5/15/2018. Background. Disclosure Statement

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1 5/15/218 Efficacy of Bronchoscopically-Administered in the Setting of Primary Graft Dysfunction after Lung Transplantation Primary Investigator: Sana Ahmed, PharmD Research Associates: Matthew Soto-Arenall, PharmD, BCPS-AQ Cardiology, BCCCP Daniel Jackson, PharmD, BCPS David Erasmus, MD, MBChB Contact: Disclosure Statement These individuals have the following to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation: Sana Ahmed: Nothing to disclose Matthew Soto-Arenall: Nothing to disclose Daniel Jackson: Nothing to disclose David Erasmus: Nothing to disclose 217 MFMER slide MFMER slide-125 Presentation Objective At the end of this presentation, attendees will be able to: Evaluate the efficacy of bronchoscopicallyadministered surfactant on improving pulmonary function post lung transplant Background Target audience: Pharmacists 217 MFMER slide MFMER slide-127 Lung Transplant Mainstay of therapy and most effective treatment option in patients with end-stage lung disease Exhausted or refractory to less invasive, conservative therapies Can improve quality of life, extend life expectancy Remains associated with significant morbidity and mortality Primary Graft Dysfunction Transport of a donor lung from the site of procurement to the recipient requires submitting the organ to: Ischemic conditions Cold storage Eventual reperfusion Results in diminished lung compliance Clinically, this results in alveolar collapse, ventilation-perfusion mismatching, and pulmonary edema with impaired oxygenation Hartert M, et al. Dtsch Arztebl Int. 214; 111(7): MFMER slide-128 Shargall Y, et al. JHLT. 25; 24: Veldhuizen RA, et al. Am Rev Resp Dis. 1993; 148: MFMER slide-129 1

2 5/15/218 Primary Graft Dysfunction ISHLT definition: syndrome of acute lung injury developing within the initial 72 hours after lung transplantation with the degree of associated hypoxemia determining its severity PGD is a major cause of morbidity and mortality in the early post-transplant period Clinical course and pathophysiology of the most severe forms of PGD are most similar to acute respiratory distress syndrome Therapies for Primary Graft Dysfunction Mechanical and pharmacologic options: ECMO may be necessary for severe cases of PGD The use of surfactant has been briefly described for PGD; however, there is a lack of well-defined data Less invasive Nonsurgical Why? Easily available Snell GI, et al. JHLT. 217;36(1): Lee JC, et al. Proceedings of the American Thoracic Society. 29; 6: MFMER slide MFMER slide-131 Ability to reduce surface tension on the alveoli, allowing for recruitment of additional, functional alveoli Stabilizes the alveoli during end-expiration, mitigates atelectasis and alveolar edema, and provides optimal surface area for gas exchange Select Literature Review Novick JR, 1997 Hohfield JM, 1999 Strueber M, 1999 Amital A, 29 Animal models augmented survival, enhanced oxygenation and improved lung compliance Lung transplant recipients with severe PGD (n = 6) Continuously nebulized surfactant with subsequent improvement in lung compliance and tidal volume, reduction in alveolar-arterial oxygen gradient Lung transplant recipients with severe PGD (n = 5) Failed conventional therapies Intratracheal surfactant via bronchoscopic instillation as salvage therapy Improvement in acute setting, no deaths at 6 months A-a gradient can assess degree and determine cause of hypoxemia. 217 MFMER slide MFMER slide-133 Purpose PGD is one of the most common complications of lung transplantation with an incidence reported between 1 and 25% Early mortality Late outcomes Methodology Given the limited data on successful treatment options for PGD and the associated morbidity and mortality, this study aims to examine the efficacy of this non-surgical therapy in lung transplant recipients 217 MFMER slide MFMER slide-135 2

3 5/15/218 Mayo Clinic in Florida Study Design Academic medical center & specialty clinic (34 beds) One of the largest transplant programs in the country: 393 (217) Lung transplant: ~6 (since 21) Single-center, retrospective cohort analysis 217 MFMER slide MFMER slide-137 Data Collection Relevant data were obtained post-operatively through a review of the patients medical records: Radiographic data from chest x-ray Presence or absence of pulmonary infection Concomitant PGD treatment was defined as: Use of inhaled pulmonary vasodilators (nitric oxide or prostacyclins), statins, ACE inhibitors or ARBs, and/or anti-thrombin III Study Objectives Primary Objective Effect of bronchoscopically-administered surfactant on severe PGD as defined by the ISHLT grading scale Grade Infiltrates on chest PaO 2/FiO 2 ratio radiograph PGD Grade No Any PGD Grade 1 Yes > 3 PGD Grade 2 Yes 2 3 PGD Grade 3 Yes < 2 Secondary Objectives All-cause 3-day and 1-year mortality Development of donor-specific antibodies (DSA) and bronchiolitis obliterans syndrome (BOS) at 1 year 217 MFMER slide MFMER slide-139 Screening Criteria Patients screened 175 Results Exclusion criteria 19 Non-severe PGD Nonsurfactant MFMER slide MFMER slide-141 3

4 5/15/218 Baseline Demographics Baseline Demographics Variable (n = 45) Non-surfactant (n = 43) p-value Age, years, mean ± SD ± ± Male sex, n (%) 32 (71.1) 22 (51.2).54 Lungs transplanted, double, n (%) 3 (66.67) 29 (67.44).938 Pre-intervention PGD Grade.823 Grade 2, n (%) 23 (51.11) 23 (53.49) Grade 3, n (%) 22 (48.89) 2 (46.51) Indication for Transplant Non-surfactant MFMER slide MFMER slide-143 Baseline Demographics Infection = statistically significant Confounding Variables ACE inhibitor or ARB Non-surfactant PG ino ATIII Statin Primary Outcome = statistically significant 6 Severe PGD Post-Intervention Non-surfactant Hours 48 Hours 72 Hours 217 MFMER slide MFMER slide-145 = statistically significant Outcomes Impact of Number of Doses on Severe PGD 24 Hours 48 Hours 72 Hours Dose 2 Doses 3 Doses 4 Doses Outcomes PaO 2 /FiO 2 Ratio Non-surfactant T T1 T2 T A-a Gradient (mmhg) T T1 T2 T3 217 MFMER slide MFMER slide-147 4

5 5/15/218 Secondary Outcomes day 4.65 Mortality Non-surfactant year 11.9 Variable (n = 45) Non-surfactant (n = 43) p-value 1-year DSA formation, n (%) 15 (36.59) 14 (37.84).99 1-year BOS, n (%) 7 (17.7) 5 (13.51).759 Limitations Single center, retrospective chart review Small sample size Inclusion of only the most severe forms of PGD Potential selection bias towards the use of surfactant in clinically more acutely ill patients Uncontrolled variables Number of doses/timing of surfactant administration, use/duration of concomitant PGD therapies Lack of donor information Unknown if findings such as prolonged ischemia times or age of donor lungs would have altered results 217 MFMER slide MFMER slide-149 Clinical Implications ISHLT: Important consideration in clinical research Lack of concrete data, high morbidity and mortality Associated with increased risk of: Chronic lung Bronchiolitis allograft obliterans dysfunction syndrome Long-term pulmonary deterioration Independently associated with poor prognoses Few studies have evaluated the effects of surfactant on short- and long-term outcomes in transplant population This is the largest study to date evaluating the effect of surfactant in lung transplant recipients with PGD Conclusion Despite an overall higher PGD Grade in the group treated with surfactant, 1-year mortality was no worse trending towards decreased mortality. Surrogate markers of pulmonary function, DSA and BOS did not differ between the two groups at 72 hours. Future adequately powered, RCTs warranted Understand the influence and benefits of surfactant use in this population 217 MFMER slide MFMER slide-151 Knowledge Assessment True or False: Based on the available data, there is strong evidence to support the use of surfactant to improve pulmonary function in patients with severe PGD post lung transplant. Acknowledgements Matthew Soto-Arenall, PharmD Daniel Jackson, PharmD David Erasmus, MD, MBChB 217 MFMER slide MFMER slide-153 5

6 5/15/218 Efficacy of Bronchoscopically-Administered in the Setting of Primary Graft Dysfunction after Lung Transplantation Primary Investigator: Sana Ahmed, PharmD Research Associates: Matthew Soto-Arenall, PharmD, BCPS-AQ Cardiology, BCCCP Daniel Jackson, PharmD, BCPS David Erasmus, MD, MBChB Contact: 217 MFMER slide-154 6