Download The insertion of a chest tube should also be considered if there is

Pleural Effusion in Children
Review Article
Keywords: children; pleural; effusion
ABSTRACT
Respiratory diseases including pleural effusions are a very common source of morbidity and
mortality among children. The management of pleural effusion in children has been a topic of
dispute between physicians and surgeons. This manuscript details up-to-date review of pleural
effusion in children including medical modalities as well as surgical. A search of the pub-med
database was carried out, using a combination of the following terms: pleural, effusion, and
children. Different book chapters related to the topic were also reviewed.
Keywords: lung; infection; pleura; children
METHODS
A search of the PubMed database was carried out, using different combinations of the following
terms: pleural, effusion, and children; alteplase, streptokinase, pleural and effusion; urokinase,
streptokinase, pleural, and effusion; urokinase, alteplase, pleural , and effusion; Video ,Assisted,
Thoracoscopic, Surgery, firbinolytics, pleural and effusion. The initial search was conducted for
manuscripts published between 2009 and 2014; however, the results were not adequate and we
extended our search back to the year 1976. The primary search was designed to capture studies
pertaining to our topic. Supplemental searches were also conducted. In addition, the searches
were limited to studies on humans and published in English, and focused on children. After
retrieval, each paper was read to verify relevance and appropriateness for review, based
primarily on study design and ascertainment of necessary variables. We included randomized
controlled trials (RCTs) and retrospective studies with adequate sample size; review articles were
included as well. We excluded 11 articles because they did not fit our inclusion criteria. The
search and selection of articles was conducted by Dr Hendaus, while Dr Janahi, an expert in the
topic, approved the references. Meta-analysis was not conducted due to the limited published
articles. For instance, part of our manuscript compares the efficacy among fibrinolytics, and the
efficacy of Video Assisted Thoracoscopic Surgery compared to the use of fibrinolytics in the
outcome of children with pleural effusion. Not too many articles touched on the comparisons
mentioned above; hence Meta analysis was not practical. Therefore we opted for literature
review.
INTRODUCTION
1
Respiratory diseases are a very common source of morbidity and mortality among children
[1].The mean age of children with pleural effusion and empyema is 3-6 years with 50-80%
affecting males [2].
The development of empyema consists of three stages: Stage 1, also described as the early
exudative phase, constitutes the collection of thin reactive fluid and few cells in the pleural
space; stage 2, is described as the fibro-purulent phase, involves the formation of loculations; and
Stage 3 is the organizing phase and it involves the creation of a thick layer of fibrin that encloses
the lung [3].
The management of pleural effusion in children has been a topic of dispute between physicians
and surgeons. Many treatment modalities have been suggested and applied, including
intravenous antibiotics with or without thoracocentesis, chest drain insertion, intra-pleural
fibrinolytics, and video-assisted thoracoscopic surgery (VATS). The different modes of
management could be attributed to the variability in presentation of the disease [4].
Some authors believe that in the early stages of the disease, antibiotics and chest tube drainage
should suffice [5] , but could be associated with high failure rate and prolonged hospital stay
[4].However, advanced stages require decortication to allow lung re-expansion [6].
MICROBIOLOGY
The probability to identify an organism in the pleural fluid specimens is low [7]. The British
Thoracic Society recommends that Gram stain, AFB stain, and microbiologic culture be obtained
on all pleural fluid samples [8]. In addition, nucleic acid amplification through polymerase chain
2
reaction (PCR) and antigen testing are indispensable tools in the detection of microorganisms
and hence in the management of pleural effusion. It is recommended to obtain a pleural fluid
white blood cell (WBC) count, with cell differential analysis to differentiate between bacterial,
mycobacterial and malignancy etiologies [9].
Although different organisms can cause empyema S. pneumoniae is considered to be the most
common cause [10]. Other causes are methicillin-sensitive Staphylococcus aureus (MSSA) [1112], and methicillin-resistant S. aureus (MRSA) [13].
Moreover, S. pyogenes, Haemophilus influenzae, Mycoplasma pneumoniae, Pseudomonas
aureginosa, other Streptococcus spp and Mycobacterium tuberculosis have been reported [8].
IMAGING
Chest Radiograph
Chest radiography is usually the first imaging modality in the work up of parapneumonic
effusion, but it cannot confirm the diagnosis. Chest radiograph might show early signs of
parapnemonic effusion like obliteration of the costophrenic angle and a meniscus shape area up
the lateral chest wall [14].
Ultrasonography
3
Ultrasonography is a safe mode of imaging and can be used to confirm the presence of pleural
effusion [15]. A lenticular shape might imply the presence of a loculation when using the mode
of ultrasonography [14].
Computed Tomography (CT)
If the diagnosis of pleural effusion is not clear after performing a chest radiograph or a chest
ultrasound, then chest CT will be the next step. For complicated cases of pleural effusion, it is
also warranted because it can detect lung pathology and pulmonary abscess [16]. When ordering
a Chest CT, intravenous contrast should be added to enhance pleural vision [15].
However, the disadvantages of a chest CT are the exposure of a patient to relatively high
radiation [15], and the inability to visualize thin pleural septation or fibrin [17].
DIAGNOSTIC TAP
If the health care provider suspects that the effusion is not of infectious etiology, then it will be
recommended to perform a diagnostic tap for cytological analysis before chest drain insertion. In
this case, you might be avoiding chest drain insertion and the complications associated with
anaesthesia or sedation [8].
BIOCHEMISTRY/MICROSCOPY
Fluid from bacterial infections, and sometimes tuberculosis, are predominantly neutrophils. On
the other hand, lymphocytosis is detected in autoimmune diseases, tuberculosis, chylothorax and
malignancy. If the fluid appears turbid, it is usually due to high cell count or high lipid content
[18].
4
Serous fluids are categorized into transudates and exudates. Transudative effusion usually refers
to a non-inflammatory process (alteration of hydrostatic or colloid osmotic pressure), where it
infers from ultrafiltration process across a membrane. It is usually low in protein [19].
On the other hand, exudates refer to an inflammation or inflammatory process, where it infers
capillary permeability [19].A pleural fluid:serum protein ratio greater than 0.5, a pleural fluid
LDH activity above 200U/L or a pleural fuid:serum LDH ratio greater than 0.6 is usually
diagnostic of exudative effusion [19].
However, other authors state that pleural fluid parameters, such as glucose, protein, lactate
dehydrogenase levels and pH are not recommended since they don’t change the management of
pleural effusion [9].
MANAGEMENT
Prevention
The preferred treatment of pleural effusion is prevention via proper immunization [18].
Antibiotics Use
Many practitioners use the option of antibiotics alone when managing a small pleural effusion in
patients with no respiratory distress. Although it is an acceptable option, further intervention
must be followed if the effusion is enlarging or patient is deteriorating [8, 20].
The initial treatment of all pleural effusion should be the use of antibiotics. For children with
small effusions (less than 10 mm on lateral decubitus chest radiograph or opacification of less
than one-fourth of the hemithorax), the choice of broad spectrum antibiotics, chest radiographs
and good clinical exam should suffice on an outpatient basis [9].
5
Children with larger pleural effusion should be hospitalized and the use of intravenous
antibiotics is warranted [8].
Intravenous cefotaxime or ceftriaxone could be used as empiric treatment until cultures results
are known. Clindamycin or vancomycin could be added for community acquired methicillin
resistant (CA-MRSA) is suspected [9].
The current practice of first line empiric treatment of antibiotics is cefotaxime plus vancomycin
because of the increased prevalence of drug resistant organisms [21].
The practitioner should be, however, aware of the most common causes of community acquired
pneumonia in the area as a guidance towards the initial empiric treatment. For instance,
ampicillin or penicillin G might also be considered as first-line drugs in fully immunized
children in areas where local penicillin resistance in invasive strains of pneumococcus is
uncommon [9].
For penicillin allergic patients, clindamycin should be used. Meropenem is an alternative if no
improvement [22].
Different patients’ populations should be kept in mind. In children whom you suspect aspiration,
coverage of anaerobes should be initiated. Coverage of gram-negative organisms in children with
parapneumonic effusion due to nosocomial infection is also indicated [21].
As far as Mycobacterium tuberculosis, treatment is warranted only if the index of suspicion is
high [8].
After initiating antibiotics empiric management, follow the culture results. If the culture is
positive, then narrow the coverage according to the organism identified [22].
6
Unfortunately, there are high proportions of cultures that come back negative, so the
recommendation is to continue the initial blind antibiotic treatment, especially if the patient is
clinically improving. The duration of treatment differs among practitioners, but the majority of
medical centers continue the intravenous antibiotics until the patient is afebrile or when the chest
tube is removed. Usually amoxicillin-clavulanic acid is given at discharge for 1-4 weeks, but
definitely longer if needed [8].
Thoracocentesis and Chest Tube
There was a debate whether thoracocentesis will suffice in terms of managing pleural effusion or
whether going straight to chest tube insertion is the preferred option. In small effusions,
thoracocentesis would be helpful in fluid aspiration and hence guidance towards the appropriate
antibiotic use. Simple needle thoracocentesis is an option for older children, but if repeated
thoracocentesis is required, then chest tube will be the better choice [8].
Small tubes (8-12 French) are reported as good as larger tubes [18].The indications for chest tube
drainage as recommended by the Pediatric Infectious Diseases Society and the Infectious
Diseases Society of America [9] are as follow:

There is no indication for chest tube insertion in pleural effusion less than 10 mm on a
lateral decubitus radiograph or if the opacification constitutes less than one-fourth of the
hemithorax.

There is no indication for chest tube insertion in pleural effusion if there is more than 10
mm of fluids but the opacification constitutes less than half of the hemithorax, the
effusion is not consistent with empyema and if the patient is not in respiratory distress.
7

Chest tube is definitely indicated in opacities larger than half of the hemithorax and with
quantity of fluids of more than 10 mm in children with respiratory distress and fluid
consistent with empyema.
However, in a study conducted by Shoseyov et al, stated that there is no difference between
repeated ultrasound-guided needle thoracocentesis (RUSGT) and Chest tube insertion in terms of
mean duration of temperature, mean fluid drained, duration of antibiotic use and duration of
hospitalization stay [23].
The insertion of a chest tube should also be considered if there is failure to respond to 48 to 72
hours of antibiotic therapy, hypoxia, hepercapnia, large amounts of free flowing pleural fluid
and if there is evidence of fibropurulent effusions (pH <7.0, glucose <40 mg/dL [2.22 mmol/L],
LDH >1000 IU [16.67 kat/L] [21].
Fribrinolytics
The use of intrapleural fibrinolytics is being used with success worldwide for the management of
complicated pleural effusions and empyema. Its use improves drainage without systemic
fibrinolysis or hemorrhage. The worldwide success has been reported between 44% and 100%
[24].
8
The British Thoracic Society (BTS) and the American Pediatric Surgical Association suggest
fibrinolytic therapy as a component of the medical option for patients in whom the pleural fluid
is thick or loculated [8, 25].
The three fibrinolytics that have been in use are streptokinase, urokinase, and tissue plasminogen
activator (tPA) [26].
Urokinase(UK)
UK is a fibrinolytic agent that specifically catalyzes the cleavage of the arginine–valine bond in
plasminogen [27].
BTS [8] and PIDS [9] (Pediatric Infectious disease society) recommend the usage of urokinase
as follows: 40,000 units in 40 mL 0.9 percent saline for children one year and older, and 10,000
units in 10 mL 0.9 percent saline for children younger than 1 year. This dose should be
administered twice daily (with a four-hour dwell time) for three days; if the response is not
adequate, then additional doses can be administered after six doses. Intrapleural bupivacaine (0.5
to 1.0 mL/kg of a 0.25 percent solution) can be used for pain control.
A multicentre randomized placebo controlled trial in children [28], showed that the length of
hospital stay was shorter with the use of UK compared to patients where normal saline was
administered. Stefanutti et al [29] also supported the use of UK and their study showed that
9
intrapleural urokinase has been shown to be effective in the treatment of pleural effusions in
children.
Streptokinase
Streptokinase has same mechanism of action like UK; however, it is of bacterial origin rather
than a recombinant human enzyme [29].The recommended dose is 12,300 to 136,000 U/kg per
dose diluted to 50 ml volume with sterile saline solution into the intrapleural space via chest tube
over 5 minutes [30].
In a study published by Yao et al showed that intrapleural fibrinolytic treatment with
streptokinase is safe and effective and it can avert the need for surgery in most cases. Safety was
reported as no major side effects after streptokinase instillation while efficacy was measured by
Pleural fluid drainage which was almost four times higher in the streptokinase group compared
to the control group [31]. Since streptokinase is of bacterial origin, possible side effects are fever,
allergic reactions, and anti-streptokinase antibody production [30, 32-33].
Tissue plasminogen activator (tPA)
TPA binds to fibrin in a thrombus then converts the entrapped plasminogen to plasmin, and
finally initiates local fibrinolysis. Alteplase's serum half-life is 4-6 minutes, but can be prolonged
when alteplase is bound to fibrin in a clot. The instillation of intrapleural tPA usually does not
lead to plasma pharmacologic concentrations [34].
10
The recommended dose of intrapleural tPA is 4 mg in 40 mL of normal saline. The first dose is
given at the time of chest tube placement with 1 hour dwell time; the dose can be repeated once
daily for 3 days (total of 3 doses) [21].
A study conducted at the Hospital for Sick Children in Toronto, Canada showed that intrapleural
tPA led to a higher pleural fluid drainage compared to normal saline (691 mL vs 360 mL). The
duration of chest tube placement was 84 hours for the early administration of intrapleural tPA
group compared to 130 hours for the control group. The authors did not report local or systemic
bleeding after intra-pleural tPA administration [35].
So which fibrinolytic to use?
The efficacy of fibrinolytics use might reach 90% [36-37].Urokinase and streptokinase has the
same effectiveness in treating complicated pleural effusions and empyemas [24]. Although it has
a higher cost, urokinase is preferred over streptokinase due to its lower allergenic risk [29].
Urokinase and alpteplase were compared in a retrospective review study that included 71
children with pleural fluid effusion.The study concluded that Primary treatment success was 98%
for alteplase and 100% for urokinase, with no major complications. However, pleural fluid
drainage was higher with alteplase than urokinase during the 1st and 2nd days of fibrinolytic
therapy, and for the duration of thoracostomy drainage [38].
In the literature review, there were no randomized studies comparing the effectiveness of
streptokinase and alteplase in managing complicated pleural effusion.
11
VATS (Video-assisted thoracic surgery)
Quite a few pediatric surgeons consider primary surgical intervention as the best mode of
managing pleural effusion [39].However, there is so far not enough data to support their
approach [3].
It is warranted to consult surgeons if there is failure of chest tube drainage, antibiotics and
fibrinolytics. Surgical approach is also needed if the patient has persisting sepsis in combination
with a persistent pleural effusion after the use of antibiotics and chest tube drainage. In addition,
surgery is required in cases of empyema with significant lung pathology, bronchopleural fistula
with pyopneumothorax, and secondary empyema [8].
VATS is usually indicated for drainage of purulent material, decortications of the fibropurulent
septa, irrigation of the pleural cavity and visualization of the evacuation to allow re-expansion of
the lung [40].
Fibrinolytics vs. VATS
A study done by Kilic et al [36] suggests that intrapleural fibrinolytic treatment is an effective
and safe in children with thoracic empyema and can obviate a thoracotomy in most cases.
In a second study, in which 60 children were randomized to receive either percutaneous chest
drain with intrapleural urokinase or video-assisted thoracoscopic surgery (VATS);the authors
concluded that urokinase treatment is the better economic ,while no difference in clinical
outcome between the 2 groups was noted [41].In addition St. Peter el al [42] showed that the
12
outcome data showed no difference in days of hospitalization after intervention, days of oxygen
requirement, days until afebrile, or analgesic requirements.
Faber et al [43] echoed the non-operative approach as effective. The study evaluated 75 pediatric
empyema cases and it showed that non-operated children were admitted to the PICU less
frequently than those who were operated and there was no significant statistical difference in
overall hospitalization.
On the other hand, Cohen et al [39] conducted a systematic review that showed the superiority of
primary operative therapy compared with non-operative approaches. Operative management was
associated with a lower mortality rate, lower re-intervention rate, shorter length of
hospitalization, decreased time with a thoracostomy tube, and shorter course of antibiotic
therapy, compared with non-operative therapy. A Cochrane Systematic Review on surgical
versus non-surgical management of pleural empyema conducted by Coote et al[44] was also in
favor of the operative approach showing that surgical group had higher primary treatment
success. In addition, the study showed that all streptokinase medical failures required VATS and
surgical patients had shorter hospital stay.
In a large study, Shah et al included 3500 patients with pleural effusion that underwent different
procedures: chest tube without fibrinolysis (n = 1762), chest tube with fibrinolysis (n = 623),
VATS (n = 408), and thoracotomy (n = 797). The study concluded that length of stay was similar
in patients that underwent VATS and chest tube insertion with or without fibrinolysis [45].
13
Outcome and Prognosis
Children with pleural effusion usually do well and their lung functions return to normal in the
majority of children regardless of the management mode of pleural effusion [46], though some
studies showed minor asymptomatic restrictive [47] or obstructive[46] abnormalities.
Follow Up
Children with pleural effusion should be seen for follow up within 4–6 weeks of discharge; the
timing depends on the child’s clinical status at discharge [8].Chest radiography findings are
abnormal at discharge, and a radiograph should be obtained at 4-6 weeks [8] .Complete
radiological resolution is usually expected by 3-6 months [5,24].
Summary and Recommendations
A conscientious path must be followed when managing a case of pleural effusion in children.
The severity of the case and the progress of the disease usually dictate the approach.
Antibiotics Use
All infants and children with pleural effusion should be initiated on broad-spectrum antibiotics.
If the organism is known, then narrowing the antibiotic spectrum is recommended. If the patient
is hospitalized, then Intravenous antibiotics should be continued until the child is afebrile.
Oral antibiotics such as amoxicillin-clavulanic acid are then given at discharge for 1–4 weeks,
but longer if there is residual disease.
For atypical cases such as non-bacterial pleural effusion or suspected tuberculosis, a consultation
with the specialist will be warranted.
Imaging
A plain chest film should be the initial imaging test. A lateral/decubitus view might help in the
diagnosis.
Chest ultrasound will confirm the pleural fluid and might show loculations .
Chest CT should be reserved for the complicated or doubtful cases to avoid unnecessary
radiation exposure.
14
Chest Tube
Chest tube is definitely indicated in opacities larger than half of the hemithorax and with quantity
of fluids of more than 10 mm in children with respiratory distress and fluid consistent with
empyema.
Fibrinolytics
Intrapleural administration of fibrinolytics is an effective treatment for complicated
parapneumonic effusions and pleural empyemas (pleural effusion is thick or loculated).
Any of the three of fibrinolytics can be used (urokinase, streptokinase and alteplase); however,
urokinase is the most studied among the three options and is probably the preferred agent if
available.
VATS
Patients should be considered for surgical treatment if they have persisting sepsis in association
with a persistent pleural collection, despite chest tube drainage, fibrinolytics and antibiotics use.
Follow up
Children with pleural effusion or empyema should be seen for follow up within 4–6 weeks of
discharge. Chest radiographs are usually abnormal at discharge, and a radiograph should be
obtained after 4-6 weeks.
LIMITATIONS
Our manuscript portrays a comprehensive review of pleural effusion in children, especially the
management options. However, our limitation was the inability to conduct a Meta-analysis; this
is mostly attributed to the lack of published articles comparing different modes of management
of pleural effusion in children.
15
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Table 1. Fibrinolytics used and their recommended doses
Urokinase(UK)
Streptokinase
Tissue plasminogen
activator (tPA)
*40,000 units in 40 mL 0.9
percent saline for children
one year and older.
12,300 to 136,000 U/kg per
dose diluted to 50 ml
volume with sterile saline
solution
The recommended dose of
intrapleural tPA is 4 mg in
40 mL of normal saline. The
first dose is given at the
time of chest tube
placement with 1 hour
dwell time; the dose can be
repeated once daily for 3
days (total of 3 doses)
*10,000 units in 10 mL 0.9
percent saline for children
younger than 1 year.
*It should be administered
twice daily (with a fourhour dwell time) for three
days; if the response is not
adequate, then additional
doses can be administered
after six doses.
20