MIST2

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Rahman, N. "Intrapleural Use of Tissue Plasminogen Activator and DNase in Pleural Infection". NEJM. 2011. 365(6):518-526.
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Clinical Question

Among patients with empyema, does the combination of tPA and DNAse improve resolution of pleural loculation, as evidenced by radiographic pleural fluid density?

Bottom Line

Major Points

Parapneumonic effusions and empyema are significant sources of morbidity and mortality. Antibiotics have difficulty penetrating the fibrinopurulent phase of pleural space infections. Video assisted thorascopic surgery (VATS) with decortication and washout are the gold standard for suitable candidates, however the procedure is invasive and many patients are not operative candidates. The investigation of intrapleural agents therefore are of interest as an additional treatment modality.

MIST2 followed the investigation of MIST1, an RCT of 454 patients [1], which found that administration fo tPA to patients with a pleural infection did improve mortality, need for surgery, hospital stay, lung function, or cause radiographic changes. Metanalysis shortly thereafter supported this conclusion [2] .

The major difference in MIST2 is the additional coadministration of intrapleural DNase, which is purported to improve fluid viscosity and prohibit bacterial biofilm formation. The results of MIST2 demonstrated a statistically significant decrease radiographic pleural opacity and hospital stay with tPA+DNase. MIST2 is a landmark paper in that it provides support and guidance for the quantity and agents to be administered for pleural effusions refractory to traditional medical managment. This regimen is particularly useful for patients who are poor surgical candidates, although can also be utilized in addition to surgical and medical intervention.

Guidelines

  • The American Association for Thoracic Surgery consensus guidelines for the management of empyema.
    • Class IIa: intrapleural fibronolytics should not be routinely used for complicated pleural effusion and early empyemas, although it is potentially beneficial, particularly in early loculations and empyema[3]

Design

  • Multicenter, United Kingdom
  • N=210
  • Double blinded, 2x2 factorial trial
  • Enrollment: December 2005-November 2008
  • Mean follow-up: 3-12 months
  • Analysis: Factorial study analysis of interactions of 2x2 table with primary outcome, with reflex significance at 5% comparing each intervention with placebo. Continuous outcomes analyzed as linear regression, binary outcomes as logistic-regression.
  • Primary outcome: Change in pleural opacity of hemothorax 1 week after treatment, or last radiographic prior to surgery/death
  • Modified intention to treat was performed comparing those with either tPA and/or DNAse (i.e. all intervention groups compared) to double placebo for the primary outcome
  • Secondary outcomes: referral for surgery, duration of hospital stay, adverse events

Population

Inclusion Criteria

One of the following 3 criteria
  • Clinically purulent criteria
  • Bacterial evident on gram stain
  • Pleural pH > 7.2
  • Age 18 or older

Exclusion Criteria

  • Age < 18
  • Previous treatment for empyema including surgery, intrapleural tPA, or intrapleural DNAse
  • Known sensitivity to tPA/DNAse
  • Coincidental stroke
  • Major hemorrhage/trauma
  • Major surgery within 5 days
  • Ipsilateral previous pneumonectomy
  • Pregnancy/lactation
  • Life expectancy < 3 months due to a pleural condition other than empyema
  • Pleural opacity < 5% hemithorax area


Baseline Characteristics

“Presented are the Characteristics of the tPA-DNase Group”

  • Age — yr 60±19
  • Male sex — no. (%) 31 (60%)
  • Percent of hemithorax occupied with pleural fluid 44.2% ± 24.9%
  • Duration of symptoms before randomization — days Median 13
    • Interquartile range 7-22
  • Small-bore tube, <15 French — no. (%)† 48 (94%)
  • Community-acquired infection — no. (%) 45 (87%)
  • Radiographic evidence of loculation — no. (%) 49 (94%)
  • Purulent pleural fluid — no. (%) 27 (52%)
  • Positive Gram’s stain or culture of pleural fluid — no. (%) 4(8%)
  • Pleural-fluid pH Median 6.9
    • Interquartile range 6.8–7.1
  • Lactate dehydrogenase in pleural fluid — IU/liter Median 3418
    • Interquartile range 3418


Interventions

  • tPA (10mg Actilyse, Boehringer Ingelheim)+ DNAse (5mg Pulmozyme, Roche) (N=48)
  • tPA + placebo (N= 48)
  • placebo + DNAse (N=46)
  • double placebo (N =51)
  • 6 did not receive medication
  • 11 < 5% pleural opacity at baseline
  • Intrapleural injections were given twice daily for 3 days. Chest tubes were clamped for 1 hour to allow for administration.


Outcomes

Comparisons are intervention vs. double placebo (modified intention to treat, as described above)”

Primary Outcomes

“Pleural opacity change from day 1 to day 7/surgery/death”

tPA-DNase
-29.5% vs. -17.2% (-7.9%, 95% CI -13.4 to -2.4%; P=0.005);
tPA
-17.2% vs. -17.2% (2.0%, 95% CI -4.6 to 8.6%; P=0.55);
DNase
-14.7% vs. -17.2% (4.5%, 95% CI -1.5 to 10.5%; P=0.14);


Secondary Outcomes

Surgical referral

tPA-DNAse vs. double placebo;
4.1% vs. 16% (OR 0.17, 95% CI 0.03 to 0.87; P=0.03):
tPA vs. double placebo:
6.3% vs. 16% (OR 0.29, 95% CI 0.07 to 1.25; P=0.10):
DNase vs. double placebo:
39% vs. 16% (OR 3.56, 95% CI 1.30 to 9.75; P=0.01):

Hospital Stay

tPA-DNAse vs. double placebo (days);
11.8±9.4 vs. 24.8±56.1 (Percent different -14.8%, 95% CI, -53.7 to -4.6%; P<0.001):
tPA vs. double placebo:
16.5±22.8 vs. 24.8±56.1 (Percent different -8.6%, 95% CI -40.8 to 3.3%; P=0.21):
DNase vs. double placebo:
28.2±61.4 vs. 24.8±56.1 (Percent different -3.6%, 95% CI −19.0 to 30.8%; P=0.73):

Subgroup Analysis

  • No differences were noted in preplanned analysis: purulent vs. nonpurulent fluid, large bore vs. small bore chest tube, loculation vs. no loculation

Adverse Events

  • 3% mortality before 7 days
  • 2 intrapleural hemorrhages
  • 2 GI bleed
  • 30 non-serious adverse events (pain, altered mental status, erythema, rash)

Criticisms

  • 30% of patients did not show radiographic evidence of consolidation
  • Statistical methodology has been challenged [4], [5]


Funding

  • Unrestricted educational grant to the University of Oxford from Roche UK
  • On author received lecture fees from ResMed UK, and another received lecture fees from Boehringer Ingelheim UK.
  • No other conflicts of interest

Further Reading

  1. Maskell NA et al. U.K. Controlled trial of intrapleural streptokinase for pleural infection. N. Engl. J. Med. 2005. 352:865-74.
  2. Tokuda Y et al. Intrapleural fibrinolytic agents for empyema and complicated parapneumonic effusions: a meta-analysis. Chest 2006. 129:783-90.
  3. Shen KR et al. The American Association for Thoracic Surgery consensus guidelines for the management of empyema. J. Thorac. Cardiovasc. Surg. 2017. 153:e129-e146.
  4. Kahan BC & Morris TP Reporting and analysis of trials using stratified randomisation in leading medical journals: review and reanalysis. BMJ 2012. 345:e5840.
  5. Kahan BC & Morris TP Improper analysis of trials randomised using stratified blocks or minimisation. Stat Med 2012. 31:328-40.