Oxygenation improvement, carbon dioxide elimination, hemodynamic parameters, and the amount of vasopressor substitution were documented before, as well as 2 and 24 hours after ILA initiation. The ILA led to an acute and moderate increase in arterial oxygenation; hypercapnia was promptly and markedly reversed within 2 hours, which allowed a less aggressive ventilation strategy by reducing tidal volume, PEEP, and peak inspiratory pressure. The incidence of complications was 24% (Table 3). Switching from initially 19F cannulae to the currently used 15 or 17F cannulae has resulted in fewer ischemia problems.
Bein suggested an algorithm for lung protection with the use of the ILA (Figure 1). In patients who range between ALI and ARDS according to the lung injury score (LIS) of approximately 2.5, and who are ventilated in a lung protective mode for 6–12 hours, an ILA should be implanted if blood gas analysis does not improve (pH <7.25). The underlying idea for this strategy is to prevent progressive deterioration and VALI. Characteristics of the ILA are: 1) very effective CO2 removal, 2) moderate but statistically significant oxygenation improvement, 3) ease of handling, 4) relatively low costs in comparison with ECMO, 5) long-term setting application (up to 100 days has been reported), 6) lower acceptable Activated coagulation time (ACT) levels than for ECMO.
Options for Bridge to LTx
Mechanical Ventilation Before LTx
The most frequently used approach to bridging acute lung failure patients to recovery or to LTx is the use of noninvasive or even invasive ventilatory support. During the past two decades, positive-pressure ventilation has helped to improve survival in patients with acute lung failure, but VALI remains a significant problem. Table 4 summarizes the advantages and disadvantages of mechanical ventilation. There is evidence that mechanical ventilation before LTx is a significant risk factor for post-LTx mortality23 and often leads to MOF.24 As a consequence, many transplant centers consider mechanical ventilation a contraindication for transplantation with only 3% undergoing LTx finally after being bridged by mechanical ventilation.25 At the final consensus panel discussion, the following main concerns regarding LTx in ventilated patients were identified: 1) ventilation-associated airway colonization may increase the risk of postoperative pneumonia. 2) Ventilation-associated complications, e.g., sinusitis, thromboembolism, hemodynamic compromise, and others may increase the risk of LTx and negatively impact on the outcome. 3) Prolonged sedation and ventilation lead to muscular wasting with delayed recovery, critical illness polyneuropathy and myopathy, and development of other infection sites such as skin ulceration. 4) Emergency intubation for acute hypoxemia or mechanical resuscitation (cardiopulmonary resuscitation; CPR) may lead to an unclear neurological situation before LTx. 5) Complications of a prolonged artificial airway may lead to post-LTx complications, such as swallowing dysfunction, tracheomalacia, and tracheal stenosis.
Mechanical Ventilation Before LTx: The Hannover Experience
Absolute and relative contraindications in mechanically ventilated HU LTx candidates according to the Hannover Thoracic Transplant Program (HTTP) protocol were presented by Gottlieb and Simon and are depicted in Table 5. Patients that show three of the delineated relative or one of the absolute contraindications are not considered to be appropriate LTx candidates.
The HTTP differentiates between three scenarios to evaluate mechanically ventilated patients before LTx (Table 6). These scenarios are based on the Hannover experience (n = 750 LTx procedures) as well as on outcomes reported in the literature. According to previous reports, only “scenario C” patients (“unstable” mechanical ventilation) have a significantly reduced post-LTx survival. A retrospective analysis of data from patients with “unstable” pre-LTx mechanical ventilation (scenario C) from January 2000 to September 2005 at the HTTP revealed an increase in the proportion of patients with “unstable” mechanical ventilation before LTx from 5% to 17%. Of these 39 scenario C patients (19 women, 20 men), 35% received additional extracorporeal gas exchange. The 1-year survival in the total cohort was 45%.
ECMO: The Vienna Experience
ECMO was introduced as a clinical application of extra pulmonary lung assistance in 1972 and, until recently, was the only treatment option for patients with ventilation-refractory lung failure. Although occasionally successful as a bridge to recovery or transplant,33 ECMO is associated with a range of severe complications.34 Potential treatment time with ECMO is very limited, and reported survival of patients that undergo LTx off ECMO is extremely poor with a 1-year survival of 40% or less.35
Wisser focused on peri- and postoperative management of lung transplant patients in which ECMO has been applied electively. Three main indications for the use of ECMO are: first, as a rescue therapy after LTx (primary organ failure); second, as a bridge to transplantation; and last as a protective concept intraoperatively or intra- and postoperatively during transplantation, as previously reported by the Vienna group in patients with pulmonary hypertension (PH).36
According to the Vienna experience, intraoperative elective application of ECMO or cardiopulmonary bypass provides hemodynamically stable conditions throughout the implantation period of both lungs and allows for controlled reperfusion of the grafts. This strategy prevents the so-called “first lung syndrome,” which occurs because of hyperperfusion of the first implanted lung during implantation of the second lung. The commonly seen right ventricular hypertrophy in patients with PH may add to this phenomenon.
Briefly, between 1999 and 2001, 17 patients with PH underwent bilateral LTx at the Vienna Lung Transplant Program. Femoral venoarterial ECMO support was set up. The flow was 50% of predicted cardiac output and there was prolonged ECMO support for the first 8 hours to allow protective ventilation and prevent overflow to the lungs in the early period after transplantation. Weaning was initialized after 4 hours, ECMO stepwise reduced, and after 8 hours explanted. This experience resulted in excellent initial organ function. Underlying mechanisms may include the concept of controlled reperfusion combined with protective ventilation.
In another study at the Vienna LTx Program, between 2001 and 2006 ECMO was used in a total of 146 of 308 LTxs (247 bilateral lung transplantation (BLTX), 59 single lung transplantation (SLTX), 2 heart-lung transplantation (HLTX)). In 77 patients intraoperative and in 54 patients intra- and postoperative support was applied. The complications that occurred are listed in Table 7. Three-month and 1-year survival curves are shown in Figures 2 and 3.
Bridge to LTx With Extracorporeal Ventilation: The Hannover Experience
Fischer presented the Hannover experience on the first application of ILA (Figure 4) as a bridge to LTx in a prospective observational study.37 Briefly, between March 2003 and March 2005, 176 LTx were performed at the HTTP including 54 HU LTx. Approximately 25% of HU listed patients at the HTTP require invasive mechanical ventilatory support. Twelve patients meeting HU criteria, who developed severe ventilation-refractory hypercapnia and respiratory acidosis despite maximal conventional ventilatory support, received ILA implantation in an arterialvenous femorofemoral position.
Brief summary of findings: 1) duration of ILA support was 15 ± 8 days (4–32 days). Interventional Lung Assist was explanted in all cases at the end of the LTx procedure. 2) ACT was 160–180 seconds after injection of a bolus of 10,000 IU heparin followed by continuous infusion. 3) Three patients required change of the device because of accidental clotting levels at ACT <150 seconds. 4) Four patients died from MOF (two before LTx, two on day 16 and day 30, respectively, after successful bridging to LTx with ILA). 5) Six hours after ILA implantation Paco2 levels decreased and pH increased significantly and remained stable. Further data are summarized in Table 8. 6) Only a slight, but statistically insignificant rise in oxygenation was noted. 7) All patients were hemodynamically stable throughout the bridging process.
The Hannover study showed the applicability of the ILA as a bridge to LTx in patients with end-stage lung failure who could not be sufficiently supported by mechanical ventilation.
Alternative Strategies: Controlled Reperfusion of Nonheart Beating Donor (NHBD) Lungs
Despite improvements in organ preservation, reperfusion injury remain a major cause of morbidity and mortality after LTx. According to International Society for Heart and Lung Transplantation Registry, graft failure is responsible for approximately 30% of deaths during the first 30 days after LTx.39 Bhabra et al. 40 first demonstrated in a rat model the need for lower initial reperfusion pressure to limit ischemia reperfusion injury. Van Raemdonck stated that controlled ventilation of a cold ischemic lung also is important. De Perrot et al. 41 ameliorated ischemic reperfusion injury in a rat lung transplant model by ventilating the ischemic graft in a controlled ventilatory mode (Table 9).
Van Raemdonck dedicated the second part of his talk to the topic of ex vivo lung perfusion. Fewer than 25% of all available multiorgan donors have lungs suitable for transplantation.43 Alternative sources such as organs from so-called NHBD might increase the potential donor pool. Steen et al. 44 performed the first successful single LTx with a lung from an NHBD after a warm ischemic interval of 65 minutes. In a porcine ex vivo model, lungs from NHBDs were transplanted into healthy recipient pigs and retained normal function during a 24-hour observation period.45 Rega et al. 46 demonstrated that interim ex vivo evaluation of NHBD lungs is a valid and safe method to assess graft function.
Van Raemdonck and his group hypothesized that, if the quality of inferior donor lungs could be improved outside the donor, some of them might still become suitable for transplantation. They performed a feasibility study47 in which human lungs rejected for transplantation were considered for ex vivo reperfusion. Starting in 2002, 20 double lungs in total were preserved, explanted, packed, and stored in an ice box until preparation. The stored lung was unpacked and cannulated. Blood from a reservoir passed an oxygenator used as a deoxygenator by sending nitrogen through the membranes. The deoxygenated blood passed a leukocyte filter and then entered a plastic box with the (heart-)lung block that was ventilated with 50% oxygen. Finally, the oxygenated blood flowed back. Assessments were performed on the inflow and outflow lines. Controlled reperfusion of the lung was performed. Composition of the reperfusion solution: Steen solution, deleukocyted red blood cell (15% hct), NaHCO3 (0.8 M) 45 ml/L, CaCl2 10 mg/ml, heparin 10.000 IU/L, nitroglycerine 2 mg/L, Tienam 500 mg. To limit alveolar injury from mechanical shear stress the lung was ventilated in a controlled manner.
The following graft parameters were measured during 2 hours: 1) pulmonary vascular resistance (dynes × sec × cm−5), pulmonary arterial flow (PAF) L/min, mean arterial pressure (MAP) and pulmonary arterial pressure (PAP) cm H2O, oxygenation index: Po2/Fio2 (mm Hg), wet-to-dry weight ratio. During the 2-hour period, there was no significant change in the measured parameters, meaning that the ex vivo system was not deteriorating. Results of this study indicated that it is technically feasible to reperfuse lungs for at least 2 hours; the system is stable for at least 2 hours; the system might serve as a model for further studies.
As a perspective, ex vivo lung perfusion may be a method to: 1) predict graft function in NHBDs I–II, 2) reassess graft function in HBD, 3) optimize inferior quality of lungs, 4) prolong the cold ischemic interval, 5) condition lungs against early and long-term graft dysfunction.
Extracorporeal ventilation in LTx brings new light to the concept of protective ventilation. Experimental and first clinical studies were able to show a potential role and benefit of extracorporeal ventilation, although it has to be underscored that controlled data are currently not available. The major indications seem to be bridge to transplantation, bridge to recovery in patients with primary graft dysfunction, and controlled reperfusion during transplantation, which requires the additional use of a blood pump. Future studies therefore have to be carefully designed, which may be reasonably performable in a multi-institutional setting only given the relatively small number of patients.
Fischer presented the outline of a phase I clinical investigation of safety and efficacy of the ILA as a bridge to lung transplant, which currently is being performed at the University of Toronto, Canada in a single-center trial. This study evaluates the safety of the Novalung (ILA) by collecting performance data on the device during extracorporeal lung support and by calculating the complication and failure rates observed with the device.
Appendix: Important Questions and Answers
Bridge to Lung Transplantation: What are the Options?
Patients with end-stage lung failure on the waiting list for transplantation can be treated with intermittent and long-term noninvasive ventilatory support using a mask or a helmet. In severe cases, mechanical ventilation is an additional option, but it is well known to be a risk factor for post-LTx mortality and should therefore be avoided if possible. If mechanical ventilation fails, extracorporeal gas exchange such as ECMO or, more recently the use of lung assist devices (e.g., Novalung) can be considered for bridge to lung transplantation in selected patients.
What is the Role of Extracorporeal Support Before LTx? What Are the Entry Criteria?
The Hannover study and additional case reports suggest that patients with pre-LTx ventilation-refractory hypercapnic lung failure can be supported with pumpless extracorporeal gas exchange and successfully bridged either to recovery or to transplantation. The contraindications for this type of support are severe arteriosclerosis and hemodynamic instability/shock. In patients with severe hypoxic failure, however, a pump-driven mode such as ECMO might be required. Extracorporeal gas exchange has been used for bridge to lung transplantation even in patients with systemic infection. Mechanical ventilation and/or extracorporeal gas exchange per se is no longer a contraindication for lung transplantation.
Are There Different Indications for ECMO and ILA?
Unlike ECMO, ILA is a pumpless device and a stable hemodynamic condition of the patient is a prerequisite. It removes carbon dioxide and thereby efficiently reverses hypercapnia. Hypoxemia is certainly not the primary indication, although the Regensburg group presented data on significantly improved oxygenation with the Novalung. The Hannover group, however, was not able to support this based on their experience.
What is the Success Rate of Different Bridging Strategies (MV, ILA, ECMO) in HU Lung Transplant Candidates?
There are no clinical data available comparing the outcome of ILA versus ECMO before lung transplantation. Mechanical ventilation before lung transplantation has been shown by the ISHLT Registry2 to be a significant risk factor for postlung transplantation mortality.
Where is the Cutoff Point Between Protective Ventilation and Injurious Ventilation?
A clear cutoff point has not yet been defined. Reducing the invasiveness of mechanical ventilation by applying reduced tidal volume, reduced PEEP, and PIP as shown by the ARDSNet Study significantly reduced mortality in mechanically ventilated patients, but some suspect that any positive pressure applied to the lung might be harmful.
What is the Role of ILA in Acute Graft Failure After LTx?
The role of ILA in acute lung failure after LTx has yet to be studied. However, the Toronto Lung Transplant Program has recently successfully used the Novalung ILA in a venoarterial mode supported by a centrifugal pump in a patient with primary graft dysfunction after single lung transplantation (Keshavjee S, personal communication 2006).
Is There an Indication for ILA Use in Nonintubated Patients? What Are the Criteria?
Although the application of ILA in nonintubated awake patients is an intriguing idea, it has not as yet been performed for bridge to lung transplantation. For this reason, no clinical criteria have been defined, and no evidence is available. This approach merits future investigation.
The members of the International iLA Study Group acknowledge the professional assistance in coordinating this manuscript by Ms. Maike Haas, Research Assistant at the Hannover Medical School.
1. World Health Organization: The World Heath Report 1998. Life in the 21st Century. A Vision for All
. Geneva, World Health Organization, 1998.
2. Trulock EP, Edwards LB, Taylor DO, et al
: Registry of the International Society for Heart and Lung Transplantation: Twenty-third official adult lung and heart-lung transplantation report—2006. J Heart Lung Transplant
25: 880–892, 2006.
3. de Perrot M, Bonser RS, Dark J, et al
: ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction. Part III: Donor-related risk factors and markers. J Heart Lung Transplant
24: 1460–1467, 2005.
4. de Perrot M, Weder W, Patterson GA, Keshavjee S: Strategies to increase limited donor resources. Eur Respir J
23: 477–482, 2004.
5. Hosenpud JD, Bennett LE, Keck BM, et al
: Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease. Lancet
351: 24–27, 1998.
6. Macklin CC: Transport of air along sheaths of pulmonic blood vessels from alveoli to mediastinum. Arch Intern Med
64: 913–926, 1939.
7. Petersen GW, Baier H: Incidence of pulmonary barotrauma in a medical ICU. Crit Care Med
11: 67–69, 1983.
8. Weg JG, Anzueto A, Balk RA, et al
: The relation of pneumothorax and other air leaks to mortality in the acute respiratory distress syndrome. N Engl J Med
338: 341–346, 1998.
9. Dreyfuss D, Saumon G: Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med
157: 294–323, 1998.
10. Parker JC, Ivey CL, Tucker JA: Gadolinium prevents high airway pressure-induced permeability increases in isolated rat lungs. J Appl Physiol
84: 1113–1118, 1998.
11. Dreyfuss, D, Soler, P, Basset, G et al
: High inflation pressure pulmonary edema: Respective effects of high airway pressure, high tidal volume, and positive endexpiratory pressure. Am Rev Respir Dis
137: 1159–1164, 1988.
12. Ranieri VM, Giunta F, Suter PM, Slutsky AS: Mechanical ventilation as a mediator of multisystem organ failure in acute respiratory distress syndrome. JAMA
284: 43–44, 2000.
13. Stuber F, Wrigge H, Schroeder S, et al
: Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury. Intensive Care Med
28: 834–841, 2002.
14. Imai Y, Parodo J, Kajikawa O, et al
: Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA
289: 2104–2112, 2003.
15. Vincent JL, Akca S, De Mendonca A, et al
: SOFA Working Group: Sequential organ failure assessment. The epidemiology of acute respiratory failure in critically ill patients. Chest
121: 1602–1609, 2002.
16. Brochard L, Roudot-Thoraval F, Roupie E, et al
: Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trial Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med
158: 1831–1838, 1998.
17. van Kaam AH, Lachmann RA, Herting E, et al
: Reducing atelectasis attenuates bacterial growth and translocation in experimental pneumonia. Am J Respir Crit Care Med
169: 1046–1053, 2004.
18. Villar J, Kacmarek RM, Hedenstierna G: From ventilator-induced lung injury to physician-induced lung injury: Why the reluctance to use small tidal volumes? Acta Anaesthesiol Scand
48: 267–271, 2004.
19. Reng M, Philipp A, Kaiser M, et al
: Pumpless extracorporeal lung assist and adult respiratory distress syndrome. Lancet
356: 219–220, 2000.
21. Bein T, Weber F, Philipp A, et al
: A new pumpless extracorporeal interventional lung assist in critical hypoxemia/hypercapnia. Crit Care Med
34: 1372–1377, 2006.
22. Lewandowski K, Rossaint R, Pappert D, et al
: High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation. Intensive Care Med
23: 819–835, 1997.
23. Smits JM, Mertens BJ, Van Houwelingen HC, et al
: Predictors of lung transplant survival in eurotransplant. Am J Transplant
3: 1400–1406, 2003.
24. Imai Y, Parodo J, Kajikawa O, et al
: Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA
289: 2104–2112, 2003.
25. Taylor DO, Edwards LB, Boucek MM, et al
: Registry of the International Society for Heart and Lung Transplantation: Twenty-second official adult heart transplant report–2005. J Heart Lung Transplant
24: 945–955, 2005.
26. Madden BP, Kariyawasam H, Siddiqi AJ, et al
: Noninvasive ventilation in cystic fibrosis patients with acute or chronic respiratory failure. Eur Respir J
19: 310–313, 2002.
27. Massard G, Shennib H, Metras D, et al
: Double-lung transplantation in mechanically ventilated patients with cystic fibrosis. Ann Thorac Surg
55: 1087–1091, 1993.
28. Baz MA, Palmer SM, Staples ED, et al
: Lung transplantation after long-term mechanical ventilation: Results and 1-year follow-up. Chest
119: 224–227, 2001.
29. Bartz RR, Love RB, Leverson GE, et al
: Pre-transplant mechanical ventilation and outcome in patients with cystic fibrosis. J Heart Lung Transplant
22: 433–438, 2003.
30. Niedermeyer J, Hoffmeyer F, Strüber M, et al
: Lungentransplantation bei beatmeten Patienten. Intensivmed
36: 183–189, 1999.
31. Meyers BF, Lynch JP, Battafarano RJ, et al
: Lung transplantation is warranted for stable, ventilator-dependent recipients. Ann Thorac Surg
70: 1675–1678, 2000.
32. Adams DH, Cochrane AD, Khaghani A, et al
: Retransplantation in heart-lung recipients with obliterative bronchiolitis. J Thorac Cardiovasc Surg
107: 450–459, 1994.
33. Jurmann MJ, Haverich A, Demertzis S, et al
: Extracorporeal membrane oxygenation as a bridge to lung transplantation. Eur J Cardiothorac Surg
5: 94–97, 1991.
34. Fischer S, Bohn D, Rycus P, et al
: Extracorporeal membrane oxygenation (ECMO) for primary graft dysfunction (PGD) after lung transplantation: Analysis of the Extracorporeal Life Support Organization (ELSO) Registry. J Heart Lung Transplant
25(suppl 2): A231, 2006.
35. Fischer S, Struber M, Haverich A: [Current status of lung transplantation: patients, indications, techniques and outcome]. Med Klin (Munich)
97: 137–143, 2002.
36. Wisser W, Marta G, Senbaklavaci O, et al
: BLTX with intra- and postoperatively prolonged ECMO in patients with pulmonary hypertension: Beneficial effect on initial organ function. J Heart Lung Transplant
20: 224–225, 2001.
37. Fischer S, Simon AR, Welte T, et al
: Bridge to lung transplantation with the novel pumpless interventional lung assist device NovaLung. J Thorac Cardiovasc Surg
131: 719–723, 2006.
38. Matheis G: New technologies for respiratory assist. Perfusion
18: 245–251, 2003.
39. Hertz MI, Mohacsi PJ, Taylor DO, et al
: The registry of the International Society for Heart and Lung Transplantation: introduction to the Twentieth Annual Reports—2003. J Heart Lung Transplant
22: 610–672, 2003.
40. Bhabra MS, Hopkinson DN, Shaw TE, et al
: Controlled reperfusion protects lung grafts during a transient early increase in permeability. Ann Thorac Surg
65: 187–192, 1998.
41. de Perrot M, Imai Y, Volgyesi GA, et al
: Effect of ventilator-induced lung injury on the development of reperfusion injury in a rat lung transplant model. J Thorac Cardiovasc Surg
124: 1137–1144, 2002.
42. de Perrot M, Keshavjee S: Lung preservation. Semin Thorac Cardiovasc Surg
16: 300–308, 2004.
43. Egan TM, Boychuk JE, Rosato K, et al
: Whence the lungs? A study to assess suitability of donor lungs for transplantation. Transplantation
53: 420–422, 1992.
44. Steen S, Sjoberg T, Pierre L, et al
: Transplantation of lungs from a non-heart-beating donor. Lancet
357: 825–829, 2001.
45. Steen S, Liao Q, Wierup PN, et al
: Transplantation of lungs from non-heart-beating donors after functional assessment ex vivo. Ann Thorac Surg
76: 244–252, 2003.
46. Rega FR, Jannis NC, Verleden GM, et al
: Long-term preservation with interim evaluation of lungs from a non-heart-beating donor after a warm ischemic interval of 90 minutes. Ann Surg
238: 782–792, 2003.
Copyright © 2008 by the American Society for Artificial Internal Organs
47. Neyrinck A, Rega F, Jannis N, et al
: Ex vivo reperfusion of human lungs declined for transplantation: A novel approach to alleviate donor organ shortage? (abstract) J Heart Lung Transplant
23: S172–S173, 2004.