[ Original Research Disorders of the Pleura ]

Lytic Therapy for Retained Traumatic

Hemothorax
A Systematic Review and Meta-analysis
Brandon S. Hendriksen, MD, MPH; Marcos T. Kuroki, MD, PhD; Scott B. Armen, MD; Michael F. Reed, MD;
Matthew D. Taylor, MD; and Christopher S. Hollenbeak, PhD

BACKGROUND: Intrapleural lytic therapy has been established as an important modality

of treatment for many pleural disorders, including hemothorax and empyema. Retained
traumatic hemothorax is a common and understudied subset of pleural disease. The current
standard of care for retained traumatic hemothorax is operative management. The use of lytic
therapy for avoidance of operative intervention in the trauma population has not been well
established.
METHODS: Randomized controlled trials (RCTs) and non-RCTs reporting operative inter-
vention following the use of intrapleural lytic treatment for retained traumatic hemothorax
were identified in the literature. The primary outcome was avoidance of surgery following
treatment with any lytic agent. Meta-analysis was performed to pool the results of those
studies. Subgroup analysis by type of lytic therapy and analysis of length of stay were also
performed.
RESULTS: One RCT and nine non-RCTs including 162 patients were pooled in the analysis.
Avoidance of surgery following treatment with any lytic agent was found to be 87% (95% CI,
81%-92%). Tissue plasminogen activator resulted in 83% operative avoidance (95% CI,
71%-94%), and other, non-tissue plasminogen activator lytic agents resulted in 87% operative
avoidance (95% CI, 82%-93%). The average length of stay for patients undergoing lytic
therapy was 14.88 days (95% CI, 12.88-16.88).
CONCLUSIONS: Lytic therapy could reduce the need for operative intervention in trauma
patients with retained traumatic hemothorax. RCTs are indicated to definitively evaluate the
benefit of this approach. CHEST 2019; 155(4):805-815

KEY WORDS: intrapleural; lytic therapy; retained hemothorax; tissue plasminogen activator;
trauma

ABBREVIATIONS: LOS = length of stay; RCT = randomized controlled
trial; TPA = tissue plasminogen activator; VATS = video-assisted
thoracoscopic surgery
AFFILIATIONS: From the Department of Surgery (Drs Hendriksen,
Kuroki, Armen, Reed, Taylor, and Hollenbeak), Pennsylvania State
University College of Medicine, Hershey, PA; Department of Health
Policy and Administration (Dr Hollenbeak), College of Health and
Human Development, Pennsylvania State University, University Park,
PA; and the Department of Public Health Sciences (Dr Hollenbeak),
Pennsylvania State University College of Medicine, Hershey, PA.
FUNDING/SUPPORT: The authors have reported to CHEST that no
funding was received for this study.
CORRESPONDENCE TO: Brandon S. Hendriksen, MD, MPH, Penn-
sylvania State University College of Medicine, Department of Surgery,
500 University Dr, P.O. Box 850, Hershey, PA 17033; e-mail:
bhendriksen@pennstatehealth.psu.edu
Copyright Ó 2019 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: https://doi.org/10.1016/j.chest.2019.01.007

chestjournal.org 805
Hemothorax is a distinct form of pleural effusion with
multiple etiologies, most commonly caused by trauma.
Both blunt and penetrating thoracic trauma are
associated with hemothorax. Notably, 60% of
multitrauma patients have thoracic trauma, suggesting
that patients with traumatic hemothorax often have
other injuries requiring careful assessment and
treatment.1 The first-line treatment of hemothorax is
drainage. This can often be performed through the
successful placement of a thoracostomy tube.2 However,
undrained or retained hemothorax occurs in 10% to
35% of cases.3-5 This produces problematic morbidity as
27% to 33% of those patients will go on to develop
empyema.6,7 The Eastern Association for the Surgery of
Trauma practice management guidelines for retained
hemothorax are as follows: Level 1 evidence suggests
early video-assisted thoracoscopic surgery (VATS) is the
first-line treatment for patients with retained
hemothorax. Level 3 evidence suggests that intrapleural
thrombolytic therapy may be considered in subacute
collections in patients with significant surgical risk
factors.8
The Eastern Association for the Surgery of Trauma
guidelines suggest that there may not yet be enough
Methods
Literature Source and Screening
A systematic review was performed by searching MEDLINE, Web of
Science, and Cochrane Database of Systematic Reviews for all
randomized controlled trials (RCTs) and non-RCTs published
between January 1, 1950 and November 1, 2017 reporting the use of
intrapleural lytic therapy and resultant operative intervention
following identification of retained traumatic hemothorax. All
languages were included in the review. An identical set of key words
was used in each title and abstract search: “Trauma OR Traumatic”
AND “Lytic OR Fibrinolytic OR Fibrinolysis OR TPA OR Tissue
Plasminogen Activator OR Urokinase OR Streptokinase” AND
“Hemothorax OR Pleural Effusion OR Empyema OR
Parapneumonic Effusion.” Relevant articles identified in references
were included. PROSPERO (the International Prospective Register of
Systematic Reviews) was used to search for unpublished systematic
reviews. The Cochrane Central Register of Controlled Trials was
used to search for unpublished RCTs. All available abstracts
published online that were presented at annual meetings for the
American Association for the Surgery of Trauma (2003-2017), the
Eastern Association for the Surgery of Trauma (2010-2018), and
the Western Trauma Association (2010-2018) were searched.
Definitions
Retained traumatic hemothorax was defined as radiographic evidence
of remaining, noninfected, undrained fluid following treatment of
traumatic hemothorax with tube thoracostomy. Avoidance of
operative intervention was defined as no further surgical treatment
following initial tube thoracostomy for the treatment of retained
traumatic hemothorax through the time of patient discharge.
806 Original Research
evidence for lytic therapy to have a significant role
in traumatic, undrained hemothorax. However, a
number of studies have demonstrated varied results with
the use of intrapleural lytic therapy for nontraumatic
etiologies of effusion. Specifically, Rahman and
colleagues,9 in MIST 2 (the second Multicenter
Intrapleural Sepsis Trial), found that in patients with
pleural infection a combination of tissue plasminogen
activator (TPA) and DNase lytic therapy resulted in
fewer surgical procedures and shorter lengths of stay. A
review of the literature shows a dearth of information
regarding lytic therapy in trauma patients with retained
hemothorax. Most of the studies that have been
performed combine multiple etiologies, which results in
low sample sizes of hemothorax caused by trauma. In an
analysis solely of trauma patients, Hunt and colleagues10
summarized the current literature and concluded that
there should be a role for fibrinolytic therapy due to
perceived clinical improvements following treatment.
Quantitative evaluation of those perceived
improvements has not yet been performed. The aim of
this study was to perform a systematic review and meta-
analysis in order to quantify the avoidance of operative
intervention following lytic treatment for retained
traumatic hemothorax.
Determination for operative management following the use of lytic
therapy was based on the degree of resolution of the retained
hemothorax. Resolution was defined by decreasing fluid collection on
radiographic imaging. The degree of resolution necessary to avoid
surgery was based on clinical judgment and defined differently
across the studies. Evaluation criteria used to evaluate intrapleural
lytic treatment, along with other study characteristics, are shown in
Table 1.3-5,11-17
Inclusion Criteria
Specific inclusion criteria included: (1) identification of patients with
traumatic hemothorax initially treated with tube thoracostomy, (2)
treatment with lytic therapy, (3) reported rate of surgical
intervention following treatment with lytic therapy, and (4) reported
total hospital length of stay from admission to discharge for patients
undergoing lytic therapy.
Exclusion Criteria
Single case studies, animal studies, and basic science reports were
removed. Studies that did not specify the type of hemothorax as
traumatic were excluded. It should be noted that some studies
that included multiple types of effusions were included, but
only the traumatic hemothoraces were analyzed. Postoperative
hemothorax was excluded. Infected hemothorax and empyema
were excluded. Studies without reported operative intervention
rates following lytic therapy were excluded for the purpose of
analysis. Studies reporting average length of stay without a
standard deviation were not included in the subgroup analysis
of length of stay.
[ 155#4 CHEST APRIL 2019 ]
 ] Summary of Studies Included in Meta-analysis
chestjournal.org

TABLE 1

Patients
With Patients
Retained With No
Total Traumatic Criteria for Operative Operative
Quality Patients Hemothorax Lytic Lytic Treatment Evaluation of Lytic Intervention Avoidance
Study/Year Design Scorea Treatment (No.) (No.) Doseb Strategy Treatment (No.) (%) LOS (d)
Barthwal Retrospective 5 STK 200 12 250k Lytic administered > 500 mL 11 91.7 NA
et al11/2016 IU every 8 h
3 for cumulative
a single chest tube
treatment cycle. drainage with
Cycle repeated radiographic
every 48 h if > improvement
100 mL chest
tube drainage
with minimal to
moderate
radiologic
improvement
UK 100k
IU
Kumar et al4 RCT RCT STK 146 17 150k Lytic administered Disappearance 12 70.6 12
/2015 IU twice daily for 3 d of CXR
opacification
after 24 h of
therapy
Stiles et al14/ Retrospective 5 TPA 7 7 24 mgc Up to 5 lytic Not defined 6 85.7 13.6
2014 administrations
Caylor et al15/ Retrospective 5 TPA 24 24 10 mg Lytic administered Not defined 20 83.3 NA
2014 once
daily for 3 d
Kimbrell et al3/ Prospective 6 STK 203 25 250k Lytic administered Disappearance 23 92.0 17.5
2007 IU once daily for 3 d of CXR
for a single opacification
treatment cycle; OR < 300 mL
up to 2 cycles of fluid on CT
scan after 2
treatments
UK 100k
IU

(Continued)
807
 ] (Continued)
808 Original Research

TABLE 1

Patients
With Patients
Retained With No
Total Traumatic Criteria for Operative Operative
Quality Patients Hemothorax Lytic Lytic Treatment Evaluation of Lytic Intervention Avoidance
Study/Year Design Scorea Treatment (No.) (No.) Doseb Strategy Treatment (No.) (%) LOS (d)
ˇ
Oguzkaya Retrospective 7 STK 596 31 250k Lytic administered Improvement 22 71.0 14.5
et al5/2005 IU daily for up to 3- on CXR
7d
Skeete et al16/ Retrospective 6 TPA 41 8 50 mgc Not defined Improvement 6 75.0 NA
2004 on CXR
Inci et al12/ Prospective 6 STK 24 24 250k Lytic administered Improvement 22 91.7 16.9
1998 IU once daily up to on CXR
6d
UK 100k
IU
Jerjes-Sánchez Prospective 6 STK 48 12 250k Lytic administered > 50% 11 91.7 NA
et al13/1996 IU once daily until < clearance of
100 mL chest pleural
tube drainage in opacity on
24 h CXR
Casanova Prospective 6 UK 18 2 100k Lytic administered Decrease in 1 50.0 NA
Viúdez IU three times daily CXR
et al17/1995 for a single opacification
treatment cycle and
improvement
in aerated
lung area

CXR ¼ chest radiograph; LOS ¼ length of stay; NA ¼ not available; RCT ¼ randomized controlled trial; STK ¼ streptokinase; TPA ¼ tissue plasminogen activator; UK ¼ urokinase.
a
Newcastle-Ottawa Scale star rating.
[

b
Dose administered for a single treatment.
155#4 CHEST APRIL 2019

c
Most commonly administered dose, or median.
]
Methods of Review and Bias/Quality Assessment
The Preferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) statement was used as a guideline for
performance of the meta-analysis.18 Two reviewers performed the
initial literature search and removed duplicate articles. The reviewers
then independently screened abstracts to ensure that all inclusion
and exclusion criteria were met. Full text articles were obtained for
the remaining studies and were independently assessed for final
eligibility. Discrepancies were discussed and resolved between the
two reviewers.
The Cochrane Collaboration’s tool for assessing risk of bias, as
described in the Cochrane Collaboration handbook 5.1.0, was used
to assess the bias of RCTs.19 Selection bias was assessed through
review of random sequence generation and allocation concealment.
Performance bias was assessed through review of participant and
personnel blinding. Detection bias was assessed through review of
outcome assessor blinding. Attrition bias was assessed through
review of completeness of data presentation, and reporting bias was
assessed through review of possible selective reporting. Bias was
determined to be low, high, or unclear.
The quality of non-RCTs was assessed using the modified Newcastle-
Ottawa Scale, which uses an ordinal system of stars for scoring.20 A
maximum number of nine stars can be awarded to each study, with
more stars representing higher quality. Up to four stars can be
awarded through evaluation of patient selection, two stars for
comparability, and three stars for outcome evaluation. Two reviewers
Results
Literature Search Results
The initial database search identified 70 studies. Seven
more studies were added after searching references,
gray literature, and unpublished literature. Duplicates
were removed, resulting in 60 studies for further
screening. After screening, 43 studies were excluded:
nine studies analyzed delayed complications of
retained traumatic hemothorax (eg, empyema), nine
studies were reviews without quantifiable data,
seven studies were descriptive single case reports,
five studies did not include lytic treatment, four
studies investigated nontraumatic hemothorax, four
studies did not quantify the outcomes of interest,
two studies investigated an unrelated indication for
fibrinolysis, two studies were clinical
recommendations, and one study examined lytic
treatment in animals. Seventeen studies remained
for full-article review. After review we excluded
seven more studies: three studies did not report the
primary outcome (whether or not surgery was
required after lytic treatment), three studies did
not adequately differentiate the outcomes of
traumatic hemothorax from nontraumatic
hemothorax, and one study did not include retained
hemothorax related to trauma. This process is shown
in Figure 1.
chestjournal.org
independently scored each study and discrepancies were discussed
and resolved.
Statistical Analysis
The primary outcome measured was avoidance of operative
intervention following administration of lytic therapy. Data on
patients treated with lytic therapy and definitely specified as either
undergoing further operative intervention or not were recorded and
pooled. Data were also pooled for subgroup meta-analyses of the
primary outcome. Subgroups were formed to analyze type of lytic
therapy (TPA or other [streptokinase and/or urokinase]) as well as
length of stay (LOS). Mean LOS with standard deviations was
reported only in a select number of studies.
Heterogeneity of the combined studies was assessed by calculating Q
(P < .1) and I2 (# 50%), using the Cochran Q test and Higgins-
Thompson methodology, respectively.21 The DerSimonian-Laird
random effects model was employed for meta-analysis where
heterogeneity was significant, and a Mantel-Haenszel fixed-effects
model was used otherwise.
Sensitivity analysis was performed by running alternative statistical
effects models (eg, fixed effects when random effects had been used)
and by performing a leave-one-out analysis. Publication bias was
assessed using Begg’s rank correlation test (P < .10) and visually
examined through funnel plots.22 All analyses were performed with
R software (version 3.1.0; https://www.r-project.org) with the rmeta,
metafor, and hetmeta routines.
Study Characteristics and Quality
A total of 10 studies containing 225 patients with retained
traumatic hemothorax met inclusion criteria. Of these
patients, 162 were treated with lytic therapy and included
in the analysis. Study characteristics are summarized in
Table 1. One RCT from India met inclusion criteria.
Assessment of bias suggested low selection, attrition, and
reporting bias. High performance bias was noted due to
an inability to blind surgeons/patients to operative
intervention. Detection bias was considered unclear
as several assessors had varying degrees of involvement in
administration of patient treatment. One retrospective
cohort study with a comparison arm from Turkey
was included with a seven-star quality rating. The
remaining studies were case series: four prospective
(Mexico, Spain, Turkey, US) all with a quality rating of six
stars and four retrospective (US) with quality ratings of
five or six stars.
Meta-Analyses of Operative Avoidance Following
Lytic Therapy
The rate of avoiding operative intervention following
administration of any type of lytic therapy was
reported in all 10 studies.3-5,11-17 Pooling this outcome
revealed an overall operative avoidance rate of
87% (95% CI, 81%-92%), shown in Figure 2. No
heterogeneity was noted in the pooled studies (Q ¼
10.2, df ¼ 9, P ¼ .3334, I2 ¼ 15.07%).
809
 Records identified through Additional records identified
Identification
database searching through other sources
(n = 70) (n = 7)

Records after duplicates

removed
(n = 60) Records excluded after initial screen (n = 43)
• Treatment of delayed complication
of retained hemothorax (9)
Screening

• Unrelated indication for fibrinolysis (2)

• Descriptive case report (7)
Records screened
• Literature review (9)
(n = 60)
• Clinical recommendations (2)
• Animal study (1)
• No lytic therapy (5)
• Nontraumatic hemothoraces (4)
• Outcomes not reported (4)

Full-text articles excluded (n = 7)

Full-text articles assessed • Traumatic and nontraumatic cases
Eligibility

for eligibility not differentiated (3)

(n = 17) • Primary outcome not reported (3)
• Nontraumatic cases only (1)

Studies included in
qualitative synthesis
(n = 10)
Included

Studies included in quantitative

synthesis (meta-analysis)
(n = 10)

Figure 1 – PRISMA flow diagram of data collection. PRISMA ¼ Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Dividing the primary treatment of lytic therapy into
TPA and non-TPA subgroups resulted in further pooled
outcomes. Three studies representing 39 patients were
included in the evaluation of TPA treatment.14-16 TPA
was found to have a slightly lower operative avoidance
rate of 83% (95% CI, 71%-94%), as shown in Figure 3.
No heterogeneity was noted in the pooled studies (Q ¼
0.311, df ¼ 2, P ¼ .86, I2 ¼ 0%). The remaining seven
studies were pooled to evaluate non-TPA fibrinolytic
agents.3-5,11-13,17 These agents included a combination of
streptokinase and urokinase. Figure 4 shows the
summarized operative avoidance rate of 87% (95% CI,
82%-93%). No heterogeneity was noted in the pooled
studies (Q ¼ 9.3579, df ¼ 6, P ¼ .1544, I2 ¼ 33.19%).
Meta-analysis of Length of Stay
LOS was evaluated as a secondary outcome. Some
studies reported days between lytic therapy treatments
and other studies reported days following initial
thoracostomy tube placement. This analysis only pooled
data from the five studies reporting complete LOS from
admission to discharge, including 104 patients.3-5,12,14
The average length of stay for all patients undergoing
lytic therapy regardless of whether operative
intervention was also required was 14.9 days (95% CI,
12.9-16.9) (Fig 5). There was significant heterogeneity
noted in the pooled studies (Q ¼ 10.2, df ¼ 4, P ¼ .037,
I2 ¼ 65.4%).
Sensitivity Analysis and Publication Bias
Sensitivity analysis was performed by multiple
techniques, including a leave-one-out strategy as well as
calculation of the pooled effects using the alternative
statistical models (eg, fixed effects used in place of
random effects). No significant differences in outcomes
were noted following sensitivity analysis. Publication

810 Original Research [ 155#4 CHEST APRIL 2019 ]

 Study Operative Avoidance Figure 2 – Meta-analysis of operative
avoidance following treatment with
Barthwal 2016 0.92 (0.76-1.07) lytic therapy for retained traumatic
hemothorax.
Kumar 2015 0.71 (0.49-0.92)
Caylor 2014 0.86 (0.6-1.12)
Stiles 2014 0.83 (0.68-0.98)
Kimbrell 2007 0.92 (0.81-1.03)
Oguzkaya 2005 0.71 (0.55-0.87)
Skeete 2004 0.75 (0.45-1.05)
Inci 1998 0.92 (0.81-1.03)
Jerjes-Sanchez 1996 0.92 (0.76-1.07)
Casanova Viudez 1995 0.5 (–0.19-1.19)

Summary 0.87 (0.81-0.92)

0 0.2 0.4 0.6 0.8 1

bias was graphically assessed through funnel plots,
shown in Figure 6. In spite of our inclusion of
unpublished studies and gray literature, publication bias
was noted in the pooled studies used to determine
operative avoidance following lytic therapy (P ¼ .03).
No publication bias was noted for the studies used to
determine length of stay.
Discussion
Trauma patients are a unique population with
substantial variety in mechanism and combination of
injuries that can complicate care. This remains the most
common setting for hemothorax. Following tube
thoracostomy, retained traumatic hemothorax occurs in
10% to 35% of cases and results in significant
morbidity.3-5 Current trauma guidelines recommend the
use of VATS for the treatment of retained hemothorax.
However, in a multicenter trial DuBose and colleagues7
found that a second VATS procedure is required in
about 25% of cases, and a third VATS procedure may be
required in 5% of patients. Moreover, VATS and
thoracotomy may result in acute or chronic pain, which
can compromise respiratory function. Clearly, there are
opportunities to improve care for these patients.
Intrapleural lytic therapy has been considered as a
possible adjunctive or alternative treatment for retained
traumatic hemothorax, especially for patients who are
poor operative candidates. This study demonstrates that
operative avoidance following intrapleural lytic therapy
ranges from 81% to 92%. Using TPA as the lytic agent,
effectiveness ranges from 71% to 94%. The average
length of stay for trauma patients undergoing treatment
with lytic therapy ranges from 13 to 17 days.
In this systematic review and meta-analysis, avoidance
of operative intervention was the primary outcome
assessed. Evaluation of the effect of lytic treatment must
have been paramount to determining whether operative
intervention was necessary in each study, but evaluation
varied from study to study because of a lack of specific
definitions or precedent identified in the literature.
Ultimately, operative intervention was provided when
lytic treatment “failed” based on clinical judgment.
Therefore, the findings of our study could be restated
to say that despite frequent complications associated
with retained traumatic hemothorax and level 1,
evidence-based guidelines recommending surgery,
physicians felt that the extent of resolution following
lytic therapy for retained traumatic hemothorax
warranted discharge without further intervention in
81% to 92% of patients.

Study Operative Avoidance

Caylor 2014 0.86 (0.6-1.12)

Stiles 2014 0.83 (0.68-0.98)
Skeete 2004 0.75 (0.45-1.05)

Figure 3 – Meta-analysis of operative avoidance

Summary 0.83 (0.71-0.94)
following treatment with TPA lytic therapy for retained
traumatic hemothorax. TPA ¼ tissue plasminogen
0.5 0.6 0.7 0.8 0.9 1 1.1 activator.

chestjournal.org 811
Figure 4 – Meta-analysis of operative Study Operative Avoidance
avoidance following treatment with
non-TPA lytic therapy for retained Barthwal 2016 0.92 (0.76-1.07)
traumatic hemothorax. See Figure 3
Kumar 2015 0.71 (0.49-0.92)
legend for expansion of abbreviation.
Kimbrell 2007 0.92 (0.81-1.03)
Oguzkaya 2005 0.71 (0.55-0.87)
Inci 1998 0.92 (0.81-1.03)
Jerjes-Sanchez 1996 0.92 (0.76-1.07)
Casanova Viudez 1995 0.5 (–0.19-1.19)

Summary 0.87 (0.82-0.93)

0 0.2 0.4 0.6 0.8 1

Because of significant variations in study designs,
operative avoidance was further assessed by the type of
intrapleural lytic therapy used. The agents used were
streptokinase, urokinase, and TPA. The studies by
Barthwal and colleagues,11 Kimbrell and colleagues,3
and Inci and colleagues12 used varying combinations of
these medications. The studies by Kumar and
ˇ with lytic treatment. Critics of lytic treatment suggest
colleagues,4 Oguzkaya and colleagues,5 and Jerjes-
Sánchez and colleagues13 used streptokinase. The studies
by Stiles and colleagues,14 Caylor and colleagues,15 and
Skeete and colleagues16 used TPA, while the study by
Casanova Viúdez and colleagues17 treated patients with
urokinase. There was significant variation in the dosage
of therapy administered. Furthermore, the timing of
administration, number of administrations, and time
between doses varied as there is no previous precedent
to follow. Streptokinase was first described as a
treatment for pleural exudations by Tillett and Sherry in
1949.23 Urokinase was developed after antibodies,
developed primarily from streptococcal disease, were
found to interact poorly with streptokinase. Production
of urokinase was halted for a time when the Federal
Drug Administration (FDA) became concerned that
transmission of viral disease may have been possible due
to the way that the drug was manufactured.24 At present,
urokinase has been reapproved for specific therapies.
Alteplase, or TPA, is the latest lytic agent developed.25
For that reason, TPA was independently studied as a
subgroup analysis. TPA was found to have a mean rate
of surgery avoidance of 83%, slightly lower than the
mean of all other therapies of 87%.
LOS is an important secondary outcome to consider
that operative management can be completed in hours
whereas administration of lytic therapy often requires
multiple doses over several days. While LOS, and more
specifically timing, was commonly reported, the end
points of timing varied with studies measuring total
hospital LOS, time after placement of thoracostomy
tube, and time after drug administration. In the studies
identified, the most common measurement was total
hospital LOS. Pooled data showed a mean LOS of
15 days with a range between 13 and 17 days. For
perspective, DuBose and colleagues7 reported a mean
LOS of 30.1 days for patients who developed infection
during observation of retained traumatic hemothorax.
Kumar and colleagues,4 in an RCT comparing VATS
and intrapleural streptokinase, found that the mean LOS
for VATS was 10 days. VATS and intrapleural lytic
therapy both reduced LOS compared with complicated
retained hemothorax, but VATS may reduce hospital
LOS even further at the expense of a surgical procedure
being performed, and the increased costs, infection risks,

Study LOS (Days)

Kumar 2015 12 (9.62-14.38)
Stiles 2014 13.6 (6.93-20.27)
Kimbrell 2007 17.5 (14.48-20.52)
Oguzkaya 2005 14.5 (13.02-15.98)
Inci 1998 16.9 (13.68-20.12)

Summary 14.88 (12.88-16.88)

Figure 5 – Mean hospital length of stay in patients with
retained traumatic hemothorax treated with lytic ther-
apy. LOS ¼ length of stay. 8 10 12 14 16 18 20

812 Original Research [ 155#4 CHEST APRIL 2019 ]

 Operative Avoidance
0 0
0.088
SE
SE
0.177
0.265
0.354
0 0.5 1 1.5
Observed Outcome
Figure 6 – Funnel plots of the SE by mean difference for operative avoidance and length of stay.
and negative outcomes associated with the longer LOS
following lytic treatment compared with VATS need to
be strongly considered. It is important to keep in context
that a number of other factors play a role in LOS and are
not accounted for in these studies. These factors may
include, but are not limited to, multiple traumatic
injuries, severity of trauma, time until diagnosis of
hemothorax, time until diagnosis of undrained
hemothorax, and medical comorbidities. Likely
associated with LOS is tube thoracostomy duration. To a
certain extent, it might be surmised that patients with
longer hospital stays had longer durations with
thoracostomy tubes or vice versa. This important
association was not assessed in the pooled studies.
Overall safety, adverse events, and complications
associated with intrapleural lytic therapy remain
understudied and raise reasonable concerns for further
widespread implementation. In particular, the potential
for bleeding complications, both systemic and
intrapleural, needs to be addressed. Many multitrauma
patients with undrained hemothorax have solid organ
injuries or require nonthoracic surgery that would
promote extra consideration before the use of lytic
therapy. Berglin and colleagues26 and Davies and
colleagues,27 in separate studies addressing systemic
effects of streptokinase, concluded that intrapleural
administration does not appear to activate fibrinolysis in
any physiologic or statistically measurable way. There
have been no similar studies evaluating systemic
absorption of intrapleural TPA administration.
Therefore, an understanding of the pharmacokinetics of
TPA is relevant. The half-life is biphasic with an initial
half-life of 3 to 5 min, followed by an elimination half-
life of 27 to 46 min with metabolism occurring
predominantly in the liver. Intrapleural diffusion is
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Length of Stay
0.85
1.701
2.551
3.402
10 15 20
Observed Outcome
limited by high molecular weight.28 Combining this
information with the finding that none of the 162
patients included in the pooled studies were noted to
have bleeding complications may give some confidence
that systemic absorption is low. Intrapleural bleeding
remains a matter of importance with unsatisfactory
description in the literature.
Complications that were noted in the pooled studies
include two cases of transient disorientation, peritubal
inflammation, transient fever, and worsening pain with
administration of therapy.3,4,13
This study has several important limitations. Perhaps
the most notable limitation is the clinical heterogeneity
of the included studies, which includes differences in
treatment, patient characteristics, and outcome
assessment. Treatment dosing, time between doses, the
number of doses, and the amount of time with the
medication instilled in the intrapleural cavity are some
of the variables that were not standardized across
treatments. However, it should be noted that many of
these variations were purposefully similar as the study
designs built on each other. Patient characteristics
including age, comorbidities, and differing traumatic
injuries appear to be unaccounted for, but this describes
well the trauma population; furthermore, most studies
combine traumatic patients with other disease
etiologies. Our study was designed to remove this
important confounding, making the varied but solely
traumatic patient population a strength of this
analysis. Finally, variation in evaluation of lytic
treatment needs to be considered. Most studies used
radiographic evidence to help make clinical judgments
about the need for surgery. The lack of specific
definitions and diagnostic criteria for evaluating
813
undrained hemothorax and determining the need for
operative intervention is readily apparent.
Another limitation that needs to be considered is long-
term follow-up. Only four of the included studies
described follow-up (ranging from 2 to 14 months) after
discharge.5,12-14 It is conceivable that following hospital
discharge some patients were readmitted at different
hospitals or not captured in a retrospective analysis and
required operative intervention that was not recorded.
Future studies will need to monitor patients longer and
record more definitive outcomes than operative
avoidance. Consideration should be given to a number
of complications that need to be reviewed over an
extended length of time including but not limited to
delayed hemothorax, development of empyema, and
need for additional tube thoracostomy.
Finally, the strength of a meta-analysis is limited to the
quality of studies pooled. Our review demonstrated that
current literature investigating lytic treatment for
retained hemothorax is extremely limited and consists
mostly of case series that contain relatively low-level
evidence. Even the RCT noted that the sample size used
was underpowered.4 Thus, our meta-analysis, while
suggestive, does not to provide definitive evidence that
lytic treatment is effective. It does, however, suggest that
there is potential for lytic treatment to be useful in cases
where operative intervention should be avoided. We
suggest strongly that an RCT, preferably
multiinstitutional with definitions agreed on by
experienced trauma physicians, should be carried out to
determine the overall effectiveness and usefulness of
lytic treatment for the trauma patient.
Conclusions
Our study suggests that intrapleural lytic therapy shows
promise in the treatment of retained traumatic
hemothorax and could reduce the need for operative
intervention. This may be especially important for
treating higher risk populations such as the elderly,
those with multiple comorbidities, and others who are
poor surgical candidates. A multiinstitutional RCT is
warranted and should be directed at developing a
standardization of protocol, addressing long-term
outcomes, and assessing effectiveness beyond avoiding
operative intervention. In addition, both cost-
effectiveness and quality of life analyses may help
determine whether lytic therapy should be used as an
adjunct or as standard of care.

Acknowledgments clinical trial for optimum treatment of traumatic haemothoraces. Interact

Author contributions: Study concept and
design: B. S. H., M. T. K., S. B. A., M. F. R., M.
D. T., and C. S. H. Acquisition and analysis of
data: B. S. H., M. T. K., and C. S. H.
Interpretation of data: B. S. H., M. T. K., S. B.
A., M. F. R., M. D. T., and C. S. H. Drafting of
the manuscript: B. S. H., M. T. K., S. B. A., M.
F. R., M. D. T., and C. S. H. Critical revision
of the manuscript for important intellectual
content: B. S. H., M. T. K., S. B. A., M. F. R.,
M. D. T., and C. S. H. Study supervision: B. S.
H., S. B. A., M. F. R., and C. S. H.
Financial/nonfinancial disclosures: None
declared.
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