavity, and the tube is drained into a colostomy bag.

Patients treated by open drainage have an open chest wound for a prolonged period. In one series, the median time for healing the drainage site was 142 days. With decortication, the period of convalescence is much shorter, although patients who are markedly debilitated do not tolerate decortication.

In decortication, all the fibrous tissue is removed from the visceral pleural peel, and all pus is evacuated from the pleural space. Decortication is a major thoracic operation requiring full thoracotomy; therefore, decortication is not tolerated by critically ill patients. Decortication is the procedure of choice for patients in whom pleural sepsis is not controlled by closed-tube thoracostomy, intrapleural thrombolytic agents, and, possibly, thoracoscopy. Mortality rates as high as 10% have been described with this procedure. Decortication should not be performed solely to remove the thickened pleural peel; the thickened pleural peel usually resolves over several months. If the pleura remains thickened with symptom-limiting reduction in pulmonary function after approximately 6 months, decortication can be considered.

Postpneumonectomy empyema thoracis, an uncommon but life-threatening complication, is often associated with a bronchopleural fistula. Treatment of bronchopleural fistula depends on several factors, including the extent of dehiscence, degree of pleural contamination, and general condition of the patient. Early diagnosis and aggressive therapeutic strategies for controlling infection, closing the fistula, and sterilizing the closed pleural space are mandatory. Repeated debridement, VATS, endoscopic application of tissue glue, and stenting may be additional management strategies. [41]

Consultations

Most patients can be treated by pulmonary and/or infectious diseases specialists.

An interventional radiologist may be needed to place small-bore drainage catheters for difficult-to-access loculated effusions.

Patients with persistently loculated effusions or unresolving empyema thoracis may require surgery and should be seen by a thoracic surgeon.

Diet

No dietary restrictions are recommended for patients with parapneumonia effusions and empyema, other than what is dictated by comorbidities.

Activity

No specific activity restrictions are recommended for patients with parapneumonic effusions and empyema. Their activity level may be limited by comorbidities and any interventions required to treat their infection.

Complications

Complications are related to adverse events related to incomplete drainage of infected pleural fluid. These include chronic, indolent infections, chest tube site infections, trapped lung, bronchopleural fistulas, and pneumothoraces.

Untreated infections may lead to sepsis, septic shock, and death.

Prevention

Early diagnosis and intervention (thoracentesis and/or drainage procedure), may obviate the need for surgical treatment.

Long-Term Monitoring

Often, prolonged antibiotic therapy is required, particularly in patients who have anaerobic infections. The length of antibiotic therapy is generally dictated by the response to antibiotics and clinical and radiologic resolution.


MEDICATION


Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Antibiotics

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting. Initiate therapy with intravenous antibiotics and transition to oral agents or equivalent agents based on clinical response. Oral antibiotics can be used to transition from intravenous therapy; they allow completion of a full course of therapy without the need for intravascular access or inpatient hospitalization. The antibiotic choice should focus on the most likely pathogens, ranging from anaerobic infections to community-acquired pathogens, to nosocomial or healthcare–associated pathogens, to resistant gram-positive pneumonias.

Penicillin G (Pfizerpen)

Penicillin G interferes with the synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.

Penicillin VK (Beepen-VK, Betapen-VK, Pen.Vee K, Robicillin VK, V-Cillin K, Veetids)

Penicillin VK is preferred to penicillin G because of increased resistance to gastric acid. Treatment must continue for 10 full days. The probability of relapse of a GAS infection after therapy is 50% if penicillin is discontinued after 3 days of therapy.

Amoxicillin (Amoxil, Biomox, Trimox)

Amoxicillin has better absorption than penicillin VK and administration is every 8 hours instead of every 6 hours. For minor infections, some authorities advocate administration every 12 hours. This is probably the most active of penicillins for non–penicillin-susceptible S pneumoniae.

Ampicillin and sulbactam (Unasyn)

This is a drug combination of a beta-lactamase inhibitor with ampicillin. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. It is an alternative to amoxicillin when the patient is unable to take medication orally. It covers skin, enteric flora, and anaerobes, but is not ideal for nosocomial pathogens.

Clindamycin (Cleocin, Cleocin Pediatric, ClindaMax Vaginal)

Clindamycin is a semisynthetic antibiotic produced by 7(S)-chloro-substitution of 7(R)-hydroxyl group of the parent compound lincomycin. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Clindamycin widely distributes in the body without penetration of the CNS. It is protein bound and excreted by the liver and kidneys.

Clindamycin is available in parenteral form (ie, clindamycin phosphate) and oral form (ie, clindamycin hydrochloride). Oral clindamycin is absorbed rapidly and almost completely and is not appreciably altered by the presence of food in the stomach. Appropriate serum levels are reached and sustained for at least 6 hour following an oral dose. No significant levels are attained in cerebrospinal fluid. It is also effective against aerobic and anaerobic streptococci (except enterococci).

Moxifloxacin (Avelox)

Moxifloxacin inhibits the A subunits of DNA gyrase, resulting in the inhibition of bacterial DNA replication and transcription. It is indicated for community-acquired pneumonia, including multidrug-resistant S pneumoniae.

Amoxicillin and clavulanate (Augmentin, Augmentin XR)

This combination inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. The addition of clavulanate inhibits beta-lactamase producing bacteria. It is a good alternative antibiotic for patients allergic to or intolerant of the macrolide class. It is usually well tolerated and provides good coverage of most infectious agents. It is not effective against Mycoplasma and Legionella species. The half-life of an oral dosage form is 1-1.3 hours. It has good tissue penetration but does not enter cerebrospinal fluid.

For children older than 3 months, base dosing on the amoxicillin content. Because of the different amoxicillin/clavulanic acid ratios in the 250-mg tablet (250/125) versus the 250-mg chewable tablet (250/62.5), do not use the 250-mg tablet until child weighs more than 40 kg.

Cefoxitin (Mefoxin)

Cefoxitin is a second-generation cephalosporin with activity against some gram-positive cocci, gram-negative rod infections, and anaerobic bacteria. It inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins; it inhibits the final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death. Infections caused by cephalosporin- or penicillin-resistant gram-negative bacteria may respond to cefoxitin.

Ceftriaxone (Rocephin)

Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. The bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin-binding proteins. It exerts its antimicrobial effect by interfering with the synthesis of peptidoglycan, a major structural component of the bacterial cell wall. Bacteria eventually lyse because of the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested.

Ceftriaxone is highly stable in the presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria. Approximately 33-67% of the dose is excreted unchanged in urine, and the remainder is secreted in bile and ultimately in feces as microbiologically inactive compounds. It reversibly binds to human plasma proteins, and binding has been reported to decrease from 95% bound at plasma concentrations less than 25 mcg/mL to 85% bound at 300 mcg/mL.

Cefepime (Maxipime)

Cefepime is a fourth-generation cephalosporin. Its gram-negative coverage is comparable to ceftazidime but it has better gram-positive coverage (comparable to ceftriaxone). Cefepime is a zwitter ion; it rapidly penetrates gram-negative cells. It is the best beta-lactam for intramuscular administration. Its poor capacity to cross the blood-brain barrier precludes its use for the treatment of meningitis. It may be more active than ceftazidime against Enterobacter species because of enhanced stability against beta-lactamases.

Cefuroxime (Ceftin, Kefurox, Zinacef)

Cefuroxime is a second-generation cephalosporin that maintains gram-positive activity of the first-generation cephalosporins; adds activity against Proteus mirabilis, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Moraxella catarrhalis. Cefuroxime binds to penicillin-binding proteins and inhibits the final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death. The condition of the patient, the severity of the infection, and the susceptibility of the microorganism determine the proper dose and route of administration. It resists degradation by beta-lactamase.

Cefaclor (Ceclor)

Cefaclor is a second-generation cephalosporin that binds to one or more of the penicillin-binding proteins, which, in turn, inhibits cell wall synthesis and results in bactericidal activity. It has gram-positive activity that first-generation cephalosporins have and adds activity against P mirabilis, H influenzae, E coli, K pneumoniae, and M catarrhalis. It is indicated for infections caused by susceptible mixed aerobic-anaerobic microorganisms. Determine the proper dosage and route based on the condition of the patient, the severity of the infection, and the susceptibility of the causative organism.

Piperacillin and tazobactam sodium (Zosyn)

Nosocomial pneumonia caused by P aeruginosa should be treated in combination with an aminoglycoside. This is an antipseudomonal penicillin plus beta-lactamase inhibitor. It inhibits the biosynthesis of the cell wall mucopeptide and is effective during the stage of active multiplication.

Cefprozil (Cefzil)

Cefprozil is a second-generation cephalosporin that binds to one or more of the penicillin-binding proteins, which, in turn, inhibits cell wall synthesis and results in bactericidal activity. It has gram-positive activity that first-generation cephalosporins have and adds activity against P mirabilis, H influenzae, E coli, K pneumoniae, and M catarrhalis. Determine the proper dosage and route based on the condition of the patient, the severity of the infection, and the susceptibility of the causative organism.

Levofloxacin (Levaquin)

Levofloxacin is rapidly becoming a popular choice in pneumonia. It is good monotherapy for pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

Ertapenem (Invanz)

The bactericidal activity results from the inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin-binding proteins. It is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, cephalosporinases, and extended-spectrum beta-lactamases. It is hydrolyzed by metallo-beta-lactamases. Ertapenem is indicated for community-acquired pneumonia due to S pneumoniae (penicillin-susceptible isolates only), including cases with concurrent bacteremia, H influenzae (beta-lactamase–negative isolates only, or M catarrhalis).

Clarithromycin (Biaxin)

Clarithromycin is a semisynthetic macrolide antibiotic that reversibly binds to the P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.

Imipenem and cilastatin (Primaxin)

This combination is an extremely potent broad-spectrum beta-lactam antibiotic. It is rapidly hydrolyzed by the enzyme dehydropeptidase I located on the brush border of renal tubular cells, hence its combination with cilastatin (a reversible inhibitor of dehydropeptidase I). It is used for the treatment of multiple-organism infections in which other agents do not have wide-spectrum coverage or are contraindicated because of a potential for toxicity.

Meropenem (Merrem IV)

Meropenem is a carbapenem, not a beta-lactam antibiotic. It is a bactericidal broad-spectrum carbapenem antibiotic that inhibits cell wall synthesis. It is effective against most gram-positive and gram-negative bacteria. It has slightly increased activity against gram-negative bacteria and slightly decreased activity against staphylococci and streptococci compared with imipenem.

Azithromycin (Zithromax)

Meropenem acts by binding to the 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis not affected. It concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest concentration in phagocytes may contribute to drug distribution to inflamed tissues. It treats mild-to-moderate microbial infections. Plasma concentrations are very low, but tissue concentrations are much higher, giving it value in treating intracellular organisms. Meropenem has a long tissue half-life. Newer macrolides offer decreased GI upset and the potential for improved compliance through reduced dosing frequency. They also afford more improved action against H influenzae compared with erythromycin.

Vancomycin (Lyphocin, Vancocin, Vancoled)

Vancomycin is classified as a glycopeptide agent that has excellent gram-positive coverage, including methicillin-resistant S aureus. To avoid toxicity, the current recommendation is to assay vancomycin trough levels after a third dose drawn 0.5 hours prior to the next dosing. Use creatinine clearance to adjust the dose in patients diagnosed with renal impairment.

Linezolid (Zyvox)

Linezolid prevents the formation of functional 70S initiation complex, which is essential for the bacterial translation process. It is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. It is used as an alternative in patients allergic to vancomycin and for the treatment of vancomycin-resistant enterococci.

Metronidazole (Flagyl, Protostat)

Metronidazole is an imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. It is used in combination with other antimicrobial agents (except for C difficile enterocolitis). It is not standard practice to use metronidazole alone because some anaerobic cocci and most microaerophilic streptococci are resistant. Use it in combination with a beta-lactam in the treatment of anaerobic pneumonia and complicated pleuropulmonary infections.

Fibrinolytic agents

Class Summary

Fibrinolytic agents are indicated for the restoration of circulation through previously occluded vessels by dissolution of intraluminal thrombus or embolus not dissolved by the endogenous fibrinolytic system. In pleuropulmonary infections, fibrinolytic activity and dissolution of fibrin strands increases drainage of pleural fluid, which, in turn, may facilitate resolution of the infection. Important to note is that streptokinase and urokinase are no longer available in the United States.

Alteplase (Activase)

Alteplase is a tissue plasminogen activator that exerts effect on the fibrinolytic system to convert plasminogen to plasmin. Plasmin degrades fibrin, fibrinogen, and procoagulant factors V and VIII. Its serum half-life is 4-6 minutes but its half-life is lengthened when bound to fibrin in a clot. It is used in the management of acute myocardial infarction, acute ischemic stroke, and pulmonary embolism. Heparin and aspirin are not given for 24 hours after a tissue plasminogen activator. It must be given within 3 hours of stroke onset. Exclude hemorrhage by CT scan. If hypertensive, lower blood pressure with labetalol, 10 mg intravenously. The safety and efficacy of concomitant administration with aspirin and heparin during the first 24 hours after the onset of symptoms have not been investigated.

Mucolytic Agents

Class Summary

Large amounts of neutrophil-derived DNA released from dead neutrophils increase sputum viscosity. Mucolytics, such as dornase alfa, an enzyme that hydrolyses the DNA, are used to improve airway clearance.

Dornase alfa (Pulmozyme)

Dornase alfa is a recombinant human DNase (rhDNase) that cleaves and depolymerizes extracellular DNA and separates DNA from proteins. This allows endogenous proteolytic enzymes to break down the proteins, thus decreasing viscoelasticity and surface tension of purulent sputum

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