Recent Challenges to Standard Criteria

1. Recent Challenges to Standard Criteria • Zafar et al, J CardiovascSurg2012;143:919-25 • Quotes the Consensus Report from The Pulmonary Council of International Society of Heart and Lung Transplant • “The origins of the standard arterial blood gas (P/F ratio) for suitability of a donor is shrouded in the mists of time” • “It is more puzzling as to why this standard has been so closely adhered to” • States that “there are no studies which address this issue specifically”

2. Recent Challenges to Standard Criteria • Zafar et al, J CardiovascSurg2012;143:919-25 • Retrospective review UNOS data base 1/2000-11/2009 • 12,045 lung txn with P/F ratios available • 80% P/F>300 • 20%<300 (5% P/F 201-300 + 15% P/F<200) • No differences in graft survival based on donor P/F ratio were found

3. Extended Criteria Lung Donors • Recent review, Snell et al: CurrOpin Organ Trans 2013, 18:507-512 • Extended donors accounted for 24-77% of lungs transplanted across 10 LTx programs • 2 subgroups of extended • General donor medical concerns: older age, hx cancers, (+)hepatitis serologies lead to chronic allograft dysfunction • Lung specific issues: prior smoking, asthma, aspiration, infection, fluid overload lead to acute graft dysfunction

4. Extended Criteria Lung Donors • Recent papers from Australia, Japan, and a center in Spain report that 54-63% of donor offered lungs were used for transplantation without demonstrable differences in outcome between ideal and “extended” donor lungs

5. Reasons for suboptimal donor lung function Donor Factors – Preexisting conditions Asthma, smoking, infection, etc Cause of death related Aspiration, contusions, fractures, pneumos, infection Head injury – neurogenic pulm edema Vent induced injury / infection Brain death related Donor Management related

6. Effect of Brain Death Physiology on Lung Function From shifts of catecholamine storm Dysregulation of neurohumoral factors Pro-inflammatory mediator release Endothelial permeability Mechanism of injury/ initial management Trauma , aspiration, infection, transfusion Neurogenic pulmonary edema Cardiogenic and non-cardiogenic pulmonary edema Atelectasis Hypoventilation,secretions,no cough, no gag High FiO2 Hypoxia Decreased Lung compliance

7. , Respiratory Systems Issues in Brain Dead Donor • No spontaneous respiratory effort • No coughing, sigh breaths, movement • Hypoxemia • Atelectasis/ plugging • Aspiration • Pulmonary edema (neurogenic, vasogenic) • Inflammatory response • Small percentage ~10% with ARDS • Decreased CO2 production

8. Respiratory Goals in DBD Donor • “Normal” ventilation and oxygenation • pH 7.35-7.45, PaCO2 35-45, O2 sats >95% • Limit Ventilator Associated Complications • Oxygen toxicity • <= 40% oxygen, the lower the better • Barotrauma • Plateau <30-35, PIP<35-40, MAPs<20-25 • Generally need PIPs in mid 20s for acceptance • Volutrauma – • TV 6-8 ml/kg of ideal body weight • PaO2/ FiO2>300

9. What Ventilator Mode to use? • No one mode proven “ideal” • Goals: Reduce atelectasis, avoid ventilator induced lung injury • Practices historically diverse based on OPO and local Lung Transplant Program/ Surgeon biases • VCV • PCV/ PRVC/ PCIRV • Any mode with high PEEP • Extreme PCIRV – APRV/ BiVent/ BiLevel • HFOV

10. Strategic Pause Few good studies available in donors, must adapt some of what we know from ICU care integrated with brain dead physiology

11. Resp Goals – Getting There • Mindset: All donors are lung donors until proven not • Alveolar recruitment strategies: Goal P/F>300 and avoid toxicities • CPAPwould be best but donors need a little ventilation • CPAP/Sigh maneuvers • VCV/PCV+ High PEEP->PCIRV, extreme PCIRV (APRV, BiVent, BiLevel, other names), HFOV • Early and repeated bronchoscopy – with minimal saline lavage • Albuterol, mucomyst, chest physiotherapy, suctioning, positioning • Adjunct meds: corticosteroids, naloxone • Fluid Status - euvolemia, loop diuretics

12. PEEP and lung recruitment Reversibility of Lung Collapse and Hypoxemia in Early Acute Respiratory Distress Syndrome. Borges et al Am J RespCrit Care Med 2006

13. Determinants of Improved Oxygenation • Oxygenation via mechanical vent support is improved by • Increase in FiO2 • Increase in Mean Airway Pressure • May be achieved in many ways ie: increasing PEEP, increasing PIP (either by increasing volume or pressure) • Improving VQ matching

15. Determinants of Effective Ventilation CO2 production (minimal with BD) CO2 elimination: Minute ventilation Recall that MV = TV x RR If alveolar ventilation falls, PCO2 rises linearly and also affects oxygenation

16. To adjust ventilation • Change TV • Change RR • Improve VQ matching • Try to recruit more surface for gas exchange • Treat any existing airway obstruction • Provide adequate cardiac output

17. Inadequate ventilation • DOPE Pneumonic – mechanical problem • Displacement, Obstruction, Pneumothorax, Extubation • An underlying medical issue: asthma, COPD, etc • Aspiration/ ARDS

18. Recruitment maneuvers: Pitfalls Suctioning=derecruitment – especially open suctioning Sigh/sustained CPAP with aim to increase alveolar recruitment May be more effective in pts on low PEEP May cause overdistention in pts on high PEEP Elevated intrathoracic press-barotrauma, decrease cardiac output

19. Back to our donor • You (the OPO) consult with the team that has been caring for the patient and decide to initiate PC ventilation, 6 ml/kg TV based on ideal weight, increase PEEP to 10, take the I-time to a 1:1 ratio, order a bronch. You wait for 4 hours and the repeat ABG is • pH7.36/pCO2 36/pO2 90/ bicarb 19/ BE -4 on FiO2 of 60% giving a PF ratio of 150 • What now?

20. What tidal volume should you target? A. 6-8 ml/kg B. 10-12 ml/kg C. 15-20 ml/kg D. 500-700ml irrespective of weight E. I count lung expansion and adjust accordingly

21. Low TV • Mascia et al JAMA 2010;304(23):2620-27 • RCT at 10 European centers (2004-09) • Gp 1: TV 10-12 ml/kg, PEEP 3-5, open suction, apnea test. • Gp 2: 6-8 ml/kg TV, PEEP 8-10, closed suction, apnea test with CPAP Results: • 54% vs. 95% met criteria for transplantation (p<0.001); 27% vs. 54% actually used; 6 mo. survival identical

22. Volume Control Ventilation (VCV) • Tidal volume set, control risk of Volutrauma • Controls minute ventilation so PaCO2 and pH • Pressure is determined by volume and compliance so risk of barotrauma, de-recruitment may cause pneumo… • Limitation: in Donor Lung Management, variable PIP, MAP (higher PIP and lower MAP for same TV compared to PCV – worse oxygenation/ recruitment, increase risk of barotrauma

23. Pressure Control Ventilation (PCV) • Larger inflation volumes may cause distension and exacerbate lung injury • Pressure cycled ventilation limits barotrauma • Airway flow decreases to limit mean and peak airway pressures • Limitations: variable tidal volumes so unreliable ventilation, risk of volutrauma

24. Pressure Regulated Volume Control (PRVC) • “Variable” or dynamic pressure control setting • Permits delivery of TVs with decelerating flow in a predefined pressure range – controlled volume with variable pressure to achieve • As recruitment occurs PIP decreases which may lead back to de-recruitment

25. San Antonio Lung Transplant Donor management protocol (SALT) Angel et al. Am J RespirCrit Care Med. 2006 Sep 15;174(6):710-6 • Key features • Transplant pulmonologist involved • Recruitment manouver, euvolemia/ diuresis, prevent aspiration (HOB 30º, cuff 25 mm Hg), bronchoscopy • PC 25, PEEP 15 for 2 hrs, then TV 10 ml/kg, PEEP 5, then ABG • Lung procurement improved: 25% vs. 11.5% • “Poor” donors provided 53% of the 121 transplants • 30 day and 1 year graft function identical

26. Extreme PCIRV(APRV/ BiVent/ BiLevel) • In spontaneously breathing the ventilation is spontaneous as well as during the low Plow Phase • In the non breathing patient or deceased donor these are PC or PCIRV modes of mechanical ventilation depending on the settings chosen • Hi and low Pressures (Phi/ Plow) set with a Hi and Low Times (Thi/ Tlow) delivered as decelerating flow

27. Extreme PCIRV(APRV/ BiVent/ BiLevel) • Hi and low Pressures (Phi/ Plow) set with a Hi and Low Times (Thi/ Tlow) delivered as decelerating flow • The higher the Thi/ Tlowratio is, the more inverse the I:E ratio is – it is not limited as in PC mode (max I:E 3-4:1) • Can get out to 12:1 or possibly higher • GOSH DAN, THAT IS EXTREME!!

28. Extreme PCIRV(APRV/ BiVent/ BiLevel) • Hi and low Pressures (Phi/ Plow) set with a Hi and Low Times (Thi/ Tlow) delivered as decelerating flow • The higher the Thi/ Tlowratio is, the more inverse the I:E ratio is – it is not limited as in PC mode (max I:E 3-4:1) • In the brain dead donor, think CPAP with release • Allows for increasing TV as recruitment occurs so • Need to adjust dP down to avoid volutrauma • Need to assure adequate ventilation • Less of issue in BD as less CO2 produced

29. Extreme PCIRV In spontaneously breathing ventilation is spontaneous as well an additional washout of CO2 during the Plow Phase In the non breathing patient like DBD donors, is PC or PCIRV mode of mechanical ventilation depending on the Time settings chosen

30. Extreme PCIRV • Improve oxygenation: Increase Phi, Thi, decrease Tlow • To transition begin with plateau press from previous vent settings as Phi (no higher than 35) • Thiinvert from 3:1 to 5:1 then 8-10:1 as able usually need to end about 4-6 sec • Ventilation: Higher Phiincreases dP • Plowdecreased to zero • Tllow0.6-0.8 sec to start may decrease to 0.4 if needed for increased SaO2 if MV adequate (to 0.2 in peds donors)

31. APRV in Donors 45 consecutive donors in Michigan 2003-2008, 20 ACV vs. 25 APRV starting in 2004 APRV donors slightly younger (34 ±11 vs. 41 ±12years) P/F ratio 498 ± 43 vs. 334 ± 104 APRV group: 42/50 potential lungs (84%) vs. ACV 7/40 lungs (18%) Graft survival at 1 and 3 years comparable to national averages Hanna, et al, JAMA Arch Surg. 2011;146(3):325-328. doi:10.1001/archsurg.2011.35

32. What about HFOV(High Frequency Oscillating Ventilation) • Set Mean Airway Pressure • Delivers hundreds of small TV breaths per minute • Little risk of Volutrauma • Little risk of Barotrauma • Little likelihood of lungs being accepted for transplantation • To foreign to transplant surgeons • Seen as last ditch modality for ARDS • But, you never know ….

33. Recruitment protocol (Quebec) Optimize ventilator settings (tidal volume, RR, pressure) Baseline blood gas with Fi2 100%; PEEP 5 Recruitment maneuver 30 seconds CPAP 30 (Hemodynamics monitored-prevent hypotension/decreased organ perfusion), 2 minutes on prior ventilator settings, repeat 30 seconds CPAP at 30 Then 1 hour of normal ventilation- FiO2 40%, PEEP, 10, PIP <30 mm Hg, then FiO2 100%; PEEP, 5 cm H2O for 20 minutes and obtain Blood Gas After blood gases are assessed, FiO2 is decreased to <50% Improved rate of lung utilization from 20% in 2005 to 24% in 2008 in Quebec. (2/3 were suitable for transplantation) Noisexet al. TransplProc2009; 41: 3284-3289

34. Lung Protocol-Michigan • Solumedrol q 6h, Ancef/Clinda, Naloxone, Albuterol/Atrovent q 4h, Inline suctioning, Mucomyst for thick secretions, Lasix/Bumex PRN, CPT q 2-4h • 10 ml/kg TV, MAP < 35, PEEP 5-8, FiO2 adjusted, pCo2 35-45 (If MAP> 35, changed to pressure control mode) • 2005-2008, from 37 lungs to 135 (↑267%) • Kirschbaum, Progress in Transplantation 2010; 20: 28-32

35. Adjunct Strategies • Steroids • Bronchodilators – Albuterol • current RCT - CTDN • Naloxone • Chest physiotherapy • Repeated bronchs, vest therapy, prone positioning • Mucolytics – mucomyst • Ex-vivo lung perfusion

36. Conflicts/Challenges • The lungs vs. rest of the organs (espkidneys) • I do not see this as much of an issue. The goal is maintaining adequate DO2 to the organs which include the lungs. • Aided by the increasing use in donor management of minimally invasive hemodynamic monitoring tools • Awaiting results of the MOnIToR study should be out later this year • Ventilator • Oxygen toxicity, Barotrauma, Volutrauma, Infection, Inflammation

37. Steroids High dose steroid administration steroids improves oxygenation 15 mg/kg solumedrol vs. no steroids No steroid treatment->decrease in PaO2 Steroid treatment->increase in PaO2 and increased lung utilization (25/80 vs. 3/38) (Follette DM, et al. JHLTx 1998) Administration of 1 g solumedrol reduced pulmonary fluid accumulation and was associated with increased donor yield (Venkateswaran RV et al, Ann Thor Surg 2008)

38. What about Naloxone? • Endorphins elevated in high altitude pulm edema. Gave Naloxone 0.1 mg/kg • 19 donors between 2002-2004 at Lifequest • PaO2 during O2 challenge increased from 329 ±171 to 363 ±193, (p=NS) • 1st dose N: 12 increased and 7 decreased • 2nd dose N: 14 increased and 5 decreased Eagan et al, Progress in Transpl 2009; 19(3): 267-271

39. OPO Management: days 4-6 ABG 7.42/ 36/ 160/ 18/ -3.5 Patient initially fluid resuscitated, given steroids, T4 and weaned off norepi, begun on low dose dopamine and given lasix x 1 • Bronch, recruitment • Vent change initially to PC, I:E 1:1, PEEP 10 then to PCIRV out to 7:1 P hi 24, P low 0, T High 4.5, T low 0.7 • Targeted TV ~8 ml/kg

40. Case continues -Now day 6 has remained on extreme PCIRV out to 10:1 with improving CXR and ABGs -Current PF ratio is 550 on PC 1:1, PEEP 5, TV 8 ml/kg with nl pH and pCO2 -You are ready to make lung offers What is the most important thing to have happen now? • Continue current management and hope the PF ratio maintains • Return to VC/AC, 8 ml/kg, PEEP 5 • Continue on 100% FiO2 • Get the transplant surgeons to come to the OR to look at the lungs • Continue recruitment approach until the lungs are recovered

41. On the HorizonEx-Vivo Lung Perfusion Warm perfusion on vent with nutritional perfusate Allows for ex-vivo recruitment, enables reassessment of marginal donors – still uses P/F ratio Leukocyte filter-reduces inflammation Extends WIT Allows for “conditioning” of DCD lungs

42. On the HorizonDCD lung recovery Not the focus of this talk but increasing data suggests this offers a significant additional opportunity to increasing available lungs for that work well post transplantation.

43. Summary-Mechanical Ventilation All donors are potential lung donors and managed in that way A tiered aggressive ventilator strategy including adjunctive therapies are key to optimizing donor lung yield Alternatives to CMV/SIMV are better for recruitment Limiting vent trauma remains paramount with mechanical ventilation 300 may not be the right answer, and may be resulting in lungs lost that could be transplanted We are in this together. Communication between the ICU team, the OPO team and the Transplant program teams will only improve what we are able to accomplish Transplant surgeons recover lungs for transplantation The science of donor/ donation tied to recipient outcomes is critical for advancing this young field

44. Principles of management • Elevate HOB 20-30 degrees, turn patient, consider prone positioning, chest physiotherapy • Inflate ETT cuff to 25 cm H2O • Suction + “PEEP” maneuver/Recruitment maneuvers • Bronchodilators (Albuterol: RCT at CTDN) • Steroids/Hormonal resuscitation • Bronchoscopy – early and possibly repeated • Antibiotics • Aggressive tiered ventilator strategy • VC->PC->PCIRV->extreme PCIRV • Take your time

45. Collaboration • There is a critical shortage of lungs for life saving transplantation • Optimum care for a potential donor requires a close working relationship between the OPO, the hospital staff MD, RN, RT, social services, chaplain services, etc. who have been caring for the patient. • Hospital professionals • recognize the potential donor, support organ function until the family may make an informed decision • significant knowledge of the patients family • achieving appropriate physiological parameters • experts in management of the critically ill patient • Ventilator approaches • medication choice and dosages • OPO personnel • end of life donation consultants • experts in the process of organ donation