Mixing It Up: Coadministration of tPA/DNase in Complicated Parapneumonic Pleural Effusions and Empyema : Journal of Bronchology & Interventional Pulmonology

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Mixing It Up

Coadministration of tPA/DNase in Complicated Parapneumonic Pleural Effusions and Empyema

Bishwakarma, Raju MD*; Shah, Shiwan DO*; Frank, Luba MD; Zhang, Wei MS*; Sharma, Gulshan MD, MPH*,‡; Nishi, Shawn P.E. MD*

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Journal of Bronchology & Interventional Pulmonology: January 2017 - Volume 24 - Issue 1 - p 40-47
doi: 10.1097/LBR.0000000000000334
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Abstract

Despite advancement in medical care, the incidence of complicated parapneumonic pleural effusions and empyema (CPEE) continues to rise.1–3 In total, 20% to 40% of hospitalized patients with pneumonia develop empyema.4 Mortality of empyema ranges from 20% to 30%.1,3,5,6 Mortality tends to be higher in the elderly, immunocompromised patients, and patients with multiple comorbidities.1,3,5 First-line therapy consists of antibiotics with chest tube drainage.5,6 However, failure of medical therapy occurs in up to 30% of patients in which surgical drainage and decortication is necessary5–7 but associated with significant morbidity and mortality.8–11

Recently, intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) has been shown to improve drainage of CPEE, decrease length of hospital stay, and reduce surgical referral in the recent Multicenter Intrapleural Sepsis Trial 2 (MIST 2).6 This double-blinded 2×2 factorial trial randomized 210 patients with pleural infection to one of the 4 treatment arms: tPA 10 mg and placebo, tPA 10 mg and DNase 5 mg, DNase 5 mg and placebo and double placebo. Medications were given intrapleurally using a “serial administration protocol”: “medication 1” was instilled via chest tube and clamped to allow a 1-hour dwell followed by opening of the chest tube for a 2-hour drainage to prevent admixing, then “medication 2” was administered using the same procedure.12 This was performed twice daily for 3 days (12 total instillations). Although effective, this protocol is time consuming, requiring trained personel to administer medications 4 times daily, and return between administrations on 4 additional occasions to open the chest tube for drainage. Even in a strict randomized controlled trial setting such as MIST2, reported compliance rate was 71%.6 Studies showed that complexity of treatment is 1 factor associated with poor adherence to a regimen.13

Our rationale for coadministering tPA/DNase was to simplify the treatment by decreasing the number of intrapleural administrations and need to manipulate the chest tube. Serial administrations of tPA and DNase were likely used in prior studies as, per manufacturer prescribing information for DNase, mixing could lead to adverse physiochemical and/or functional changes of DNase or the admixed compound.14 However, coadministration efficacy and safety have been shown in animal models with CPEE.15,16 Piccolo and colleagues reported up to 30 of 107 patients were coadministered tPA and DNase. A separate analysis of these patients was not presented, but overall, the safety and efficacy results of their study were similar to MIST2.17

The standard of care at our institution has been a “co-administration treatment” in which 10 mg tPA and 5 mg DNase were administered together via chest tube followed by 20 to 30 mL of saline flush and allowed to remain in the pleural space for 2 hours twice daily for 3 days (6 administrations) to treat intrapleural sepsis. Dose, duration, and twice daily administration were guidelines based on MIST2 but were ultimately left at the discretion of the treating physician. The aim of this retrospective review of data was to report our experience with this regimen in patients with CPEE.

MATERIALS AND METHODS

This is a retrospective observational study of patients who were treated with coadministered intrapleural tPA (Alteplase) and DNase for complicated parapneumonic effusion from January 1, 2012 to April 30, 2015 at the University of Texas Medical Branch. This practice is standard of care at our institution. Informed consent was not necessary due to the nature of the study and this study was approved (VUID-168) by the Institutional Review Board at the University of Texas Medical Branch. All records were deidentified before analysis. Electronic medical records were reviewed for patient demographics, pleural fluid characteristics, laboratory data, chest tube size, timing of administration, total duration of treatment, and patient outcomes.

Study Cohort

Patients were identified retrospectively through search of the pharmacy database for receipt of tPA and DNase. Of these, patients who received tPA and DNase intrapleurally for the treatment of a CPEE were included in the study. CPEE was defined based on ACCP consensus guidelines18 as pleural fluid with any of the following: (1) exudative and loculated in a patient with community or hospital-acquired pneumonia, (2) Gram stain or culture positive, (3) macroscopically purulent. Pleural fluid pH is not readily measured at our institution and is not used as a criteria for chest tube insertion. Exclusion criteria were pleural space infections as a complication of a procedure or viscous perforation or age below 18 years.

Intervention Details

All patients underwent initial diagnostic thoracentesis and then chest tube drainage. The decision to insert a chest tube and when to initiate intrapleural tPA/DNase therapy was determined by the attending physician. Loculation was determined by chest imaging: chest x-ray (CXR), computed tomographic scan, or bedside sonogram. Intrapleural medications were given using a “coadministration route” twice daily for 3 days: 10 mg tPA and 5 mg DNase were simultaneously administered via chest tube followed by 20 to 30 mL of saline flush. The chest tube was clamped and the coadministered medications were allowed to “dwell” 2 hours before the chest tube was opened for drainage. Routine chest tube “flushes” were not performed unless indicated before instillation of intrapleural medications. Selection of antibiotics, timing of treatment, number of treatment doses, and removal of chest tube were per attending physician discretion.

Outcomes

Our primary outcome was successful treatment defined as clinical and radiologic improvement of pleural space infection upon hospital discharge without the need for surgical intervention. Clinical improvement was defined as normalization of temperature, white count, and blood pressure. Treatment failures were defined as patients who received surgical intervention or died before hospital discharge. Secondary outcomes of interest were dose and length of treatment, length of hospital stay, radiologic improvement, treatment complications, and 90-day mortality. Radiologic improvement was defined as a decrease in pleural opacification of the hemithorax on follow-up CXR after the third to seventh day of intrapleural treatment as assessed by an independent radiologist (Fig. 1).

F1
FIGURE 1:
Representative chest x-ray images at day 0 and after receiving 3 days of intrapleural coadministered tissue plasminogen activator/deoxyribonuclease.

Statistical Analysis

Patient characteristics were summarized using counts and percentages of categorical variables. Statistical analysis was performed on a per-patient basis. Length of hospital stay, treatment and chest tube duration, and lactate dehydrogenase are presented as median and interquartile range. All analyses were performed using SAS version 9.2 (SAS Inc., Cary, NC).

RESULTS

From January 1, 2012 to April 30, 2015, 39 patients received at least 1 coadministered tPA and DNase dose for CPEE (Table 1). Baseline characteristics of the study cohort are summarized in Table 2. Patients were relatively young and were admitted to general hospital beds. Half had at least 1 major comorbidity. Pleural fluid was radiographically loculated in all patients, grossly purulent in over half (58%), Gram stain positive in half, and culture positive in over a third. Streptococcus viridians was most commonly isolated, either alone or with another organism. The majority of patients were managed with an image-guided 14 Fr or smaller pigtail chest tube and received intrapleural tPA and DNase within 48 hours of chest tube placement.

T1
TABLE 1:
Individual Patient and Treatment Data
T2
TABLE 2:
Patient Demographics and Baseline Characteristics of Patient With Complicated Parapneumonic Effusion and Empyema Treated With Coadministered tPA/DNase

Treatment Success

Processes and outcomes are shown in Table 3. Overall, 33/39 patients (85%) were successfully treated with intrapleural coadministered tPA/DNase. Treatment failure occurred in 6/39 (15%): 3 (7.6%) patients were referred for surgery and 3 (7.6%) patients died. Of patients who received surgery, 1 patient improved clinically and radiologically but underwent video-assisted thoracoscopic surgery (VATS) decortication with pleural biopsy due to suspicion of malignancy. Another patient underwent VATS decortication after only 2 intrapleural treatments. The third patient had been treated for empyema 2 months prior at another institution, presented with repeat CPEE with lung entrapment, and underwent VATS decortication after completing 6 doses of intrapleural treatment with clinical improvement, but minimal radiologic improvement.

T3
TABLE 3:
Outcomes of Patients With CPEE Treated With Coadministration of Intrapleural tPA/DNAse

Of the 3 deaths, 1 patient presented in septic shock, multiorgan failure, bilateral group A β-hemolytic Streptococcus empyema, and died <48 hours after receiving only 1 intrapleural treatment per pleural space. Two patients had other life-threatening conditions. One patient had metastatic prostate cancer, aortic and mitral valve aminoglycoside-resistant Enterococcus faecalis endocarditis; and the other patient had terminal lung cancer and was transitioned to palliative care after receiving 3 intrapleural treatments. At 90 days, 4 patients were lost to follow-up. There were no deaths or rehospitalizations related to CPEE (9% mortality) during follow-up.

Radiographic Changes

Repeat CXRs were available on 35 patients. Pleural effusion opacity on CXR improved 3 to 7 days after initiating intrapleural treatment in 29/35 (83%).

Adverse Events

There was 1 complication (2.5%) reported as hemorrhagic transformation of effusion after the fourth intrapleural treatment was administered. Intrapleural tPA and DNase were discontinued. No further bleeding was observed and no blood products were administered. The patient improved clinically with complete drainage of the pleural effusion and was discharged without surgical intervention.

Duration of Hospital Stay

The median length of hospital stay was 14.5 days with 8.6 chest tube drainage days.

Treatment Procedure

Deviation from treatment per MIST2 protocol of twice daily instillations for 3 days occurred in 23 of 39 patients (59%). Although the majority (95%) received the MIST2 protocol dose of coadministered tPA and DNase, the number of patients receiving all 6 administrations varied. Eight patients received an extended treatment (range, 7 to 16 doses) and 13 patients received a shorter treatment (range, 1 to 4 doses). Of patients with extended treatment administrations, only 1 required surgery and received 10 total intrapleural treatments. Alternative dosages occurred in 2 patients: 1 patient with bilateral chest tubes but received 1 dose of 4 mg tPA and 5 mg DNase in 1 pleural space only; another patient received 20 mg tPA and 10 mg DNase in each hemithorax.

DISCUSSION

Our experience shows that the majority (85%) of patients with CPEE treated by a coadministration regimen of intrapleural tPA 10 mg and DNase 5 mg were successfully discharged home alive without need for surgery. This method seems to be safe and effective but warrants further study. Although direct comparisons cannot be made, the results of our study with regard to survival and rate of surgery seem similar to those mentioned in previous studies using twice daily, serially administered tPA and DNase.6,17

Patients in our study were young and have a high proportion of Gram stain and/or culture-positive pleural fluid samples. This likely reflects our institutional practice to inoculate fluids directly into culture media at the bedside and is shown to increase the proportion of patients with identifiable pathogens by >20%.19,20 Also, our hospital length of stay of 14.5 days was longer than the similar treatment arm of MIST2 of 11.8 days6 but similar to Mehta et al21 with 13 days. We feel our length of stay is skewed by 2 patients who developed CPEE during hospitalization and whose chest tubes were placed on hospital days 18 and 25. Early VATS has shown to decrease hospital length of stay in some studies.22,23 However, VATS is not always available or suitable for unstable patients or patients with comorbidity.

Strengths of our study include the broad inclusion criteria which included all patients regardless of expected prognosis or comorbidity. This adds strength to our observations. By including all patients in our analysis we present a more conservative estimate of safety and mortality. However, if we excluded 2 patients due to expected prognosis using criteria of MIST2 (one patient with terminal lung cancer, and another patient with metastatic prostate cancer and aminoglycoside resistant Enterococcus endocarditis) our adjusted rate of successful treatment would be 90% with an effective mortality at 90 days (1/39 patients died) of 2.8%.

Our study has several limitations. It is a retrospective, single-center observational study with a small number of patients. Also, radiograph appearance of pleural effusions were not quantified digitally, there were no predefined criteria for surgical intervention and all treatment decisions were made by attending physicians from various specialties with heterogeneity in management. We used subjective assessments of clinical and radiologic parameters as would be done in actual clinical practice. Radiologic improvement is assessed by the treating physician, either by personal review of images or review of radiologist reports, to determine treatment course. For the purpose of this study, we also report the assessment from an independent chest radiologist who subjectively evaluated the percentage of pleural opacification of the involved hemithorax and for radiologic improvement on day 0 and within 1 week of initiating intrapleural treatment. We did not calculate pleural effusion opacification of the hemithorax on CXR digitally because it is not a part of our daily practice. In addition, ultrasonography is a bedside examination which is performed more readily, accurately, and cost-effectively at our institution to assess pleural fluid volume and assist in treatment decisions.24 Finally, there was heterogeneity in the number and dosage of tPA and DNase administered. One argument may be those who did not complete 6 doses may only have needed chest tube drainage. Piccolo et al17 initiated intrapleural therapy, only if after 24 hours of chest tube insertion, pleural drainage remained inadequate. Still 16% of their study patients did not receive all 6 doses.17 Consensus regarding dose, frequency, timing, or number of either intrapleural treatments is lacking. Prior reports have extended duration beyond 3 days and use up to 100 mg tPA per administration.25–27 Mehta et al21 showed once-daily serial administration of tPA and DNase in a recent retrospective series was also safe and effective. This raises the opportunistic question whether the intrapleural CPEE protocol can be further simplified.

CONCLUSIONS

In our single-center study, intrapleural coadministration of tPA/DNase seems to be effective and safe in patients with complicated parapneumonic effusions and empyema. This case series supports the use of a simplified regimen which should be investigated in future prospective studies.

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Keywords:

complicated parapneumonic effusion; empyema; chest tube; fibrinolytic; tissue plasminogen activator; deoxyribonuclease

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