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Ann Thorac Surg 1997;64:1599-1604
© 1997 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Total Arteriovenous CO₂ Removal: Simplifying Extracorporeal Support for Respiratory Failure

Departments of Surgery, Medicine, and Anesthesiology, University of Texas Medical Branch and Shriners Burns Institute, Galveston, Texas

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. To reduce the complexity, complications, and cost of conventional extracorporeal membrane oxygenation, we have developed a technique of simplified arteriovenous extracorporeal CO₂ removal (AVCO₂R) with a low-resistance membrane gas exchanger for total CO₂ removal to provide lung rest in the setting of severe respiratory failure.

Methods. We initially used AVCO₂R in healthy animals to quantify the gas exchange capabilities of the system and establish ventilator management protocols for the subsequent studies of AVCO₂R in a large animal model of respiratory failure secondary to a severe smoke inhalation injury.

Results. In healthy sheep the maximum spontaneous arteriovenous flow ranged from 1,350 to 1,500 mL/min, whereas CO₂ removal plateaued at a blood flow of approximately 1,000 mL/min in which 112 ± 3 mL/min CO₂ was removed, allowing an 84% reduction in the minute ventilation of from 6.9 ± 0.8 L/min to 1.1 ± 0.4 L/min (p < 0.01) without triggering hypercapnia. A subsequent reduction in extracorporeal flow at a reduced minute volume led to the development of hypercapnia only if it decreased to less than 500 mL/min. We also applied AVCO₂R in mechanically ventilated sheep with a severe smoke inhalation injury and removed 95% (111 ± 4 mL/min) of the total CO₂ production. This allowed the minute ventilation to be reduced by 95% and the peak inspiratory pressures by 52% (both p < 0.05) over 6 hours and produced no adverse hemodynamic effects. The partial pressure of arterial oxygen was maintained above 100 mm Hg at a maximally reduced minute volume. The mean AVCO₂R flow was 1,213 ± 29 mL/min, averaging 27% ± 1% of the cardiac output.

Conclusions. We conclude that AVCO₂R in a simple arteriovenous shunt is a less complicated technique than extracorporeal membrane oxygenation and is capable of total CO₂ removal that allows a significant reduction in the minute ventilation and peak airway pressure during severe respiratory failure.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 1604.

The acute respiratory distress syndrome (ARDS) was initially described by Ashbaugh and associates in 1967 [1]. Despite recent advances in critical care, however, the overall mortality in patients with ARDS remains approximately 50%. Current management techniques are primarily supportive, in that mechanical ventilation applies positive airway pressure to achieve oxygenation and CO₂ excretion. However, experimental evidence has shown that high airway pressures are associated withpermeability pulmonary edema [2, 3] and produce histopathologic changes virtually identical to those seen in ARDS [4]. Recent work has revealed that overdistention is primarily responsible for causing the alveolar damage [5]. To reduce the risk of barotrauma-volutrauma and the potentiation of ARDS there has been a recent trend in ventilator management to limit inflation pressures and tidal volumes and allow a rise in systemic arterial CO₂ levels, an approach termed "permissive hypercapnia." Hickling and associates [6] have reported decreased barotrauma-volutrauma and improved survival in patients with ARDS achieved using strategies of permissive hypercapnia.

For editorial comment, see page 1581.

The concept of low-flow venovenous extracorporeal CO₂ removal is not new. It was proposed by Kolobow and colleagues [7] in the late 1970s as a way to remove all of the metabolically produced CO₂ while also maintaining a normal partial pressure of arterial oxygen (PaO₂) through apneic oxygenation. With the success of venoarterial extracorporeal membrane oxygenation (ECMO) for the treatment of severe ARDS [8], especially in the neonatal population, there has been a resurgence of interest in this technique that has led to many investigations into the application of extracorporeal CO₂ removal and similar technologies in the treatment of ARDS. Extracorporeal CO₂ removal, however, still requires the use of a pump in the extracorporeal circuit, and with this comes the rest of the associated complications such as tubing rupture, cavitation, and other life-threatening sequelae [9]. To overcome the need for a pump and simplify the extracorporeal circuit, Barthelemy and colleagues [10] used a pumpless artery-to-vein extracorporeal system in combination with the apneic oxygenation technique to satisfy all the gas exchange requirements of an experimental animal for up to 24 hours. Subsequently Awad and associates [11] demonstrated the feasibility of prolonged arteriovenous support for up to 7 days in animals. Both of these studies were limited, however, by the occurrence of high circuit resistance to spontaneous arteriovenous blood flow.

We have developed a technique of simplified arteriovenous extracorporeal CO₂ removal (AVCO₂R) with a low-resistance membrane gas exchanger [12] to provide lung rest in the setting of severe respiratory failure. We initially used AVCO₂R in healthy animals to quantify the gas exchange capabilities of the system and establish ventilator management protocols for the subsequent studies to be performed in a large animal model of severe respiratory failure.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
All animals received humane care in accordance with the "Guide for the Care and Use of Laboratory Animals" (NIH publication 25-23, revised 1985). The study was approved by the Institutional Animal Care and Use Committee of the University of Texas Medical Branch, Galveston, Texas, with strict adherence to the committee's guidelines regarding the humane use of animals. The study was divided into two sections: (1) performance characterization and (2) application during severe respiratory failure.

AVCO₂R Performance Evaluation to Quantify Gas Exchange Capacity in Healthy Sheep
Femoral arterial and venous catheters and a pulmonary arterial thermodilution catheter were placed in adult Suffolk ewes (n = 5) weighing 26 to 38 kg. After endotracheal intubation, anesthesia was started and maintained with inhaled halothane administered through a ventilator (Servo 900C; Siemens-Elema, Sweden) with the following settings: respiratory rate (RR), 25 to 30 breaths/min; tidal volume (TV), 15 mL/kg; fraction of inspired oxygen (FiO₂), 1.0; positive end-expiratory pressure (PEEP), 5 cm H₂O. Hemodynamic variables, including heart rate, cardiac output (CO), mean arterial pressure, pulmonary arterial pressure, central venous pressure, and pulmonary arterial wedge pressure, as well as ventilator settings including minute ventilation (MV), and peak inspiratory pressure (PIP), were continuously monitored. Arterial and mixed venous blood gases were also measured with each ventilator change, with MV and FiO₂ adjusted to maintain the arterial pH between 7.35 and 7.45, the PaO₂ between 80 and 150 mm Hg, and the partial pressure of arterial CO₂ (PaCO₂) between 30 and 45 mm Hg.

After systemic heparinization (300 IU/kg beef lung heparin; Upjohn, Kalamazoo, MI), the left carotid artery was cannulated with an 18F cannula (TF018LH; Research Medical, Midvale, UT) and the left jugular vein with a 22F cannula (TF022L; Research Medical). A membrane gas exchanger (Affinity; Avecor Cardiovascular, Plymouth, MN) was primed with normal saline solution (270 mL) and connected to the vascular cannulas after air was removed from the system (Fig 1). The activated clotting time (Hemochron 400; Edison, NJ) was maintained between 300 and 500 seconds with a continuous heparin infusion.

View larger version (19K): [in this window] [in a new window]   Fig 1. . Simple arteriovenous circuit with low-resistance membrane gas exchanger used in mechanically ventilated sheep.

The study was divided into the following segments to facilitate independent determination of the factors affecting gas exchange:

1. With the sweep gas flow held constant at 3 L/min, AVCO₂R flow was incrementally increased to unrestricted maximum flow while simultaneous incremental reductions in MV (RR and TV) were made to maintain near-baseline blood gas values. At the maximum ventilator reduction to effect lung rest, TV averaged 2 to 4 mL/kg, RR was reduced to a lower limit of 2 breaths/min, and PEEP was held at 5 cm H₂O to minimize atelectasis. The PaO₂ was maintained above 80 mm Hg by adjusting the ventilator FiO₂. Pancuronium (0.2 to 0.4 mg/kg) and sodium pentobarbital (3 to 5 mg • kg^-1 • h^-1) were given intravenously for sedation and neuromuscular paralysis to allow accurate quantification of MV and airway pressure reductions.

2. Once a maximal reduction in ventilatory support had been achieved, Qb was reduced from 1,400 to 200 mL/min by 200-mL/min increments while the sweep gas flow was held constant to determine the resultant effects of the decreasing blood flows on systemic pH, PaO₂, and PaCO₂.

Application of AVCO₂R in a Model of Severe Respiratory Failure to Evaluate Efficiency of CO₂ Removal
For the second portion of the study a second group of animals (n = 5; weight, 24 to 39 kg) were used to investigate the effect of AVCO₂R on a smoke inhalation injury model of severe respiratory failure. Catheters were placed in these animals in a fashion identical to that in the first group, a tracheostomy was made, and they were subjected to cotton smoke inhalation and insufflation under halothane anesthesia to induce severe respiratory failure to a median lethal dose (LD₅₀) level, as previously described [13]. After smoke insufflation the animals were permitted to recover and allowed free access to food and water. Initial postinjury ventilator settings were as follows: RR, 25 to 30 breaths/min; TV, 15 mL/kg; FiO₂, 1.0; PEEP, 5 cm H₂O. The FiO₂ was reduced to 0.5 once the carboxyhemoglobin level was below 10%. Hemodynamic variables, including heart rate, CO, mean arterial pressure, pulmonary artery pressure, central venous pressure, and pulmonary artery wedge pressure, as well as ventilator settings, including MV, and PIP were measured every hour. Arterial and mixed venous blood gas concentrations were also measured hourly, with MV and FiO₂ adjusted to maintain an arterial pH of between 7.35 and 7.45, a PaO₂ of between 80 and 150 mm Hg, and a PaCO₂ of between 30 and 45 mm Hg.

Twenty-four hours after the smoke inhalation injury, the animal was reanesthetized and anticoagulated to allow insertion of arterial and venous cannulas for AVCO₂R. Once the animal was fully recovered and its condition stabilized, AVCO₂R at an unrestricted Qb was initiated and maintained for 6 hours with the sweep gas flow (100% O₂) maintained at twice the Qb by the in-line gas flow regulator. Hourly during AVCO₂R, a 20% reduction in MV was made, first in TV to achieve a PIP below 30 cm H₂O, and then in RR. To minimize atelectasis, RR was not reduced to less than 2 breaths/min. The PaO₂ was maintained above 80 mm Hg by adjusting the PEEP and ventilator FiO₂. Animals were allowed to remain conscious, and when the MV was reduced to less than the animal's spontaneous MV, sodium pentobarbital (3 to 5 mg • kg^-1 • h^-1) was given intravenously to allow accurate quantification of the MV and airway pressure reductions.

Statistical analysis of each section of the study was done using one-way analysis of variance for repeated measures compared with the baseline (AVCO₂R flow, 0 mL/min).

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
All animals in both studies survived the experimental period and tolerated the interventions without adverse sequelae.

AVCO₂R Performance Evaluation in Healthy Animals
The arteriovenous shunt did not significantly alter the mean arterial pressure; however, CO showed a gradual upward trend, though this did not achieve statistical significance (Fig 2) as compared with the baseline CO. No adverse effects on remaining relevant hemodynamic variables were seen (central venous pressure, pulmonary artery wedge pressure). As the shunt increased from baseline (0.0 mL/min) to unrestricted flow (range, 1,350 to 1,500 mL/min at a CO of from 5.1 to 9.8 L/min), the mean Qb was 41.4 mL • kg^-1 • min^-1 (19% CO). With the sweep gas flow held at 3.0 L/min, CO₂ extraction increased progressively until Qb reached 1,000 mL/min, at which point CO₂ removal plateaued at 112 ± 3 mL/min. This quantity of CO₂ removal allowed the MV to be reduced from baseline requirements of 6.9 ± 0.8 L/min to 1.1 ± 0.4 L/min, an 84% reduction. At the reduced MV, AVCO₂R was able to remove 83% of total CO₂ production while maintaining normocapnia without hypoxia. Throughout, PaO₂ remained above 100 mm Hg with adjustments in the FiO₂ and 5 cm H₂O of PEEP. The pressure gradient across the AVCO₂R circuit remained less than 10 mm Hg and did not change as Qb was varied. At the maximal reduction in ventilator support, as Qb was reduced by 200-mL/min increments, hypercapnia (PaCO₂, 40 mm Hg) occurred only at flow rates of 500 mL/min (14.6 mL • kg^-1 • min^-1 = 7% CO) or less (Fig 3).

View larger version (24K): [in this window] [in a new window]   Fig 2. . Arteriovenous extracorporeal CO2 removal (AVCO2R) hemodynamics. Incrementally increasing AVCO2R blood flow (to a maximum of approximately 1,400 mL/min) with resultant effect on the mean arterial pressure and cardiac output (p = not significant).

View larger version (25K): [in this window] [in a new window]   Fig 3. . Carbon dioxide removal and resultant partial pressure of arterial CO2 (pCO2) as arteriovenous extracorporeal CO2 removal (AVCO2R) flow decreases from 1,400 to 200 mL/min at a maximally reduced minute ventilation (16% of baseline at 2 breaths/min).

View larger version (23K): [in this window] [in a new window]   Fig 4. . Reduction in minute ventilation during arteriovenous extracorporeal CO2 removal (AVCO2R) for respiratory failure. After smoke inhalation injury, 6 hours of full-flow AVCO2R (1,213 ± 29 mL/min) allowed incremental reductions in ventilator rate and tidal volume until the minute ventilation was only 5% of the baseline value (*p < 0.05), while maintaining normocapnia. (pCO2 = partial pressure of CO2.)

View larger version (23K): [in this window] [in a new window]   Fig 5. . Reduction in peak inspiratory pressure during arteriovenous extracorporeal CO2 removal (AVCO2R) at full flow (1,213 ± 29 mL/min) for 6 hours during respiratory failure. Incremental ventilator reductions in rate and tidal volume decreased the peak inspiratory pressure by 52%, as compared with baseline (*p < 0.05), while maintaining normocapnia. (pCO2 = partial pressure of CO2.)

View larger version (21K): [in this window] [in a new window]   Fig 6. . Oxygenation during arteriovenous extracorporeal CO2 removal (AVCO2R) at full flow (1,213 ± 29 mL/min). High fraction of inspired oxygen (FiO2) maintained partial pressure of arterial oxygen (pO2) throughout the 6 hours despite a 95% reduction in the minute ventilation.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

In the late 1980s ECMO for total respiratory support to provide "lung rest" was shown to improve survival in cases of neonatal ARDS and led to a surge in the number of centers performing this technique. The following survival rates have been observed for more than 10,000 cases of ECMO to date: 81% in neonates, 49% in children, and 38% in adults in patient populations estimated to have a more than 80% mortality [8]. Extracorporeal blood flow during ECMO averages 100 to 120 mL • kg^-1 • min^-1 during the venoarterial phase and 120 to 140 mL/min during the venovenous phase. Despite its relatively high cost, potential to cause complications, and need for a sophisticated team, ECMO continues to be an important tool in the therapy of respiratory failure. Kolobow and associates [7] were among the first to popularize the idea that the reason for breathing is to remove CO₂ rather than to oxygenate. Targeting CO₂ removal, Gattinoni and colleagues together with Kolobow's group, developed the extracorporeal technique of extracorporeal CO₂ removal in animals [17, 18] and for clinical application [19, 20]. Gattinoni and Kolobow and colleagues [21] also showed that low-frequency ventilation combined with extracorporeal CO₂ removal provided sufficient gas exchange and improved survival in patients with ARDS. To eliminate the extracorporeal circuit, Mortenson and Berry [22] developed an intravenacaval device (IVOX) designed to oxygenate and remove CO₂. Although innovative, the technique proved unsuccessful, because clinical trials revealed a limited surface area with insufficient gas exchange [23] and no effect on mortality.

Arteriovenous CO₂ was developed to minimize the foreign surface interactions and blood element shear stress inherent in an extracorporeal circuit with a pump and allow the use of a gas exchange membrane of sufficient surface area for total CO₂ removal. Barthelemy and coworkers [10] initially achieved significant CO₂ removal using a large membrane lung in a pumpless circuit with flows in the range of 1,200 to 2,000 mL/min. More recently, Young and colleagues [24] evaluated AVCO₂R in both a pumped and a pumpless circuit in animals with a large membrane lung and found that, despite excellent CO₂ removal, resistance was a limiting factor in the pumpless model at low flow rates. To evaluate the potential long-term use of AVCO₂R, Awad and associates [11] assessed the feasibility of long-term arteriovenous support for 7 days in awake animals and showed that this could be done without sequelae. The major limitation of these studies was high circuit resistance.

To improve the efficiency of oxygenator performance and decrease flow resistance, Goodwin and colleagues [25] used computational fluid dynamic design to develop the Affinity 2.5-m² membrane oxygenator. This device is small, requiring a prime volume of only 270 mL. Our studies show that AVCO₂R using the Affinity membrane lung in a simple arteriovenous shunt allowed approximately 1,500 mL of flow per minute with a transdevice resistance of consistently less than 10 mm Hg and that this achieved total CO₂ removal.

Arteriovenous CO₂ removal also allowed mechanical ventilatory support to be reduced to near-apneic conditions (RR, 2 breaths/min) while normocapnia was maintained at flow rates of more than 500 mL/min (14.6 mL • kg^-1 • min^-1 = 7% CO). A gradual rise in the systemic PaCO₂ was seen at flows of less than 500 mL/min while the MV was reduced to only 16% of the baseline settings. The permissive hypercapnia occurring at lower flows was well tolerated and may provide an alternative in patients in whom it may be difficult to achieve higher flow, either because of a labile cardiovascular status or limited vascular access.

Our results also indicate that normal arterial blood gas values can be maintained during severe lung injury using AVCO₂R in combination with low-frequency mechanical ventilation. Adjusting FiO₂ and PEEP during low-frequency (2 breaths/min), low-volume ventilation can prevent atelectasis and provide adequate oxygenation while the CO₂ is being removed extracorporeally. Although PEEP (5 cm H₂O) and an FiO₂ of greater than 0.9 contributed to the increase in the PaO₂ without compromising hemodynamics, the long-term effect of a high FiO₂ on injured "at rest" lungs must be further evaluated. Arteriovenous extracorporeal CO₂ removal would provide an immediate reduction in TV and PIP, which has been shown to be associated with improved survival in patients with ARDS [6].

Healthy animals tolerated the interventions without showing hemodynamic compromise despite a shunt fraction as high as 27% of the CO. Further studies to gain insight into the physiology of AVCO₂R include evaluations of the effect of the shunt on regional blood flow distribution. To further establish the relative risks and benefits of AVCO₂R and improve the design of clinical trials, additional studies must be done on large animal models of ARDS resulting from burns, trauma, and sepsis. Percutaneous cannulation techniques to facilitate vascular access will also enable a broader clinical application. Based on our data yielded by the use of AVCO₂R in a large animal model of severe respiratory failure, we have initiated an institutional phase I clinical trial on the safety and efficacy of AVCO₂R in humans with acute CO₂ retention.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Supported in part by Shriners Hospital for Burned and Crippled Children (grant 8530). No commercial or proprietary interests were present during this study.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.

Address reprint requests to Dr Zwischenberger, Cardiothoracic Surgery, University of Texas Medical Branch, Galveston, TX 77555-0528 (e-mail: jzwische{at}mspo2.med.utmb.edu).

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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