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Ann Thorac Surg 2008;85:1202-1205. doi:10.1016/j.athoracsur.2007.12.032
© 2008 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Bridge to Lung Transplantation Through a Pulmonary Artery to Left Atrial Oxygenator Circuit

Christof Schmid, MDa,*, Alois Philippa, Michael Hilker, MDa, Matthias Arlt, MDb, Benedikt Trabold, MDb, Michael Pfeiffer, MDc, Franz-Xaver Schmid, MDa

a Department of Cardiothoracic Surgery, University Hospital Regensburg, Germany
b Department of Anesthesiology, University Hospital Regensburg, Germany
c Division of Pneumology, University Hospital Regensburg, Germany

Accepted for publication December 10, 2007.

* Address correspondence to Prof C. Schmid, Department of Cardiothoracic Surgery, University Hospital, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany (Email: christof.schmid{at}klinik.uni-regensburg.de).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background: There is no mechanical device available to support patients with end-stage lung failure for weeks and months until appropriate donor organs for lung transplantation are available.

Methods: In a 38-year-old female patient with primary pulmonary hypertension a paracorporeal artificial lung (PAL) system was placed parallel to the pulmonary circulation with connections to the pulmonary artery and to the left atrium. The key component of the PAL was a low-resistance membrane oxygenator.

Results: After institution, the PAL had a blood flow of 3.5 L/min and created a PaO2/fraction of inspired oxygen ratio of 270, while the oxygenator was provided with oxygen 3L/min. The pulmonary artery pressure declined by almost 50%. The PAL worked well over 62 days until appropriate donor lungs were available. With resuming more physical activity, an increased flow through the native lung augmented the fraction of unsaturated blood arriving at the left atrium, which mandated increasing oxygen flow to the PAL.

Conclusions: The data obtained with this case encourage further research into PAL systems, which may hopefully serve as a bridge to lung transplant device in appropriate patients in the future.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Since the advent of whole organ transplantation, numerous efforts and great hope have been transferred into the development of an artificial lung, as there are more than 750,000 patients with severe lung disease in the United States, about 150,000 of whom die each year. Further applications of an artificial lung exist for victims of chemical accidents and for military personnel. Pioneering work has been accomplished in the laboratories of R. Bartlett, who has had continuous funding from the NIH for more than 30 years for the development of artificial organs. Extracorporeal membrane oxygenation (ECMO), one of his major achievements, is now an essential tool in many intensive care units, but is not suitable for long-term use [1, 2]. Actually, there is no mechanical device available to support patients with end-stage lung failure for weeks and months until appropriate donor organs for lung transplantation are available.

Oxygenators have been known for years as a key part of a heart-lung machine. Since the first clinical use of a heart-lung machine in 1953 by Gibbon, oxygenators have been steadily improved, and now a wide variety of devices is offered worldwide. Almost all oxygenators contain microporous or diffusion membranes. The oxygenators are incorporated into an extracorporeal circuit, where the blood is pushed down the line and through the oxygenator by a centrifugal pump, regardless of the resistance within the device.

A new type of oxygenator with a plasma-leakage resistant poly-methylpenten membrane, heparin coating, and a rather low gradient across the blood steam was the first to be used without a pump but by the arteriovenous pressure gradient between a femoral artery and a femoral vein. This system called the iLA Membranventilator (Novalung, Hechingen, Germany) was developed in our institution and is now commercially available, and is very successful in ongoing trials [3]. However, as femoral vessel cannulation has the disadvantage of confining patients to bed, we sought to look for opportunities that allow patient mobilization, thus offering a much better quality of life.

In this report, we describe our first patient who underwent successful implantation of a paracorporeal artificial lung (PAL) as a bridge to lung transplantation, namely, placement of the cannulas into the pulmonary vessels within the chest.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
The basic idea of paracorporeal pulmonary support, namely, placement of an artificial lung in parallel to the native organ, and shunting the blood from the pulmonary artery to the left atrium, was devised by Zwischenberger and colleagues [4] in 2002. The concept of pulmonary support was seen as especially useful for patients with pulmonary hypertension.

Our patient was a 38-year-old woman. She was 184 cm tall with a body surface of 1.98 m2. She had suffered from primary pulmonary hypertension for many years, yet the cause of it remained unknown. With clinical signs of cholecystitis and gallstones, elective cholecystectomy was performed on March 5, 2007. Twenty hours later, she suffered severe right-side heart failure and mandated external heart massage. As the patient’s condition did not stabilize after more than 2 hours, it was decided to insert a minimal extracorporeal circulation (MECC) as a life support system through right atrial and aortic cannulation after median sternotomy.

After referral to our intensive care unit, MECC flow was 4 to 5 L/min with an oxygen transfer of 250 ± 35 mL/min and a carbon dioxide elimination rate of 265 mL/min. Mechanical ventilation was reduced to lung protective values (fraction of inspired oxygen [FiO2] 0.3, tidal volume 300 mL). After surgery, four surgical revisions were necessary for bleeding along with a high transfusion requirement of blood products. Within 48 hours, the patient had severe multiorgan failure with impaired liver function (bilirubin 8.6 mg/dL, aspartate aminotransferase >3,000 U/L), and required renal placement therapy. Chest roentgenogram demonstrated all signs of an acute respiratory distress syndrome. As weaning from the MECC failed during the next 5 days and long-term respiratory support became necessary.

With the patient being in multiorgan failure, the patient’s relatives gave permission for PAL implantation. The local Ethics Committee retrospectively approved the life-saving procedure, since our institution has a large experience with artificial pulmonary support. Implantation of the PAL was performed after 9 days of MECC support (on March 14, 2007). With the patient remaining on MECC, median sternotomy was reopened. A 16-mm graft (Vascutek-Gelweave; Inchinnan, United Kingdom) attached to a polyurethane inflow VAD cannula (Medos, Aachen, Germany) was anastomosed end-to-side to the main pulmonary artery with a polypropylene running suture using a Satinsky side-clamp. The inflow cannula was then passed through the second intercostal space on the left side, carefully avoiding kinking. The outflow cannula (right-angled, 32F; Medos) was inserted into the left atrium at the base of the left atrial appendage through two pursestring sutures, and exited below the left costal arch. An oxygenator (iLA Membranventilator; Novalung, Hechingen, Germany) was connected and immediately allowed to participate in the gas exchange. As left ventricular function was not compromised, the MECC could be slowly reduced. Right ventricular function was augmented with epinephrine to generate a flow of 3.5 L/min through the PAL. After halting extracorporeal circulation and decannulation, heparin was fully reversed with protamine. A continuous flow measurement was established for the cardiac output, and for the blood flow through the PAL. The antibiotic coverage included vancomycin, meropenem, and piperacillin.

Postoperatively, no bleeding complications were seen. Kidney failure persisted for 16 days, liver failure slowly improved. Sedation was minimized but extubation failed on day 13. With the aid of a tracheostomy, weaning from the respirator could be finally achieved 4 weeks after implantation of the PAL. The weaning procedure was further facilitated by an additional treatment with nitric oxide for 3 days, followed by iloprost inhalation, sildenafil, and bosentan medication. The patient was mobilized to walk around the ward, but further kept under intensive care conditions. During that time, she remained on full anticoagulation therapy with intravenous heparin. Partial thromboplastin time was measured three times a day and maintained in a range of 50 s to 70 s. Aspirin was added reduce the risk of thrombus formation, with platelet activation being measured by aggregometry, according to Born (Mölab Aggregometry, Berlin, Germany), on a daily basis. After 62 days on PAL (plus 9 days on MECC), an appropriate donor organ was available, and the patient underwent successful double lung transplantation in a cooperating lung transplant center (May 15, 2007). After lung transplantation, a mild stroke became evident, but symptoms were rapidly vanishing.

Patient and PAL data were obtained on a daily basis. For better visualization and to account for daily variations, data of every week were pooled, and an average and a standard deviation were calculated and depicted.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Immediately after institution, the PAL had a blood flow of 3.5 L/min and created a PaO2/FiO2 ratio of 270, while the oxygenator was provided with oxygen 3L/min. The extracorporeal flow was about half of the total cardiac output. The pulmonary artery pressure declined by almost 50% to 45 to 60 mm Hg. The pressure gradient (dpMO) across the oxygenator was about 10 mm Hg.

The relationship between cardiac output and PAL flow is depicted in Figure 1. During the first 4 weeks, oxygenator blood flow remained about 3 L/min. When the patient recovered and became increasingly mobilized, cardiac output increased, and pulmonary artery pressure and pulmonary vascular resistance indicators worsened. When the gas exchange decreased owing to fibrin deposition on the oxygenator membrane (as seen by electron microscopy) with consecutive decline of blood flow, the oxygenator was exchanged (on day 16, day 36, day 40, and day 60), which improved oxygen transfer immediately. During the exchange of the PLA, the pulmonary artery pressure rose to a suprasystemic level, which was hardly tolerated. On two occasions, the patient even had to be intubated to allow the PLA exchange.


Figure 1
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  		Fig 1. Time course of paracorporeal artificial lung (PAL) blood flow (solid circles) and cardiac output (open circles). Arrows mark time points of oxygenator exchange.

 
As the patient recovered, the oxygen transfer steadily decreased from 250 mL/min to 80 mL/min, carbon dioxide decreased from at 255 mL/min to 90 mL/min, to about week 6. With resuming more physical activity, the increase of cardiac output led to an increased flow through the native lung and increased the fraction of unsaturated blood arriving at the left atrium. The patient suffered dyspnea. Since the flow through the artificial lung could not be boosted, the oxygen flow had to be increased, which increased oxygen transfer to 140 mL/min, and dramatically relieved symptoms (Fig 2).


Figure 2
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  		Fig 2. Time course of oxygen transfer (solid circles) and carbon dioxide elimination (open circles).

 
Despite clinical ups and downs over the 9 weeks during intensive care therapy, the pulmonary resistance indicators remained constant, namely, there was neither an alleviation of pulmonary hypertension nor a worsening. With protective lung ventilation (FiO2 = 0.21) and intermittent spontaneous breathing, the central venous saturation remained in a range of 50% to 70%, while the PaO2 undulated between 100 and 140 mm Hg, and PaCO2 only rarely exceeded 40 mm Hg (Fig 3).


Figure 3
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  		Fig 3. Time course of pO2 (solid circles) and pCO2 (open circles) in the pulmonary artery (mm Hg), as well as of the central venous saturation (SvO2 % [gray boxes]).

 
Anticoagulation therapy was performed with intravenous heparin to achieve a partial thromboplastin time of 50 s to 70 s (Fig 4). With normalization of the platelet numbers and function, acetylsalicylic acid was added with a dosage of 50 mg to 100 mg, starting at day 10 to suppress 70% of platelet aggregation as measured turbimetrically with arachnidonic acid.


Figure 4
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  		Fig 4. Time course of platelets (solid circles) and partial thromboplastin time (PTT) (open circles). Arrow marks time point of oxygenator thrombosis.

 

   Comment
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 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
The development of a PAL is an upcoming focus of research as there is a consistent shortage of donor organs for lung transplantation. Previous animal experiments have shown that PAL driven by the native right heart, namely, working in series with the pulmonary circulation, created a 50% incidence of right-side heart failure [5–7]. Our patient already suffered right heart failure, which made a PAL implantation in series impossible. Adding an active compliance chamber for right heart assistance improved cardiac efficiency but increased pulmonary artery pressure and was difficult to synchronize with the cardiac cycle in animal experiments [6]. The basic idea in this case was to create an oxygenating shunt past the nonfunctioning lung to improve gas exchange and to lower the pulmonary vascular resistance, thus avoiding right-side heart failure. As in electronic circuits, total resistance in parallel connections is always lower than the lowest resistance. As the blood pressure usually drops only about 10 to 15 mm Hg across the oxygenator, a significant decline of the pulmonary vascular resistance was anticipated. The oxygenator had a total gas exchange surface of 1.3 m2, and was able to transfer 80 mL oxygen (and carbon dioxide) per liter blood flow; in other words, more than 250 to 300 mL of oxygen can be shifted to the blood compartment per minute during full extracorporeal support with 3 to 4 L/min flow—which is absolutely sufficient.

Implantation of the cannulas was rather simple. The Dacron graft of the inflow cannula was simply anastomosed to the pulmonary artery, and then guided outside the chest [8]. In this case, a direct route through the second intercostal space was chosen, but a subxiphoid exit as in cardiac assist devices would have been possible too. The outflow cannula, which was inserted into the left atrium, was not optimal, as a basket mounted at the tip of the cannula is prone to thrombus formation. An open tip seems more favorable.

Anticoagulation therapy was similarly well managed. The patient was kept on continuous heparin infusion, which may be replaced by oral anticoagulation therapy in appropriate patients. Because we fought several complications, our patient was only treated with additional aspirin on an empiric basis, comparable to cardiac assist systems. It has to be mentioned that if the PAL could have been implanted in series, thromboembolism would have been of no concern, as the native lung would have acted as a filter before the systemic circulation.

Three major problems were encountered during PAL support. First, during mobilization of the patient, the gas exchange module has to be kept at or below the level of the heart. If the PAL system is elevated, a negative pressure may form along the membrane between the gas and blood component inside the oxygenator, and loosen the barrier. That may lead to an increased bubble formation, and ultimately air embolism. Because we carefully watched the management, we did not encounter an increased bubble formation. Second, problems arose when the patient recovered and started to be more mobile. Cardiac output increased, as did the flow through the damaged native lung, and thus increased the fraction of unsaturated blood delivered to the left atrium. The only means to relieve a resulting severe dyspnea was to augment the oxygen flow to the oxygenator. That worked well and could even be regulated by the patient herself. And third, as the patient was strictly dependent on the PAL, exchange of the oxygenator was hardly tolerated. Severe shortness of breath mandated us to perform half of the exchange procedure during temporary intubation and mechanical respiration in a brief narcosis. As the patient remained on intensive care, this was easy to do.

In conclusion, we report on a PAL system that was connected in parallel to the pulmonary circulation. The data obtained with this case prove that the PAL system may well serve as a bridge to lung transplant device in appropriate patients. It is not yet possible to discharge patients with the PAL, as there are too many obstacles to overcome.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Bartlett RH, Gazzaniga AB, Jefferies MR, Huxtable RF, Haiduc NJ, Fong SW. Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy Trans Am Soc Artif Intern Organs 1976;22:80-93.[Medline]
  2. Hill JD, O’Brien TG, Murray JJ, et al. Prolonged extracorporeal oxygenation for acute post-traumatic respiratory failure (shock-lung syndrome). Use of the Bramson membrane lung. N Engl J Med 1972;286:629-634.[Medline]
  3. Reng M, Philipp A, Kaiser M, Pfeifer M, Gruene S, Schoelmerich J. Pumpless extracorporeal lung assist and adult respiratory distress syndrome Lancet 2000;356:219-220.[Medline]
  4. Zwischenberger JB, Alpard SK. Artificial lungs: a new inspiration Perfusion 2002;17:253-268.[Abstract/Free Full Text]
  5. Lick SD, Alpard SK, Montoya P, Deyo DJ, Jayroe JB, Zwischenberger JB. Artificial lung prototype development ASAIO Abstracts 1999;46:230.
  6. Alpard SK, Wang D, Deyo DJ, Smolarz CM, Chambers S, Zwischenberger JB. Optional active compliance chamber performance in a pulmonary artery-pulmonary artery configured paracorporeal artificial lung Perfusion 2007;22:81-86.[Abstract/Free Full Text]
  7. Lick SD, Zwischenberger JB, Alpard SK, Witt SA, Deyo DM, Merz SI. Development of an ambulatory artificial lung in an ovine survival model ASAIO J 2001;47:486-491.[Medline]
  8. Harper DD, Alpard SK, Deyo DJ, Lick SD, Traber DL, Zwischenberger JB. Anatomic study of the pulmonary artery as a conduit for an artificial lung ASAIO J 2001;47:34-36.[Medline]

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