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Pleural empyema and outcome 431

Materials and methods

Study population

Patients with a positive culture in pleural fluids from

the 3 Danish hospitals without in-house facilities to

perform thoracic surgery (Copenhagen University

Hospital Hvidovre, Copenhagen University Hospital

Bispebjerg and Roskilde Hospital) were identified in

the laboratory database of the Department of Clini-

cal Microbiology at Hvidovre Hospital and in the

Statens Serum Institute for the periods 19962004

and 19992007, respectively. Pre-admission symp-

toms, pre-admission therapy, predisposing condi-

tions, post-admission clinical and laboratory findings,

medical and surgical treatment, outcome and the

clinical relevance of the microbiological findings

obtained from the medical records were evaluated

retrospectively.

Inclusion criteria included the clinical diagnosis

of pleural empyema with microbiological verifica-tion. Exclusion criteria included the evaluation of a

positive culture being a contamination and not being

treated as a pleural infection, or the finding of Myco-

bacterium tuberculosis in the pleural fluid.

Empyema was defined as purulent pleural fluid

or the presence of relevant positive culture in pleu-

ral fluid. Delay of pleural drainage was defined as

time from admission exceeding 2 days. A nosoco-

mial infection was defined according to the US

Centers for Disease Control and Prevention (CDC)

[13]: if the patient had been hospitalized within

4 weeks of admission, if the empyema was a com-

plication to invasive procedures, or if the empyemaor the underlying infection clinically had begun

later than 2 days after admission. Sufficient recov-

ery was defined as patients returning to their recent

health status. Insufficient recovery was defined as

not returning completely to their recent health sta-

tus. An unfavourable outcome was defined as insuf-

ficient recovery or death. Death was defined as

in-hospital death.

More detailed data on excluded cases in the

cohort, the microbiological findings, antimicrobial

susceptibility and on the initial antimicrobial therapy

is presented in a separate publication [14].

Statistics

For univariate analyses the Chi-square test and Fish-

ers exact test were used, when appropriate. For the

outcome analyses, the above-mentioned potential

prognostic factors were included in a multiple logistic

regression analysis using a backward selection tech-

nique (SPSS for Windows, v. 6.1.2, 1995; EpiInfo,

World Health Organization, Zurich, Switzerland).

The level of significance was set at p0.05.

Results

Background characteristics

In the 9-y period, 158 patients with verified pleural

empyema were included in this study. Details on the

clinical background, predisposing diseases, bacterial

aetiology and outcome are presented in Tables I and

II. In 64% of all cases (n101) the infection was

community-acquired; 27% of cases were nosocomial

(n 43) and 9% of cases (n 14) could not be

categorized.

All patients were subjected to thoracentesis by

definition. According to currently guidelines, a few of

the non-purulent pleural fluid samples were analysed

biochemically for white blood cell count (17%), pro-

tein (31%), lactate dehydrogenase (LDH) (13%), and

glucose (7%); no samples were analysed for pH.

Our patients had a median length of hospital stay

of 29 days (range 1122), and the overall mortality

was 27%. Median time to death among the studypatients was 21 days (range 3146). Dyspnoea and

cough were less frequently documented symptoms

among the patients who later died (dyspnoea 47% vs

65%, cough 28% vs 56%, p0.04, see Table I).

Therapeutic factors

Pleural drainage was done in 91% of the cases

(n 144) and was guided by ultrasound in 63%

(n91). Pig-tail drains were used in 64% (n92),

large bore drains ( 20 French) in 6% (n9), and

no drain specification (most likely pig-tail or similar

drain) was recorded for 30% (n43). Therapeuticthoracentesis with no tubing was done in 9% of the

cases (n14). The median time from admission to

drainage was 5 days (IQ-range 113 days), and delay

in drainage 2 days did not correlate with mortality

or with an unfavourable outcome (p 0.50 and

p0.95, respectively). Median duration of drainage

was 8 days.

No antimicrobial therapy was administrated in

5 cases. In 11 patients, the initial antimicrobial ther-

apy could not be categorized as either sufficient or

insufficient. Sufficient initial antimicrobial therapy

(n65) did not correlate significantly with mortal-

ity in the univariate analysis (OR 0.56, 95% CI

0.251.22, see Table III).

Local fibrinolytic therapy was performed in 24%

(37/154) of the cases, and this group had a lower

mortality than patients not treated with fibrinolytic

agents (5% vs 34%,p0.002). The median age was

similar in the 2 groups (66 y vs 64 y, p0.51), and

the group treated with fibrinolytics had a similar rate

of co-morbidity (69% vs 79%, p 0.21). By

univariate analysis, fibrinolytic therapy correlated

inversely with mortality (OR 0.11, 95% CI 0.010.47),

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432 J. Nielsen et al.

but not with unfavourable outcome (OR 1.21, 95%

CI 0.522.86) (see Tables III and IV).

Patients were admitted to a department of tho-

racic surgery in 34% of the cases (n54), and 63%

of these (n 34) had a surgical intervention per-

formed: 85% decortication, 3% VATS (video-assisted

thoracoscopic surgery) alone (without decortication)

and 9% rib resection or thoracoplasty. By univariate

analysis, mortality was lower in the group having sur-

gery (12% vs 31%, OR 0.29, 95% CI 0.070.91,

Tables III and IV), with a lower median age (61 y vs

69 y,p0.01) and with a trend towards a lower rate

of predisposing diseases (68% vs 80%,p0.12).

Multivariate analyses of outcome

Apart from early drainage and the age parameter, the

hypothesized prognostic factors correlated indepen-

dently with mortality (see Table III). Nosocomial

infection (OR 2.62, 95% CI 1.714.16) and predis-

posing conditions (OR 2.17, 95% CI 1.503.14) cor-

related to mortality and are non-preventable and

non-interventional parameters for the individual

patient. In contrast, sufficient initial antimicrobial

therapy (OR 0.45, 95% CI 0.310.65), intrapleural

thrombolysis (OR 0.13, 95% CI 0.060.28) and

thoracic surgery treatment (OR 0.27, 95% CI

0.140.52) were all factors associated with survival.

In the analysis with unfavourable outcome as the

dependent variable, a similar picture occurred (Table IV),

though the correlation to the parameters intrapleural

thrombolysis, nosocomial infection and sufficient

initial antimicrobial therapy did not independently

reach the level of statistical significance (p 0.83,

p0.09 andp0.06, respectively), with increasing

age (OR 1.77, 95% CI 1.472.14) and presence

of predisposing conditions (OR 3.64, 95% CI 2.305.76)

as independent correlating parameters.

Table I. Background data concerning bacterial aetiology, clinical features, admission data, and outcome in 158 patients with pleuralinfection (115 patients who survived and 43 who died).

All patients Patients who died Patients who survived p-Value

Age (interquartile range) 63 (5377) 66 62 0.03

Male sex 63% (n99) 61% 67% 0.45

Bacterial aetiology 0.03

Streptococci 33% 26% 36%

Mixed infection 26% 33% 23%

Staphylococcus aureus 18% 23% 16%

Enterobacteriaceae 9% 16% 6%

Anaerobic bacteria 7% 2% 9%

Other bacteria 7% 0 % 10%

Reason for hospital admission 0.37

Pneumonia 32% 23% 36%

Dyspnoea 10% 7% 11%

Cancer 8% 7% 8%

Abdominal illness 8% 14% 5%

Chest pain 6% 5% 5%

Lung disease (not pneumonia) 6% 5% 6%

Other diagnoses 30% 40% 29%

Background for the infectiona 0.001

Pneumonia 59% 33% 68%

Thoracic trauma 11% 16% 9%

Recent thoracentesis 9% 7% 10%

Abdominal focus 7% 7% 7%

Recent surgery 3% 4.6% 2.6%

Oesophageal rupture 0.6% 2% 0

Unregistered 15% 30% 3.5%

Antimicrobial therapy before admission 26% 26% 26% 0.95

Antimicrobial therapy before thoracentesis 66% 72% 64% 0.47

Symptoms at admission

Dyspnoea 60% 47% 65% 0.03

Cough 48% 28% 56% 0.002

Chest pain 44% 35% 49% 0.32

Fever 37% 30% 40% 0.25

Pleural fluid, purulent 37% 33% 39% 0.45

Pleural fluid, cloudy 27% 19% 23% 0.59

Intensive care unit stay 17% (n 27) 28% 13% 0.03Length of stay, days (median, range) 29 (3220) 27 (3146) 29 (5220) 0.08

aBy post-admission evaluation.

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Discussion

In our population, pleural empyema was a serious

and debilitating disease with 36% recovering fully,

37% with insufficient recovery, and 27% dying dur-ing hospital admission. Several of the hypothesized

prognostic factors correlated independently with

mortality, including predisposing conditions, noso-

comial infection, insufficient initial antimicrobial

therapy, intrapleural thrombolysis, and thoracic sur-

gery. Another possible important interventional fac-

tor, delay in pleural drainage, did not correlate

significantly with mortality.

Previous studies have examined the use of fibrin-

olytic therapy versus tube drainage alone in pleural

empyema with opposing results concerning mortality

or the need for later surgical intervention [1517].

Early small-scale (n 2450) randomized trials[1821] and observational or non-randomized stud-

ies [10] in adults showed the effects of intrapleural

urokinase or streptokinase on drained volume and

radiological improvement and showed a reduced

need for surgical intervention. A recent larger scale

randomized trial (n454) could not show a treat-

ment effect of intrapleural streptokinase [15], and it

is still unclear whether and when it may be of

benefit to use fibrinolytics [8,22,23]. In the present

study, we found a significant correlation between

local fibrinolytic therapy and lower mortality.

Several studies have focused on the potential ben-

efit of early surgery versus a more conservative treat-

ment algorithm [6,24,25]. A recent study [26]

confirmed the results of earlier randomized trials

[25,27] that VATS or thoracotomy as initial treat-

ment for advanced empyema is associated with better

outcomes, and this may be preferred for those

selected patients without serious medical problems

if such surgical assistance is easily available

[8,22,23,28].

To our surprise, 63% of all infected samples from

pleural empyema patients were described macro-

scopically as non-purulent. In this population, only

a minority of samples was further analysed biochem-

ically, and remarkably no documentation was found

for the measurement of pH in any sample. The diag-

nostic approach in the emergency departments and

in the departments of internal medicine seldom fol-lowed the current British Thoracic Society guidelines

[7] or the recent 2010 update [9], stressing the

importance of initial diagnostic pH measurement in

non-purulent effusions (in addition to cytology, cul-

ture, protein, LDH and glucose) to identify patients

needing early chest tube drainage. Thus there was the

potential for improvement in the diagnostic work-up

at the hospitals concerned.

The finding of a median delay of 2 days for tho-

racentesis and of 5 days until pleural drainage was

set into effect may seem excessive. Few publications

have described these therapeutic delays, but Lind-

strom and Kolbe reported similar delays of 3.4 daysand 5.2 days, respectively, in an Australian set-up [2].

Our finding that co-morbidity and increasing age

(though the latter non-significantly) correlated with

an unfavourable outcome was expected and has been

described by others [26], but appears clinically less

interesting as these factors are not preventable or

targets for intervention.

The design of our study was retrospective and

non-randomized, and the results will have limitations

Table II. Occurrence of predisposing diseases and conditions in158 patients with pleural empyema.

No. of patients (%)

Cancer 37 (23)

Severe weakening in general 29 (18)

Alcoholism ( 50 g ethanol/day) 24 (15)

COPD 20 (13)

Diabetes 18 (11)

Rheumatologic disease 10 (6)

Aspiration due to neurological disease 5 (3)

HIV infection 4 (3)

Other immune defects 3 (2)

Other 35 (22)

COPD, chronic obstructive pulmonary disease; HIV, human

immunodeficiency virus.

Table III. Correlation of in-hospital death (n43) to hypothesized factors by univariate and multivariate analysis, in patients with pleuralinfection (n133; no antimicrobials for 5 patients, missing data for 20 patients).

Univariate Logistic regression

OR 95% CI OR 95% CI

Intrapleural fibrinolysis 0.11 0.010.47 0.13 0.060.28

Nosocomial infection 3.21 1.387.50 2.62 1.714.16

Age (in quartiles) 1.99a 0.914.36 1.36 0.892.08b

Sufficient initial antimicrobials 0.56 0.251.22 0.45 0.310.65

Thoracic surgery performed 0.29 0.070.91 0.27 0.140.52

Predisposing conditions 5.20 1.4727.91 2.17 1.503.14

aComparing above the median to below the median.bBefore backward selection.

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434 J. Nielsen et al.

concerning possible treatment bias. Thus selection

bias cannot be ruled out concerning treatment with

thoracic surgery or VATS. Only cases with a positive

culture of relevant microorganisms were included in

the present study [14]. Thus, excluding culture-neg-

ative cases, which have been said to account for up

to 40% of all clinical cases, may also be a possible

selection bias [7,9]. The diagnostic and therapeutic

management was not uniform or standardized in the

3 centres in practice, which may not have been fully

controlled for in the study analyses. In a number of

the medical charts (50%), 1 or more data sets were

missing out of the 22 parameters collected. The miss-

ing data in the medical records will reduce the

statistical strength to a minor extent, as a small pro-

portion of cases (13%, n

20) was not included inthe logistic regression analyses. Thus, possibly skewed

results (caused by the missing data) in the logistic

regression analyses cannot be ruled out. Still, impor-

tant results were gained concerning the possible

background for the significant findings, and possible

suboptimal routines in the clinical handling of

patients were identified.

In conclusion, this study found an independent

correlation between survival and the possible inter-

ventional factors of sufficient initial antimicrobial

therapy, intrapleural fibrinolytic therapy and thoracic

surgical therapy. The non-preventable and non-

interventional factors of nosocomial infection andpredisposing conditions were correlated with mortal-

ity. We found that suboptimal diagnostic action may

have affected the delay in treatment, which theoreti-

cally can influence outcome. Future prospective and

thus more complete studies may further clarify the

role of these factors.

Declaration of interest: The authors state that

there are no conflicts of interest in connection with

this article.

References

Smith JA, Mullerworth MH, Westlake GW, Tatoulis J.[1]

Empyema thoracis: 14-year experience in a teaching center.

Ann Thorac Surg 1991;51:3942.

Lindstrom ST, Kolbe J. Community acquired parapneu-[2]

monic thoracic empyema: predictors of outcome. Respirol-

ogy 1999;4:1739.

Davies CW, Kearney SE, Gleeson FV, Davies RJ. Predictors[3] of outcome and long-term survival in patients with pleural

infection. J Respir Crit Care Med 1999;160:16827.

Sasse S, Nguyen TK, Mulligan M, Wang NS, Mahutte CK.[4]

The effects of early chest tube placement on empyema

resolution. Chest 1997;111:167983.

Ashbaugh DG. Empyema thoracis. Factors influencing[5]

morbidity and mortality. Chest 1991;99:11625.

Huang HC, Chang HY, Chen CW, Lee CH, Hsiue TR.[6]

Predicting factors for outcome of tube thoracostomy in com-

plicated parapneumonic effusion for empyema. Chest 1999;

115:7516.

Davies CW, Gleeson FV, Davies RJ. BTS guidelines for the[7]

management of pleural infection. Thorax 2003;58(Suppl 2):

ii1828.

Colice GL, Curtis A, Deslauriers J, Heffner J, Light R,[8]

Littenberg B, et al. Medical and surgical treatment of para-

pneumonic effusions: an evidence-based guideline. Chest

2000;118:115871.

Davies HE, Davies RJ, Davies CW; BTS Pleural Disease[9]

Guideline Group. Management of pleural infection in adults:

British Thoracic Society Pleural Disease Guideline 2010.

Thorax 2010;65(Suppl 2):ii4153.

Frey DJ, Klapa J, Kaiser D. Irrigation drainage and fibri-[10]

nolysis for treatment of parapneumonial pleural empyema.

Pneumologie 1999;53:596604.

Sen S, Senturk E, Pabuscu E, Cokpinar S, Yaman E. [Mini-[11]

mally invasive approach in the pleural fluids]. Tuberk Toraks

2010;58:717.

Heindorff H, Drenck NE. Pleural empyema. 95 cases treated[12]

at a thoracic surgery department. Ugeskr Laeger 1987;149:

2936.Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM.[13]

CDC definitions for nosocomial infections, 1988. Am J

Infect Control 1988;16:12840.

Meyer CN, Rosenlund S, Nielsen J, Friis-Mller A. Bacte-[14]

riological aetiology and antimicrobial treatment of pleural

empyema. Scand J Infect Dis 2011;43:1659.

Maskell NA, Davies CW, Nunn AJ, Hedley EL, Gleeson FV,[15]

Miller R, et al. U.K. Controlled trial of intrapleural streptoki-

nase for pleural infection. N Engl J Med 2005;352:86574.

Cameron R, Davies HR. Intra-pleural fibrinolytic therapy[16]

versus conservative management in the treatment of parap-

neumonic effusions and empyema. Cochrane Database Syst

Rev 2004;(2):CD002312.

Diacon AH, Koegelenberg CF, Bolliger CT. A trial of intra-[17]

pleural streptokinase. N Engl J Med 2005;352:22435.Bouros D, Schiza S, Tzanakis N, Chalkiadakis G, Drositis J,[18]

Siafakas N. Intrapleural urokinase versus normal saline in the

treatment of complicated parapneumonic effusions and

empyema. A randomized, double-blind study. Am J Respir

Crit Care Med 1999;159:3742.

Davies RJ, Traill ZC, Gleeson FV. Randomised controlled[19]

trial of intrapleural streptokinase in community acquired

pleural infection. Thorax 1997;52:41621.

Tuncozgur B, Ustunsoy H, Sivrikoz MC, Dikensoy O, Topal M,[20]

Sanli M, et al. Intrapleural urokinase in the management of

parapneumonic empyema: a randomised controlled trial. Int

J Clin Pract 2001;55:65860.

Table IV. Correlation of unfavourable outcome (n 101) tohypothesized factors by univariate and multivariate analysis, inpatients with pleural infection (n132; no antimicrobials for 5patients, missing data for 21 patients).

Univariate Logistic regression

OR 95% CI OR 95% CI

Age (in quartiles) 2.35a 1.134.91 1.77 1.472.14Predisposing conditions 4.21 1.7910.02 3.64 2.305.76

Nosocomial infection 3.16 1.297.94 2.16 1.363.44

Sufficient initial

antimicrobials

1.47 0.693.13 0.985 0.980.99b

Intrapleural fibrinolysis 1.21 0.522.86 0.95 0.761.19b

Thoracic surgery

performed

0.41 0.180.94 0.55 0.340.90b

aComparing above the median to below the median.bBefore backward selection.

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Diacon AH, Theron J, Schuurmans MM, Van de Wal BW,[21]

Bolliger CT. Intrapleural streptokinase for empyema and

complicated parapneumonic effusions. Am J Respir Crit

Care Med 2004;170:4953.

Light RW. Parapneumonic effusions and empyema. Proc Am[22]

Thorac Soc 2006;3:7580.

Molnar TF. Current surgical treatment of thoracic empyema[23]

in adults. Eur J Cardiothorac Surg 2007;32:42230.

Cassina PC, Hauser M, Hillejan L, Greschuchna D, Stamatis[24]G. Video-assisted thoracoscopy in the treatment of pleural

empyema: stage-based management and outcome. J Thorac

Cardiovasc Surg 1999;117:2348.

Lim TK, Chin NK. Empirical treatment with fibrinolysis and[25]

early surgery reduces the duration of hospitalization in

pleural sepsis. Eur Respir J 1999;13:5148.

Wozniak CJ, Paull DE, Moezzi JE, Scott RP, Anstadt MP,[26]

York VV, et al. Choice of first intervention is related to out-

comes in the management of empyema. Ann Thorac Surg

2009;87:152530.

Wait MA, Sharma S, Hohn J, Dal NA. A randomized trial[27]

of empyema therapy. Chest 1997;111:154851.Koegelenberg CF, Diaconi AH, Bolligeri CT. Parapneu-[28]

monic pleural effusion and empyema. Respiration 2008;75:

24150.

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