Slayt 1

1
Is early surgical treatment in localized
parapneumonial effusions and empyemas beneficial
? NO
Prof. Dr. Orhan Arseven Istanbul University
Istanbul Medical Faculty Department of
Pulmonary Disease
2
Parapneumonic Pleural effusion and pleural
empyema

• At least 20-40 of hospitalized patiens with
  community
• acquired pneumoniea develop
• Estimated mortality rate 15
• 10 -20 require surgical drainage
• The median duration of inpatient care is 15 day
• With 20 of patients remaining in the hospital
  for
• 30 days or longer

Davies CW, Kearney SE, Gleeson FV,Davies RJ.
Predictors of outcome and longtermsurvival in
patients with pleural infection. Am J Respir
Crit Care Med 19991601682-7 Ferguson AD,
Prescott RJ, Selkon JB,Watson D, Swinburn CR. The
clinical course and management of thoracic
empyema. QJM 199689285-9
3
PPE - Pathophysiology
Exudative stage Steril Fibropurulent stage
Large amounts of pleural fluid with many PNL,
bacteria, and cellular debris Fibrin
deposited in a continuous sheet covering both
the visceral and parietal pleura.
Loculation and the formation of limiting
membranes
(Fibrinous and fibrous adhesions ) Organization
stage Fibroblast activationInelastic
pleural peel ..Dense fibrous
septationsTrapped lung
4
Ultrasonography CT
5
FACTORS ASSOCIATED WITH POOR PROGNOSIS IN
PATIENTS WITH PARAPNEUMONIC EFFUSION
Pus present in pleural space
Gram stain of pleural fluid positive
Pleural fluid glucose below 40 mg / dl
Pleural fluid bacterial culture positive
Pleural fluid pH lt 7.00
Pleural fluid LDH gt 3 x upper limit for serum
Pleural fluid loculated Large non-purulent effusion
Light RW. Parapneumonic effusions and
empyema.InLight RW(eds).Pleural
diseases.4thed.2001151-81. Davies CW, et al. BTS
guidelines for the management of pleural
infections.Thorax 200358(Suppl 2)18-26.
6
Na MJ, Dikensoy Ö,Light RW. Tüberküloz ve Toraks
200856(1)113-20
7
Around 500 B.C.
HIPPOCRATES
Whatever the approach, drain infected
pleural fluid as rapidly as possible
8
Methods for treatment of complicated
parapneumonic effusions and pleural empyema

• Antibiotics
• Daily thoracentesis
• Tube thoracoscopy ( standart chest tube )
• Image guided percutaneous catheter
• Intrapleural fibrinolytic therapy
• Medical thoracoscopy
• Video-assisted thoracoscopic surgery ( VATS)
• Standart or limited ( muscle sparing)
  thoracotomy
• Chronic open drainage

9
Na MJ, Dikensoy Ö,Light RW. Tüberküloz ve Toraks
200856(1)113-20
10
Chest tube thoracostomy
What size ?

• Large ( 28 - 36 F ) tubes
• Small catheters ( 6 -14 F ) !
• - Easier to insert
• - Less painfull
• Thick viscous fluid !!

11
Intrapleural fibrinolytic therapy

• Occlusion of the catheter by viscous,
  fibrin-rich fluid
• and cellular debris
• Fibrin strands that form pleural loculations

Theory They will destroy the fibrin membrans
and facilate the drainage
12
Former studies have established that

• Fibrinolytic agents do lead to macroscopically
  effective
• in vivo lysis of intrapleural-fluid collections
• Maskell NA, Gleeson FV. Effect of
  intrapleuralstreptokinase on a loculated
  malignant
• pleural effusion. N Engl J Med
  2003348e4.
• Reduce the volume of infected pleural-fluid
  collections
• Davies RJO, Traill ZC, Gleeson FV. Randomised
  controlled trial of intrapleural streptokinase
• in community acquired pleural
  infection.Thorax 199752416-21.
• Maskell NA, Davies RJO. Effusions from
  parapneumonic infection and empyema. In
• Light RW, Lee YCG, eds. Textbook of
  pleuraldiseases. London Arnold, 2003310-28.

13
Intrapleural streptokinase

• Benefical effect on
• Radiologic appearance
• Volume of pleural drainage
• Time to defervescence
• Length of hospital stay

Lim TK, et al. Eur Respir J 199913514-18. Davies
RJ, et al. Thorax 199752416-21 Bouros D, et
al. Am. J.Respir Crit Care Med 1999,15937-42 Bour
os D, et al. Am J Respir Crit Care Med
1997155291-95
14
Uncontrolled case series

• 25 Small, uncontrolled clinical trials reports .
• Safety and efficacy for decreasing the need for
  surgical
• drainage
• Mean success rate 82 .Streptokinase (44
  -100 )
• 84
  Urokinase ( 55 -100 )

Small numbers of enrolled patients
Heterogeneous case mix ( PPE, PE) Most of
retrospective design
Bouros D, et al.Intrapleural fibrinolytic therapy
for pleural infection.Review. Pulmonary
Pharmacology and therapeutics 200720(6) 616-26.
15
Summary randomized, controlled trials of
fibrinolytics in adult patients with
parapneumonic effusions and pleural empyema
without a surgery study arm
1
Author Age range Streptok. Urokin.
Chest tube Primary outcome
years n() n()
saline n()
Bouros et al. (1592) 25 (92) 25 (92) 1. Improvement in imaging (CXR, CT and/or chest ultrasound) 2. Duration and total volume of pleural drainage 3. Time to apyrexia ( Both drugs similarly ) 4. Cost of treatment 5. Hospital stay
Davies et al. (1890) 12 (100) 12 (25) 1. Total volume of pleural drainage 2. Volume of fluid drainage between days 25 3. Improvement of chest radiograph from baseline to discharge
Bouros et al. 56 (2178) 15 (87) 16 (25) 1. Improvement in imaging (CXR, CT and/or chest ultrasound) 2. Duration and total volume of pleural drainage 3. Subjective clinical improvement 4. Time to apyrexia
16
Urokinase/saline , double-blind, 31
multiloculated PPE

• Larger volume drainage
• and higher success 87
  versus 25 (plt0.001)
• Urokinase group 2 patients required VATS
  drainage
• Plasebo group 6 /12
• - Chest radiography,
• - Duration of hospitalization,
  favored the
• 
  urokinase group
• - Duration of chest tube drainage, and
• - The time before defervescence

Bouros D, Schiza S, Tzanakis N, et al. Am J
Respir Crit Care Med 1999 15937 42
17
2
Author Age range Streptok.
Urokin. Chest tube Primary outcome
years n()
n() saline n()
Tuncozgur et al. (1585) 25 (60) 24 (29) 1. Time to apyrexia 2. Duration and total volume of drainage 3. Duration of hospital stay 4. Improvement in chest radiography and CT
Diacon et al. 3913 22 (82) 22 (48) 1. Clinical treatment success 2. Need for referral to surgery
Maskell et al. Streptokinase 6018 PLACEBO 6118 208 (69) 222 (73) 1. Death or need for surgery 2. Rates of death and of surgery 3. Radiographic outcome 4. Length of hospital stay
18
Urokinase / saline placebo 49 patients PE

• Need for decortication 29 versus 60 ,
  plt0.001
• Shorter duration of fever 7 versus 13 days,
  plt0.01)
• Grater volume of drained fluid 1.8 versus
  0.8L, plt0.001
• Shorter duration of hosp. 14 versus 21 days,
  plt 0.001

Tuncozgur B, Ustunsoy H, Sivrikoz MC, et
al. Int J Clin Pract 2001 55658 660
19
Intrapleural streptokinase for empyema
and Complicated parapneumonic effusions

• Randomised, double-blind, placebo controlled
  trial ( 22 / 22 patients )
• 24 28 F chest tube , with ultrasound guided ,
  Streptokinase Once daily for up to 7 days
• Clinical treatment success and need for referral
  to surgery
• No difference was observed after 3 days
• After 7 days streptokinase - treated patients
  had a higher
• clinical success rate ( 82 vs. 48 ,
  p0.01)
• Fewer referrals for surgery ( 9 vs. 45 , p
  0.02 )
• No significant radiologic and functional
  difference ( follow up 6 months )

Diacon AH, Theron J,et al. Am J respir Crit Care
Med 2004170(1)49-53.
20
Benefits of fibrinolytic therapy on the duration
the hospital stay !
Two study Significant benefit Bouros D, Schiza
S, Tzanakis N, et al. Am J Respir Crit Care Med
1999 15937 42 Tuncozgur B, Ustunsoy H,
Sivrikoz MC, et al. Int J Clin Pract 2001
55658 660 Three study Nonsignificant
results Davies RJ, Traill ZC, Gleeson FV.
Thorax 1997 52416 421 Diacon AH, Theron
J, Schuurmans MM, et al. Am J Respir Crit
Care Med 2004 17049 53 Maskell NA, Davies CW,
Nunn AJ, et al. . N Engl J Med 2005 352865
874
Yasuharu Tokuda, MD Dai Matsushima, et al.
Chest 2006 129783790
21
Double blind, placebo controlled,randomized
trial 52 Centers
22
MIST1 Trial
Purulent pleural fluid Acidic, pHlt7.2 Bacteria
positive
I.P. Streptokinase
Placebo Control
Alive? Needed surgery? Adverse events? Lung
Function? CXR? ( 3 and 12 months )
NEJM 352 865-874
23
MIST1 Trial

• All patient underwent chest tube drainage and
  received
• I.V. Antibiotics
• Antibiotics were choosen by the managing
  clinicians
• Intrapleural streptokinase 250.000 IU (n
  206 )
• 
  twice daily for three days
• or placebo (n 206 )

24
PRIMARY END POINT
At three months
No statistically or clinically significant
difference between the groups in the proportion
of patients Who required surgical
drenage Who died in the three months
after randomization
25
SECONDARY END POINTS

• At 12 months
• No difference patients who required surgical
  drainage
• or died.

RESULTS

• There was no benefit to streptokinase
• Mortality
• Rate of surgery
• Radiographic outcomes
• Length of the hospital stay

26
MIST1.....Different patients population !
Different treatment effect of a medical
intervention when applied to a different study
population.
Bouros et al. Preferentially selected patiens
in whom pleural
effusions did not resolve with
chest tube drainage ! MIST1
Enrolled patients with objectively diagnosed
emphyema and complicated PP
effusions
27
MIST1.Used different intervention setting !

• Streptokinase was mailed to study centers after
• randomization .
• Delayed fibrinolytic therapy
• Fibrinolytic therapy potentially
  effective
• when used in a timely manner !

28

• Inclusion criteria
• Heterogeneous patients at all stages of empyema
• formation !
• Some patients probably had organized
  (fibrous)pleural infections
• and were unlikely to benefit from
  fibrinolysis.

• The absence of CT or USG at enrollment and
• of comprehensive information on intraoperative
  findings
• - Makes it impossible to evaluate this
  factor !

29
Intervention group

• Advenced age .. 60 18
• The large proportion of patients with coexisting
• conditions ( 65 )
• Influenced some of the study end point
• Duration of the hospital stay !
• Potantial benefits of fibrinolytic
  therapy ??

30
Absences of management algorithms

• Administration of antibiotics ,
• Referral for surgical drainage made by
  judgement of a
• recruiting physician and,
• Techniques for the insertion of chest tubes

• There is not a standardized protocol
• Smaller tubes (Median, 12 French) !
• Placed without imaging !

31
Intrapleural streptokinase for empyema and
complicated parapneumonic effusions

• Randomised, double-blind, placebo controlled
  trial
• Streptokinase saline ( n22) , saline (n22)
• Standartize treatment interventions
• Larger chest tube ( 24 -28 French )
• Under ultrasonographic guidance
• Younger patients ( Mean age, 39 13 years )
• With fewer coexisting conditions ( 38 )
• Surgical drainage ( 9 vs. 45 )
• A low in hospital mortality ( 4.5 ) .
  Maskell et al. ( 23 )
• Spesific patients may benefit from fibrinolytic
  agents

Diacon AH, Theron J,et al. Am J respir Crit Care
Med 2004170(1)49-53.
32
5 studies , Fibrinolytic / placebo, randomized ,
n 575
Death ? and Surgical intervention ?
33
Difference in surgery ?
Surgery rate Surgery rate
Fibrinolytic Placebo
Davies 1997 0/12 3/12
Bouros 1999 2/15 6/16
Tuncozgur 2001 7/24 15/25
Diacon 2004 3/22 10/22
MIST1 2005 32/206 32/221
Total p0.072 44/279 (15.8 ) 66/296 ( 22.3 )
Chest et al. 2006 129 783-790
34
Conclution

• This meta-analysis does not support the rutin
  use of
• fibrinolytic therapy for all patients who
  require chest
• tube dreinage for empyema or complicated
  parapneumonic
• effusions.
• Selected patients might benefit from the
  treatment !

Tokuda Y, et al. Chest 2006 129 783-90.
35
This study has several limitations

• Number of trials / number of enrolled patiens !
• - Significant heterogenity !
• This meta-analysis had little istatisticaly
  power

• In analysing the need of surgical intervention
• Individual clinical judgement !
• Variability of
  clin. judgement

36
Pleural drainage
FUTURE INVESTIGATION
37

• Infected pleural fluid
• Viscous
• Lumpy
• Resistant to tube drainage

• Streptokinase does not improve these
  characteristics
• Despite the partial unification of the pleural
  collection,
• the fluid may still fail adequately , because
  it can not
• pass down the chest tube !

Light RW, Nguyen T, Mulligan ME, Sasse SA. The in
vitro efficacy of varidase versus streptokinase
or urokinase for liquefying thick purulent
exudative material from loculated empyema. Lung
200017813-8. Simpson G, Roomes D, Heron M.
Effects of streptokinase and deoxyribonuclease
onviscosity of human surgical and empyema pus.
Chest 20001171728-33. Simpson G, Roomes D,
Reeves B. Successful treatment of empyema
thoracis withhuman recombinant deoxyribonuclease.T
horax 200358365-6.
38
FUTURE INVESTIGATION

• Streptodornase
• Deoxyribonuclease ( Human recombinant DNAse )
• Tissue plasminogen activator ( Alteplase, t-PA)
• Single chain urokinase plasminogen activator
• Anti- growth factor antibodies

39
Reducing the viscosity of the pus !

• Recombinant DNase is a candidate for this role
• It reducess viscosity by fragmenting the free
  uncoiled
• DNA found in pus.
• Following failure of Streptokinase ( case
  report )
• Simpson
  G, et al. Thorax 2003 58365-6
• Intrapleural thrombolytic DNase MIST2
• In U.K. .Randomised , controlled study
• 5 mg recombinant DNAse, 10 mg tPA, both agents,
  saline

40
Fibrinolytic therapy ? or VATS ?
41
Fibrinolytic therapy / VATS ?

• 20 randomised, 9 to D SK, 11 to VATS
• VATS
• - Shorter drainage period and hospital stay
• Wait et al.
  Chest 1997 111 1548-51
• 60 children, 30 VATS, 30 D UK
• (Empyema)
• - No difference in drainage or hospital stay
• - VATS more expensive
• 
  Sonnappa et al. AJRCCM 2006 174 221-7

42
Immediate surgery for all?
72 pediatric multiloculated empyema Streptokinase
59, Urokinase 13 patients.2-10 day 73.7
.......rate of drainage was increased 59.7
.........Completely successful 20.8 .........
Partially successful 19.5 ......... Required
decortication
Ozcelik C, et al. Ann Thorac Surg 2003761849-53
43
VATS

• Requiring an operating room,
• General anaesthesia,
• With double lumen intubation,
• Various points of entery
• Disposible instruments

It has increased initial cost Is not
universally available and rutine use is out of
reach for the majority of heatlh care system
44
Div. of Pulmonology, Fac.of Medicine, Osmangazi
Univ.
PPE 44, Empyema 26 ( 27) Mean age
55.6 16.9 Hospitalized and treated
previously 31 (44.3 ) At another
hospital One or more comorbidity
41 (58.6 ) Mean hospital stay
18.4 9.5 days
2008
45
70 PPE, empyema
Grup Successfull
Unsuccessfull p PPE
1 19
0.003 Complicated PPE 2
19 Empyema
12 17 Total
15/70
55/70 Modality of therapy Only antibiotic
5
33 0.014 Daily thoracentesis
7 7 Tube
fibrinolytic 3
12 Thoracoscopy 0
3 Hospital stay
25 14.4 16 6.8
0.002
46
Pulmonology,Istanbul University
2000 - 2007 42 Compl.PPE, Empyema,
Retrospective analysis. USG Simple compl. PPE(
Class 4) Tube thoracostomy ( n20
) Multiloculation Culture positive . T.
thoracostomy streptokinase (
Class 5,7 )
( n 22 ) Surgical
intervention Tube thoracostomy 1 /
20 T.thoracostomy streptokinase 1 / 22
VATS
47
Tube Streptokinaz
Tube drainage
n 22 n
20 Age 53.318 50.8 11 Comorbi
dity 86.4 65 Septations
17 -- Drainage volume 948 512
ml 1600 1208 ml Drainage time 8.4 gün
11.7 gün Hosp. stay 18.5 8.3 gün 19.2
11 gün Cultur () 9 5 Clin.
Success rate 95.5 95
48
Cost

1. Compl.PPE, empyema,

Hospital stay
YTL Fibrinolytic therapy Max. hosp. Stay ( 23
days) 2.317 Min. hosp. Stay ( 8 days)
1.036 Mean
1.340 VATS ( in
surgical unite ) 5-7 days 3.000
49
E.K, 36, female
Fever 39 C
Pleural effusion Appearance Blurred WBC
11.000/mm3 PNL 76 pH 7.00 USG Multipl
loculation
Hospitalisation with 8 days story
50
Ceftriaxone 2 gr Claritromycine 2 x 500 mg
Tube thoracostomy ( 24 F ) Drainage 250 ml
. Fever is going on..
51
(No Transcript)
52
After intrapleural streptokinase ( 4 times
) Day 6 tube was removed Total drainage
1100 ml
53
C.A, 46, male
Pleural effusion - Empyema

• LDH 12.000 IU/L
• WBC 60.000/mm3
• Glukoz 30 mg/dl

USG Multipl loculation
Hospitalisation with ten days story
54
Amp. / sulbactam Clarithromycine Tube
thoracostomy 24 G
55

• Total drainage 450 ml
• - Fever is going on
• - Intrapleural Streptokinase

56

• Streptokinase 3 days
• Day 9 tube was removed
• Total drainage 1200 ml

57
Medical thoracoscopy ?
58
Medical thoracoscopy

• Performed under local anaesthesia or conscious
  sedation,
• In an endoscopy suit,
• One or two points of entery
• Reusable instruments

Tassi GF, et al. Advenced techniques in
medical Thoracoscopy. ERJ 2006281051-59
59
Typical empyema loculation
Tassi GF, et al. Advenced techniques in
medical Thoracoscopy. ERJ 2006281051-59
Removal of membranes with forceps
60
Advantages for medical thoracoscopy

• Lower costs compared with VATS.
• Mini invasive
• Is useful in the treatment of frail patients
  at
• high surgical risk

61

• Mean age 5818
• Retrospective
• 127 patients with
• multiloculated empyema
• USG guided
• 62 patients ( 49 ) received
• post interv. fibrinolysis for
• 3-5 days

62
RESULTS

• Primarly successful
• without further intervention.. 115 /127
  patients ( 91 )
• Insertion of a further chest tube (n2)
• or a second medical thoracoscopy (n2)
• Finaly 119 /12794 were healed by
• nonsurgical
  therapy
• 6 required surgical pleurectomy

Martin E, et al. Chest 20051283303-3309
63
RESULTS

• In patients treated with adjuvant fibrinolytic
  therapy
• Weak trend for a better outcome ( p 0.15 )

Chest tube drainage.Median of 7 days ( 2-23
) Time of drainage. lt 7 days58 of
cases lt
14 days..93 of cases Complication
.9/127.Subcutaneous empysema
64
Some limitations

• Full inspection of the pleural cavity !
• Pleurectomy ! !
• Debridement time consuming !

65
CONCLUTION - I

• An imported part of loculated PPE and empyema
  patients
• are successfully treated in the early period
  with USG
• guided tube and fibrinolytic therapy
• Although the MIST1 Study, it is more difficult
  to accept
• the authors that fibrinolytic therapy should
  generally
• be avoided in pleural infection !
• Additional investigation are needed to
  evaluate the role of
• anti-fibrotic, DNAse and more selective
  fibrinolytic
• drugs both as primary and adjunctive
  therapy

66
CONCLUTION - II

• Medical thoracoscopy, as a drainage procedure
  intermediate
• between tube thoracostomy and VATS, is
  significantly lower
• in cost .
• Sonographically stratified multiloculated
  empyema can safely
• and succesfully be treated by medical
  thoracoscopy.
• For this reasons, most of patients with early
  complicated
• PPE and empyema ,

do not need surgical therapy