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Ann Thorac Surg 2002;74:1011-1018
© 2002 The Society of Thoracic Surgeons
a The University of Texas Medical Branch, Galveston, Texas, USA
b MC3 Corporation, Ann Arbor, Michigan, USA
* Address reprint requests to Dr Zwischenberger, Division of Cardiothoracic Surgery, Department of Surgery, 301 University Blvd, Galveston, TX 77555-0528, USA.
e-mail: jzwische{at}utmb.edu
Presented at the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.
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Abstract |
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METHODS: Fourteen sheep were randomized to PAL (n = 8) versus VCMV (n = 6) to assess outcome. For PAL, arterial cannulas were anastomosed to the proximal and distal main pulmonary artery with an interposing snare diverting full flow through a paracorporeal loop. Acute respiratory distress syndrome was induced in both groups (48 breaths smoke insufflation, third degree burn on 40% of total body surface area). When acute respiratory distress syndrome criteria were met (24 to 30 hours after injury), the PAL was interposed in the paracorporeal loop. Both groups were managed with a VCMV algorithm minimizing tidal volume, ventilator rate, and fractional inspired concentration of oxygen (FiO2).
RESULTS: Six of eight PAL versus 1 of 6 VCMV sheep survived the 5-day study. In PAL, cardiac output, mean arterial pressure, pulmonary artery pressure, left atrial pressure, and central venous pressure remained stable. Average PAL gas transfer was 218.6 ± 17.7 mL/min O2 and 183.0 ± 27.8 mL/min CO2. Ventilator settings 48 hours after lung injury in PAL were significantly lower (p < 0.05) than VCMV (TV 210 versus 425 mL; respiratory rate 6 versus 29 breaths/min; minute ventilation 1.2 versus 10.8 L/min; FiO2 21 versus 100%). Likewise, PaO2/FiO2 ratio was normalized in PAL and still met acute respiratory distress syndrome criteria in VCMV. The PAL wet/dry ratio was significantly lower than VCMV (6.36 ± 0.63 versus 11.85 ± 1.54; p = 0.008).
CONCLUSIONS: In a prospective, randomized, controlled, unblinded, outcomes study, PAL decreased ventilator-induced lung injury in a lethal dose 80% to 100% ARDS model to improve 5-day survival.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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| The authors disclose that they have a financial relationship with MC3 Corp.
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In collaboration with MC3 Corporation (Ann Arbor, MI), our group has been developing a low-resistance, low-impedance paracorporeal artificial lung (PAL) prototype designed for weeks to months of support in a survival model of implantation in healthy sheep [4–6]. The PAL has undergone several modifications, with improvements in housing and attachments, an inlet compliance chamber, an inlet blood flow separator, and modified outlet geometry [5]. The result is a PAL prototype that functions reliably for up to 7 days. Having achieved the goal of survival in healthy sheep, the next step in development is to test the PAL in a large animal model of severe lung injury.
During the past several years, our group has developed a sheep model of acute respiratory distress syndrome (ARDS) using combined smoke inhalation with a third degree cutaneous burn [7]. This model involves a 40% total body surface area third degree burn and varying numbers of smoke breaths from a modified bee smoker through a tracheostomy. The severity of lung injury is proportional to the number of breaths: 36 breaths cause moderately severe ARDS (lethal dose 50% or LD50), whereas 48 breaths causes severe (lethal dose 80% to 100% or LD100) lung injury. Outcome studies with percutaneous arterial–venous carbon dioxide removal (AVCO2R) demonstrated that AVCO2R allowed a reduction in minute ventilation and peak inspiratory pressures [8], lessened barotrauma-induced ARDS [9], and conferred a survival advantage in a LD50 smoke/burn ARDS model [10].
We applied the PAL to our LD100 smoke/burn ARDS sheep model in a prospective, randomized, controlled, unblinded outcomes study comparing PAL to volume-controlled mechanical ventilation (VCMV) for 5 days.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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The developmental evolution of the current PAL prototype has been previously described by our group and other investigators [4, 5, 11, 12]. The experimental design of this study was a prospective, randomized, controlled, unblinded outcomes study comparing PAL to VCMV was 5 days or 105 hours (Monday morning through Friday afternoon) (Fig 1).
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Then, under the same general anesthetic, a 40% total body surface area third-degree cutaneous burn is made on both flanks using a propane torch against a template, followed by 48 positive-pressure breaths of smoke from a burning cotton towel delivered through a modified beesmoker by the tracheostomy [7]. The animals are returned to their cages and allowed to awaken. All animals receive mechanical ventilation as previously described for ARDS model development [6]. Intravenous fluids are administered according to the Parkland burn resuscitation formula: Lactated Ringer’s solution 4 mL · kg-1 · h-1 times percentage total body surface area burn for the first 24 hours; half given in the first 8 hours, the rest during the next 16 hours. After 24 hours, Lactated Ringer’s is decreased to 1 to 2 mL · kg-1 · h-1 and titrated downward depending on adequacy of oral intake and urine output.
Tuesday morning
All sheep met ARDS criteria before 14:00 (arterial oxygen tension [PaO2]/fractional concentration of oxygen [FiO2] ratio <200). Once ARDS criteria are met, the sheep is given 5,000 U of intravenous heparin, and undergoes a brief mask inhalation anesthetic (isofluorane). The pulmonary artery snare is loosened, and the external portions of the cannulas are clamped. The C-loop is removed, and the PAL interposed in its place. The cannulas are unclamped, the snare is again tightened (diverting full blood flow through the PAL), and the animal is allowed to awaken (Fig 2).
Intravenous heparin anticoagulation is continued for the duration of the study, titrating the heparin dose to an activated clotting time of 200 to 300 seconds. The sheep remain on a ventilator, treated with VCMV as a lung protective strategy to minimize volutrauma, according to our previously published ventilator management protocol [10]. Briefly, the protocol decreases the initial tidal volume (10 mL/kg) by 20% increments to achieve a peak inspiratory pressure less than 30 mm H2O. Respiratory rate is decreased to achieve arterial carbon dioxide tension (PaCO2) less than 40 mm Hg, and FiO2 is decreased to maintain PaO2 at more than 60 mm Hg.
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Control (VCMV) animals (n = 6)
Monday morning
Sheep are anesthetized, intubated, a tracheostomy performed, and the femoral vessels cannulated as in the PAL group. The sheep then undergo a 40% total body surface area burn and 48 breaths of positive-pressure smoke insufflation identical to the PAL group. The sheep remain on a ventilator for the duration of the study, according to the same VCMV algorithm as the PAL group.
Tuesday morning
All sheep met ARDS criteria before 14:00 of the second day. Once ARDS criteria are met, the sheep are given 5,000 U of intravenous heparin and maintained with a continuous heparin infusion (titrated to activated clotting time 230 to 300 seconds) until completion of the study.
Throughout the study, any animal judged to be in distress (systolic blood pressure <60 mm Hg or heart rate <40 beats/min for 1 hour, or PaCO2 >100 mm Hg or PaO2 <45 mm Hg) was euthanized.
Friday 16:00
All remaining sheep are euthanized as described. Autopsies are performed on all animals, with attention toward detecting pulmonary or systemic emboli. Lung wet/dry weights are measured.
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Results |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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A large animal survival model is important to show that an artificial lung is life sustaining, and not just compatible with animal survival. Simply removing an animal’s native lungs after PAL implant is not a clinically relevant model. The native lungs need to remain in the animal, and receive at least some pulmonary blood flow for two major reasons. First, the native lungs serve as a compliance chamber, allowing gradual filling of the left atrium. Second, the pulmonary circulation performs many vital metabolic functions, including deactivation of vasoactive compounds (bradykinin, serotonin, leukotrienes, and norepinephrine), and production of angiotensin II and prostacyclin [14]. The metabolism of these compounds decreases linearly with blood flow, and below 10% pulmonary flow an animal develops cardiovascular collapse [15]. In addition, our prior studies have shown that the metabolic rate and CO2 production are elevated early in ARDS [8]. In the current study, PAL gas exchange reached an equilibrium a few hours after onset of ARDS after which CO2 transfer and oxygenation varied less than 10%.
An artificial lung can be configured in-parallel (pulmonary artery [PA]–left atrium [LA]) or in-series (PA–PA) with the native circulation. The PA–LA configuration can either be complete (PA snared distally) or competitive (no snare). The complete PA–LA configuration not only denies the pulmonary bed of blood flow necessary for metabolic functions, but the excluded pulmonary bed is at risk for diffuse thrombosis. The competitive PA–LA configuration has the advantage of unloading the right ventricle by offering a parallel resistance bed. This configuration is recommended for pulmonary hypertension. The University of Michigan group has pursued the PA–LA configuration with their own MC3 prototype, showing that in a competitive PA–LA configuration, on average 47% of the right heart output will go through the University of Michigan Artificial Lung in healthy sheep [11] and 71% in a model of pulmonary hypertension [12]. However, the competitive PA–LA configuration inherently provides only partial gas exchange, and device change-out or malfunction risks left-sided embolism. More important, during times of intolerance to anticoagulation, the PAL cannot be removed from the circuit and replaced with a closed loop because of the resultant massive right-to-left shunting. For these reasons, our group has continued to pursue the PA–PA configuration. Although the additive impedance of the PAL and the injured lung could evoke right heart strain, the right heart (and cardiac output) tolerated the PAL with a LD100 lung injury model. In part, this could be due to the pulmonary vasodilating effect of the fully oxygen-saturated blood from the PAL into the pulmonary artery bed during lung injury [16].
The MC3/UTMB PAL is an ultra low-resistance, low-impedance membrane gas exchanger. Unlike traditional cardiopulmonary bypass oxygenators, blood enters a central port and distributes radially to an outer collection chamber to prevent shunt and improve efficiency [4]. The PAL prototype was originally made with sampling ports and slip-on connectors for acute use. Initial experience with our large animal survival model quickly showed prototype design weaknesses such as bleeding through broken ports or slipped connectors. The ports were deleted and the connectors redesigned to a more stable collet-nut design. Survival of some animals in our first series did achieve the target of 7 days [4]. However, the immediate right heart failure rate was 50%. The in-series configuration inherently places the highest strain on the right ventricle of any artificial lung configuration [17]. Three modifications were then incorporated into the PAL design: a silicone compliance chamber was added to the inflow port (to simulate the capacitance of the pulmonary arterial bed), an inflow dispersion cone was placed to more evenly distribute blood flow, and the outlet port geometry was modified. As a result, the PAL steady-flow gradient at 5 L/min blood flow dropped from 8 to 6 mm Hg. The modified PAL in normal sheep showed an increased cardiac output from 2.8 L/min to 4.2 L/min, with mean central venous pressure 6.8, and a decrease from 2.5 to 0.79 Wood units [5].
The PAL devices are made by a rapid prototyping technique using polyester resins inside a computer-generated silicone rubber mold allowing multiple design iterations and prototype fabrication. Because these are hand-built prototypes, the necessary biomaterials are less durable, and the tolerances less precise relative to commercial membrane oxygenators. We have not studied the blood/surface interactions in these early generation PAL prototypes because the final device will be constructed from more blood/surface compatible biomaterials (heparin-bonded or coated surfaces, silicone impermeable fibers, etc.).
Similarly, we have not investigated the pathophysiology of lung protective ventilation compared to the PAL at this early phase of development. However, we have evaluated the pathophysiology of lung injury in the smoke/burn sheep model treated with AVCO2R, which uses a commercially available membrane gas exchanger (Affinity AVECOR, Minneapolis, MN). We found reduced interleukin-8 mRNA and protein (possibly due to less lung stretch), fewer pulmonary neutrophils, and reduced pulmonary myeloperoxidase activity in the smoke/burn AVCO2R group versus smoke/burn controls [18]. The AVCO2R has demonstrated safety in a phase 1 clinical study [19] and is currently undergoing a phase II multicenter clinical trial as treatment for ARDS. Like our AVCO2R studies, the PAL reduced ventilator-induced lung stretch and presumably subsequent lung injury. In the near future when injection molded preproduction PAL devices with blood/surface compatible materials are available, we plan to study pathology at 48 hours with concurrent controls. Remarkably, in this study, the PAL demonstrates a survival benefit for severe (LD100) lung injury. We believe that these data imply a new potential application for the PAL as a bridge to recovery in early ARDS too severe for ventilator management or AVCO2R and too long-standing (>7 to 10 days) for extracorporeal membrane oxygenation.
Heparin has been shown to ameliorate lung injury if present before a smoke/burn injury [20, 21], possibly through antithrombin III-induced endothelial release of prostacyclin [22]. To allow ARDS development in our model, heparin was reversed immediately after cannula implant and chest closure, and before the smoke/burn injury. In addition, heparin reversal provided a window without any heparinization to allow early postoperative hemostasis. The VCMV control and PAL sheep were heparinized on the second study day, after ARDS criteria was met (PaO2/FiO2 < 200). Both groups received identical heparin exposure after induction of lung injury for the remainder of the study to eliminate heparin as an outcomes variable.
Based upon our success with the development of the PAL and the improved survival in this series, we plan additional large animal studies. First we will assess PAL long-term survival (weeks) in normal sheep. Next, we will conduct prospective, randomized, controlled, outcome studies in a LD100 model of ARDS comparing PAL to VCMV for 10 days. Finally, we will investigate the pathophysiology of PAL in a LD100 model of ARDS. Our goal is to develop clinically relevant PAL management protocols for long-term application in humans as a bridge-to-recovery or lung transplant.
In conclusion, PAL provides total gas exchange with hemodynamic stability in a PA–PA configuration to significantly decrease ventilator support with improved PaO2/FiO2 ratio and wet/dry ratio during lung injury. In a prospective, randomized, controlled, unblinded outcome study comparing PAL to VCMV, PAL decreased ventilator-induced lung injury in a smoke/burn LD100 sheep model of ARDS to improve survival. On the basis of this study, we propose a potential application for the PAL as a bridge to recovery in ARDS too severe for ventilator management or AVCO2R and too long-standing for extracorporeal membrane oxygenation.
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Discussion |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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It has been a pleasure to review this manuscript, which is part of an ongoing process that Dr Zwischenberger and his colleagues have been pursuing for more than 15 years, looking both for nontrauma and trauma applications of lung support. The animal model that he described took 3 intensive years to develop. It is a clinically relevant model, particularly in the fact that it combines a cutaneous and thermal injury, and also the control group was managed by contemporary low volume protective ventilator strategies. The initial Achilles heel had been acute right heart failure, which they appear to have controlled, predominantly with the use of a compliance chamber and also taking advantage of the protective effect of hyperoxygenation with subsequent pulmonary vasodilation.
And, Jay, you still prefer the pulmonary artery to pulmonary artery configuration over pulmonary artery to left atrium configuration for the reasons that you mentioned, including more reliable gas exchange, but the system is still susceptible to pulmonary hypertension and other vagaries of pulmonary circulation that might occur with sepsis and more prolonged acute respiratory distress syndrome. And you note that you will be doing further long-term studies and that this is limited to a 5-day survival study, but within those constraints I have the following questions.
First, given that burn wound sepsis starts to become a problem between 3 to 5 days, were any of these animals showing signs of wound infection?
Second, can you anticipate how sepsis will affect the function of the paracorporeal artificial lung?
Third, given the need for heparinization, how do you anticipate handling burn wound excision in such patients?
Fourth, you favor the sheep model because the long pulmonary artery allows you to do two anastomoses of the paracorporeal artificial lung to the main pulmonary artery. How do you anticipate modifying this for the human condition with a much shorter pulmonary artery?
And finally, you have quoted in the manuscript and in another areas that the ideal gas exchange would be as high as 800 mL. You quote 200 mL here. I take it that is just a function of the size of the animal.
Thank you very much for the privilege of discussing this paper.
DR JURO J. WADA (Tokyo, Japan): Lethal smoke insufflation oftentimes seen in big fire or jet pilot shutdown just about time of landing on the ground. (My work in Hyperbaric Medicine coincided with the Vietnam War.) In such a situation, resuscitation is on the site. The best is portable, collapsible hyperbaric chamber available in emergency ambulance. Oxygen insufflation is simple to apply on site. Paracorporeal artificial lung or another resulting method to follow would be in order. (Hyperbaric Medicine, Proceedings of IV International Congress of Hyperbaric Medicine took place in Sapporo, Japan, edited by J. Wada.)
Such a way of treating seawater (salty water) drowning during swimming would be another clinical usefulness. (Judson McNamara, University of Hawaii Cardiac Surgeon).
Listening to this paper, it is certainly a needed way to preserve donor lung; however, I get the impression from this paper that it is too drastic, a lot of danger of contamination. In early 1960s I was heavily involved in use of hyperbaric oxygenation, which has been forgotten by cardiothoracic surgeons. Nobody mentioned about its use. That is, those burn together with smoke and so forth. It happens to jet plane pilots when they come down to the ground surrounded by fire. There he dies. Those are the best candidates just at the time of a fresh burned trachea can have it.
The hyperbaric chamber is no longer a giant iron chamber weighing three tons, this is outdated. I had developed a collapsible carry-in hyperbaric chamber. A fire-exposed, dying person is put in the hyperbaric chamber without touching anything and oxygen is given into the bloodstream through the skin. Quickly, the simple collapsible hyperbaric chamber is put in the ambulance with the patient inside, brought to the hospital, then opened, and whatever the surgeons have to do to preserve the heart or make the end of life more peaceful. It would be ideal.
I am too young to practice this, but in hearing this paper, I would like to stress to everyone something good we had under the name of hyperbaric oxygenation with the use of more than the plastic collapsible chamber available in hand in the surgeon. Thank you.
DR ZWISCHENBERGER: I greatly appreciate the comments and the discussions. First of all, those of you who have worked with large animal models of acute respiratory distress syndrome fully appreciate the fact that we have no perfect large animal model of acute respiratory distress syndrome, and the fact that 90% of human acute respiratory distress syndrome is a secondary condition, not a primary condition, underlines the complexity of this problem. However, we tried to develop a model that was clinically pertinent, which is why we developed the burn and smoke inhalation combination model in our sheep, and it is with that model that we perform our outcomes studies.
I have to admit that we are pushing the envelope with 5- and 10- and 15-day studies to try to investigate the respiratory injury when in fact it is multifaceted and also involves a synergistic effect from the burn. So we may run into problems with the burn.
We had one of the sheep in this series develop sepsis, and that was the cause of death, which was outside the pulmonary injury. Therefore I share the discussant’s concern about the burn wound being a problem, and we are currently addressing the fact that we are going to do early excision of the burn wound.
Now, how are we going to do that in the face of heparin? Well, these prototypes that I describe are all handmade using a rapid prototyping fabrication technique, and the reason is because we have yet to come up with the perfect design to where we can invest in the molds necessary for final type of design and final type of material use. So I freely admit that these rapid prototype oxygenators are still embryonic in their development, and we are not yet able to fully appreciate the blood–surface interaction and how we can best control that. Be that as it may, we are going to try to use heparin-coated devices and we are going to try to use lower doses of heparin, which will allow us to control the burn wound.
Next is the fact that the sheep is a wonderful model for doing a pulmonary artery to pulmonary artery configuration, because we published that the sheep has a 5.4-cm pulmonary artery, and those of you who do cardiac surgery know that that is a very generous pulmonary artery, and humans do not have one that long. We have currently received Institutional Review Board approval to use fresh cadavers in humans to do pulmonary artery to pulmonary artery dissections and try to show how we can best orient that configuration in a human, and the congenital heart surgeons can easily tell you that the bifurcation of the pulmonary artery will lend itself to being able to use one of the branches for the distal anastomosis. So I think that that is going to work.
Finally, I share Dr Wada’s enthusiasm for alternate therapies in respiratory failure. I have spent many years trying to figure out whether it is oxygenation, hypercapnia, lung destruction, or all the inflammatory mediators that seem so popular these days as the cause of the etiology of respiratory failure. Quite frankly, I do not know the answer, Dr Wada, but I certainly share your enthusiasm, and I hope as we continue this research we can apply this technology to human use. Thank you.
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