Parapneumonic effusions and empyema are significant sources of morbidity and mortality. Antibiotics have difficulty penetrating the fibrinopurulent phase of pleural space infections. Video assisted thoracoscopic 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.
However, the MIST1 study [1] found no clinical benefit from infusion of the fibrinolytic streptokinase into the infected pleural fluid collection. Streptokinase's fibrinolytic activity is systemic while tPA's fibrinolysis tends to be more localized to thrombi, which might drive more effective lysis of pathological thrombi, which might be advantageous in degrading the loculations in pleural infections. This study is registered with ClinicalTrials. Interpretation: For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response days after intracerebral haemorrhage.
The procedure was safely adopted by our sample of surgeons. Whether the fluid production contributes to the clinical benefits of intrapleural fibrinolytic therapy, and if so to what extent, remains to be established. DNase is a naturally occurring nuclease involved in the degradation of extracellular DNA following apoptosis and bacterial lysis in humans.
Dornase alpha, or rhDNase, is produced by recombinant technology and is identical to endogenous human DNase. It is licensed for use as a nebulised mucolytic in cystic fibrosis CF patients. In CF it reduces the viscoelasticity and adhesiveness of sputum by cleaving extracellular DNA from degraded bacteria and leucocytes, separating it from its proteins. In empyema, it is believed that the increased viscosity of pus arises from the high deoxyribonucleoprotein content from leucocyte degradation 9 , 26 , 29 , 44 , and thus intrapleural DNase may serve to thin pus and improve its drainage.
This effect was not reproduced with streptokinase alone 26 , The early crude streptococcal extracts reported to be effective in empyema contained streptokinase as well as streptococcal DNase. The latter is not present in modern day purified streptokinase preparations.
Biofilm formation has been described in many common respiratory bacteria, and DNase has been shown to interfere with this matrix, potentially enhancing the effect of antibiotics The formation of biofilms within the pleural space is yet to be demonstrated, therefore this proposed mechanism in pleural infection remain unclear and warrants further investigation.
Treatment with DNase alone may not always be favorable. When DNase treatment was extended from CF to non-CF bronchiectatic patients, a randomized controlled trial found detrimental results decline in FEV 1 and increased exacerbations It is speculated that DNase potentially interrupts bacterial biofilms on airway surfaces and liberate the bacteria which can worsen infection and outcomes.
Nebulized DNase is well tolerated. Reported adverse effects include pharyngitis, chest pain, bronchospasm, rash and dyspnoea. Systemic complications are rare as the absorption following nebulisation is minimal Small studies of intravenous DNase in humans suggest that DNase is rapidly metabolised by proteases with an elimination half life of hours 48 , The pharmacokinetics of DNase in the pleural space is unknown.
The combined use of tPA and DNase has been shown to have synergistic actions in an animal model of empyema 29 , and subsequent clinical trials 9. The original hypothesis was that the two agents work synergistically: tPA breaks down fibrinous septations within the pleural space to release pockets of infected pleural fluid whilst DNase reduces fluid viscosity thus allowing more complete drainage.
This concept is almost certainly over-simplistic. The interactions of tPA and DNase on the key cellular components in an infected pleural cavity, namely the residential mesothelial cells and the recruited inflammatory cells, are essentially unknown. Whether the drugs have direct effects on bacterial clearance and interactions with antimicrobials remains to be seen. The optimal dosage, frequency, and even order of administration, and whether the drugs can be mixed as a single instillation etc.
Routinely subjecting all patients to surgery therefore appears to be unnecessary. The precise role of surgery remains uncertain without strong evidence to guide when and in whom it should be employed. Nonetheless, when drainage is inadequate and there is ongoing sepsis, surgery remains a key intervention.
The main drawback of surgery is that it is restricted to those who have relatively low peri-operative risk, thus excluding many elderly patients and those with multiple comorbidities. Reported benefits of outcome from surgery are confounded by selection bias.
The magnitude of the bias was highlighted in a retrospective analysis of 4, patients from Washington State, USA 3 , of which Those surgically managed were significantly younger by almost 10 years mean age Additionally, video assisted thoracoscopic surgery VATS , and certainly thoracotomy, have associated morbidity.
Furrer et al. Although VATS has lower analgesia requirements and a shorter length of hospital stay as compared with thoracotomy, a third of patients still experience persistent pain or discomfort at the operation site after 3 to 18 months Furthermore, close to a fifth of VATS procedures require conversion to open thoracotomy 51 , thus increasing postoperative morbidity.
For these reasons, efforts have focused on identifying a minimally-invasive intrapleural treatment as an alternative to surgery. The ideal intrapleural therapy needs to be effective, safe and affordable. Patients were randomized to receive tPA plus placebo, DNase plus placebo, both agents, or double placebos. The primary outcome was the absolute change in the pleural opacity on a frontal chest radiograph between days 1 and 7. In contrast, tPA or DNase alone did not improve radiographic clearance.
Combination therapy was associated with a reduced duration of hospitalization, by 6. Overall mortality was low and there were no differences among the groups. It is important to emphasize that only the combination therapy was effective; tPA or DNase alone offered no significant benefits.
Indeed the DNase alone group had more surgical referrals than placebo. In the MIST-2 protocol, intrapleural treatment was given at the time of diagnosis of pleural infection. The safety profile of the treatment also requires validation. In this cohort of patients who would usually be considered for surgery, except for their comorbidity, No patients died from pleural infection. The median hospital stay from first intrapleural treatment dose was 10 IQR, days.
Pleural fluid drainage increased from mL median in the preceding 24 hours to a cumulative amount of 2, mL over the 72 hours following commencement of intrapleural therapy. Follow-up CXR C showed no significant residual thickening.
Chest pain is the most frequent side effect whereas bleeding, though uncommon, remains the biggest concern among clinicians and patients. The pain typically occurs with the administration of the first dose of tPA treatment 17 ; its cause is unclear and may be multifactorial. It is possible that tPA provokes inflammatory changes in an already inflamed pleural cavity. This sudden expansion of fluid within 60 minutes and the lysis of adhesions may generate pain. Production of a large volume of hemorrhagic pleural fluid is a common observation after intrapleural administration of fibrinolytics, and often provokes anxiety.
Significant pleural bleeding, defined as a reduction of haematocrit necessitating blood transfusion, is rare. In our series significant pleural bleeding occurred in only 2 of 1. There were no episodes of haemoptysis or gastrointestinal bleeding Other studies of single agent intrapleural tPA use also supported its safety. No major bleeding events were reported from patients with pleural effusions of various etiologies who received doses of intrapleural tPA mg daily Another two studies 54 , 55 , with 45 patients combined, also found no major bleeding complications.
Isolated cases of pleural bleeding have been reported in patients treated with intrapleural tPA which were receiving concurrent anticoagulation or had end stage renal diseases 56 - We recommend that response to therapy should be assessed daily. Lack of clinical improvement should trigger searches for alternative source of infection e. Monitoring the serum haematocrit levels can be helpful in detecting significant blood loss through induced hemorrhagic pleural fluid production.
Cessation of therapy and supportive measures e. The MIST-2 data suggested that initiation of treatment significantly shortened hospitalization which argued for its use as a routine.
To date, the regimen has only been used in adults and cannot be recommended in children, and specific patient groups e. Future research should aim to optimize dosing regimes. Understanding the mechanistic actions of tPA and DNase may allow refinement of treatment and knowledge that may benefit infections of other sites. Cost analysis data will be of interest. National Center for Biotechnology Information , U. Journal List J Thorac Dis v.
During the last five years, transcatheter and surgical closure of PFO in the cyrptogenic stroke and TIA population has grown in frequency world-wide. Observational retrospective reports, from both single and multi-center experiences of over patients, suggest Patent Foramen Ovale PFO closure to reduce the risk of recurrent migraine events in these populations may be beneficial, particularly for those patients in the migraine with aura subgroup.
Although none of these reports are from prospective, randomized, controlled trials, the reports are compelling enough in their totality to support further investigation of a well defined group in a prospective manner. The patients reported in these studies were brought to PFO closure with no expectation of their procedure having any impact on their migraine.
In fact, in many cases, the discovery of a history of migraine was not made until well after the PFO closure procedure. Patients will be followed one year post-implant.
Secondary Outcome Measures : Efficacy:Change in number of attacks from baseline period compared to analysis phase. Safety: Device success during index procedure without procedural complication. Incidence of major AEs during index procedure and post-procedure as they relate to the device and protocol specified medications. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below.
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