Ventilation with low tidal volumes (Vt), reducing the risk of alveolar overdistension, decreases mortality in acute lung injury and acute respiratory distress syndrome (ARDS), and using low Vt ventilation together with an “open lung approach” (lung recruitment maneuvers and high positive end-expiratory pressure, PEEP), preventing tidal recruitment/derecruitment of lung units, reduces the incidence of hypoxia, increases survival in severe ARDS and decreases the need of rescue therapy.1–3 A method using the extreme of low Vt ventilation, i.e., apneic oxygenation, combined with an open lung approach for oxygenation and an extracorporeal circuit for CO2 removal might be even more beneficial in ARDS. In 1978, Kolobow and colleagues4 described such a technique using a pump-driven extracorporeal CO2 removal system in an animal model with normal lungs, but the method was not further elaborated. Thereafter, development and extensive testing of an arteriovenous CO2 removal shunt (AVCO2R), i.e., interventional lung assist (iLA), mainly by Zwischenberger and co-workers5–8 have made the extracorporeal CO2 removal easier and safer. Indeed, iLA has been studied both in patients and experimental models with different combinations of lung protective ventilation using low Vt, low respiratory rates or with high frequency oscillation (HFOV) and has been found to be effective.5,9,10 However, recently Dembinski and colleagues11 tested whether iLA together with ventilation with low Vt of 3 ml/kg and PEEP of 5 cm H2O would reduce the risk of ventilator induced lung injury in a porcine lung lavage injury model, but they could not demonstrate any advantage with this combined method. Likewise, Brederlau and colleagues12 reported in a similar lung lavage injury model that apneic oxygenation using low distending pressure (5 cm H2O) plus iLA could not maintain adequate oxygenation and CO2 removal.
We hypothesized that the negative results of the latter studies, as also were suggested by Dembinski and colleagues in the discussion in their article, were that the distending pressure was insufficient to recruit and to prevent derecruitment of collapse prone lung units. Therefore, the present study was designed to test, in the same kind of porcine lung lavage model as used by Brederlau and colleagues, whether apneic oxygenation using an open lung approach with an appropriate distending pressure (20 cm H2O airway pressure which equals to 14 cm H2O transpulmonary pressure in this model) combined with iLA would provide adequate oxygenation and CO2 removal.
The study was approved by the Danish National Animal Ethics Committee. Nine 85–95 kg Danish Landrace pigs were premedicated with midazolam, azaperone (Stresnil), and atropine and anesthetized with ketamine (2 mg/kg) iv and fentanyl (5 μg/kg) iv. The trachea was intubated and the lungs were ventilated (Servo Ventilator 900C, Siemens-Elema, Solna, Sweden) using volume controlled positive pressure ventilation (PEEP: 5 cm H2O; Vt: 8 ml/kg; respiratory frequency (RF): 20 min−1; inspiratory/expiratory-ratio (I:E): 1:1). Anesthesia was maintained with continuous iv infusion of ketamine (10 mg · kg−1 · h−1), fentanyl (5 μg · kg−1 · h−1) and propofol (0.3–1 mg · kg−1 · h−1). The infusion rates were adjusted to maintain sufficient anesthesia. Iv infusion of pancuronium bromide (Pavulon) (250 μg · kg−1 · h−1) was used for muscle relaxation. Monitoring with electrocardiogram and peripheral oxygen saturation (SpO2) was established. If the animal at this time point was unstable, it was excluded from the study.
Catheters were inserted into the right common carotid artery (for measurements of arterial pressure and arterial blood gases) and in the right internal jugular vein (for fluid and drug administration). A pulmonary catheter (Swan-Ganz Oximetery TD catheter, Edwards Lifesciences, Irvine, CA) was advanced via the right external jugular vein for measurements of pulmonary artery pressures, mixed venous blood gases and cardiac output (Vigilance monitor, Edwards Lifesciences). Blood gases were analyzed using an automatic blood gas analyzer (ABL system 615, Radiometer, Copenhagen, Denmark). A bladder catheter was inserted through the urethra to monitor diuresis. Body temperature of the animals was kept between 35 and 36°C by intermittent, active cooling with ice bags.
A 17 French catheter and a 19 French catheter (Novaport Vascular Access, Novalung GmbH, Hechingen, Germany) were inserted percutaneously into the external iliac artery and vein, respectively. The iliac catheters were connected to a low-resistance membrane ventilator (iLA Membrane Ventilator, Novalung GmbH). The device was primed with normal saline (150 ml) and the extracorporeal circuit was opened. The blood flow through the extracorporeal circuit was monitored by an ultrasonic flow meter (NovaFlow s, Novalung GmbH) placed on the tube from the arterial catheter. The iLA was flushed with 100% O2 (15 L/min). If PaCO2 during the experiment exceeded 55 mm Hg, the sweep gas flow was increased to 20 L/min. CO2 concentration in the efferent gas from the iLA was measured by mainstream capnography (Tidal Wave 615, Respironics, Murrysville, PA).
Apneic oxygenation was performed via tracheal gas insufflation through a catheter advanced through the orotracheal tube. A swivel on the tube allowed air to leave the airways and a water manometer secured a continuous pressure at 20 cm H2O in the system. The oxygen flow was regulated (1–3 L/min) to keep oxygen bubbling slowly in the manometer.13
Before establishing the lung injury and the experimental treatment a set of baseline values was registered.
The animal was placed in the supine position and surfactant was depleted by saline lung lavage.14 The tracheal tube was disconnected from the ventilator circuit, and 2 L of 37°C normal saline was poured into the tube. The fluid was drained passively and the tracheal tube was reconnected to the ventilator. The lungs were ventilated with pressure control (PEEP: 10 cm H2O; inspiratory pressure (IP): 35 cm H2O; RF: 20 min−1; I:E: 1:1) until SpO2 had stabilized above 95%. The whole procedure was repeated 10 times. If the lavage fluid still contained macroscopic visual signs of surfactant (i.e., white foam), the procedure was repeated until the returning lavage fluid was clear. Thereafter, a lung recruitment maneuver (pressure control; PEEP: 10 cm H2O; IP: 40 cm H2O; RF: 6 min−1; I:E: 1:1) was performed for 2 minutes to fully establish an “open lung.”15 As soon as the maneuver was completed, apneic oxygenation was initiated; the apneic oxygenation device was connected using a clamp on the orotracheal tube to prevent decrease in intrapulmonary pressure and derecruitment of the lungs.
When apneic oxygenation was commenced, blood pressures, blood gases, cardiac output, blood flow through the iLA and CO2 concentration in the efferent sweep gas from the iLA were measured. The measurements were repeated after 10 and 30 minutes and thereafter every 30 minutes until the treatment had been carried out for 3.5 hours. In 2 animals, the experimental treatment was continued for 7.5 hours, to explore longer term effects of the treatment. At the end of the experiment, the animals were killed with an intravenous overdose of pentobarbital.
The delivery of oxygen to the blood from the lungs was calculated as:
where DO2 is oxygen delivery per minute, CO is cardiac output, CHgb is hemoglobin concentration, SaO2 and SmvO2 are arterial and mixed venous oxygen saturation, respectively, and PaO2 and PmvO2 are arterial and mixed venous partial pressure of oxygen, respectively. The contribution of blood oxygenation by the iLA was calculated similarly using arterial blood samples and blood samples from the efferent side of the device.
CO2 elimination in the membrane lung was calculated on basis of the CO2 content in the efferent sweep gas:
where V̇CO2 is the CO2 elimination per minute, Qsg is the sweep gas flow to the iLA (ml/min) and FeCO2 is CO2 fraction in the efferent sweep gas.
All data are presented as median with interquartile range if not otherwise indicated.
Comparison of paired data was done with Wilcoxons matched pairs signed rank sum test. (SigmaStat for Windows version 3.5, Systat Software Inc., San Jose, CA). A p value of <0.05 was considered significant.
At baseline, before iLA and pulmonary lavage, one of the nine animals was excluded from further study because of hemodynamic instability.
The lavage procedure was repeated 11 (10, 13) times. During the last lavage procedures, SpO2 dropped below 50% in all animals. PaO2 was maintained above 300 mm Hg [median 464 (403, 502) mm Hg] during the 3.5 hours of apneic oxygenation with extracorporeal CO2 removal (Figure 1). PaCO2 increased exponentially toward 60 mm Hg (Figure 2). The inclining PaCO2 during the last hour of experimental treatment was minor, but statistically significant (p = 0.031).
Corresponding to the rising PaCO2, arterial pH declined slightly to about 7.3 (Table 1). Plasma lactate level was steady at about 1 mmol/L (Table 1). Heart rate and mean arterial pressure were stable at adequate levels (Table 1).
The two animals that were treated for 7.5 hours showed no noteworthy deviation from the previously mentioned: After 7.5 hours PaO2 in the 2 animals was 524 and 547 mm Hg, respectively, PaCO2 was 62 and 59 mm Hg, respectively, and arterial pH was 7.29 and 7.31, respectively.
Median CO2 elimination in the iLA was 180 (150, 180) ml/min, corresponding to an elimination rate of 10.4 (9.9, 11.8) mlCO2/Lsweep-gas, whereas the device had more limited abilities to supply the system with oxygen, with a median O2 contribution at 4 (−0.3, 11) ml/min. The median blood flow through the membrane lung was 2.0 (1.8, 2.1) L/min, which corresponds to a bypass flow rate of 22% of median cardiac output. Apneic oxygenation was able to secure a median O2 contribution of 185 (164, 212) ml/min. Because of technical reasons, we were not able to determine whether any CO2 was eliminated via the apneic oxygenation-device.
In this study, we showed that apneic oxygenation, using an open lung approach and AVCO2R, provided sufficient oxygenation and adequate CO2 removal for 3.5 hours in mildly hypothermic, human sized animals (85–95 kg) with surfactant depleted lungs.
We used the lavage model to compare our results with previous studies.12 Saline lung lavage depletes surfactant and induces collapse of lung regions (causing intrapulmonary shunt and impaired oxygenation), but does not induce any severe lung injury.11,12,14,16 Because oxygenation in the lavage model is very sensitive to lung recruitment maneuvers and PEEP,16,17 we abstained from using any of the proposed oxygenation rules to show collapse and surfactant depletion.11,12 This was instead shown by the lack of frothing in the returned lavage fluid. However, just after the last lavage procedures low SpO2 was noted, suggesting lung collapse. Since lung collapse is pronounced in the initial phase of ARDS,18 we believe that the lavage model is relevant for examining the issues raised in this study. As shown by Borges and colleagues18 by computed tomography examinations, the collapse in early ARDS usually reopens by lung recruitment maneuvers and high PEEP, increasing PaO2 to around 400 mm Hg, i.e., to the same levels as we found after the lung recruitment maneuver.
In a recent study by Brederlau and colleagues,12 using a pig model similar to the one used in this study, oxygenation was not maintained by the apneic approach. In contrast to our study, however, Brederlau’s team did not perform any recruitment maneuvers and furthermore used an airway pressure of 5 cm H2O, which is insufficient to prevent lung derecruitment.19 Moreover, oxygen was not delivered via a transtracheal approach as was done in our study. It becomes evident that it is essential in apneic oxygenation to open up collapsed lung units with a high airway pressure (i.e., a lung recruitment maneuver) and to keep these units open by adequately high positive airway pressure to avoid blood shunting through atelectatic lung compartments. The idea of an open lung approach for ventilation in ARDS is far from new. It was first described by Snyder20 and has since been thoroughly studied among others by Lachmann and colleagues.21
We found that PaCO2 asymptotic approaches a value between 50 and 60 mm Hg after the 3.5 hours of apneic oxygenation and extracorporeal CO2 removal (Figure 2). This confirms previous studies, indicating that CO2 is eliminated effectively via iLA.5 As we used pigs of approximately 90 kg body weight to simulate an adult patient, we believe that CO2 elimination also would be satisfactory in patients. This assumption is supported by previous results by others and by our finding that the median CO2 elimination in the membrane ventilator was 180 ml/min, which matches the production of roughly 200 ml/min in a normal person.22 Because of technical reasons, we did not measure CO2 elimination from the lungs, and we can therefore not exclude that some CO2 was washed out by the alveolar gas flow.
Body temperature was kept at 35°C–36°C to prevent hyperthermia and to decrease the metabolism. Since CO2 production increases with 6%–8%/°C, PaCO2 would probably with a normal body temperature increase to approximately 70 mm Hg, which would not have any significant side-effects in patients without intracranial pathology or persistent pulmonary hypertension.23 However, whether “permissive hypercapnia” is potentially beneficial or harmful is not settled.24 Mild hypothermia, as used in this study, has minimal side-effects. Deeper hypothermia may, on the other hand, have more pronounced side-effects, e.g., on coagulation and the immune system, but has been used successfully in patients with ARDS and is a common procedure after cardiac arrest.25,26
As mentioned, another approach to low tidal volume ventilation in ARDS is HFOV. However, it has not conclusively been shown that HFOV increases survival or reduces the incidence of iatrogenic lung injury. The reasons for this could be that HFOV does not provide as small tidal volumes in adults as formerly assumed.27 Studies have shown that tidal volumes during HFOV can be up to 210 ml.28 In addition, high mean airway pressures are often used during HFOV.29 Furthermore, initial lung recruitment, which is probably essential for an optimal HFOV treatment, might not have been carried out correctly in all studies, which could explain the failure to show a positive effect of HFOV.27 Nevertheless, in animal lung injury models HFOV maintains normal lung histology and reduces immunologic response indicating that very low tidal volumes are beneficial for the lungs.30 We speculate that apneic ventilation using the open lung approach would be equally positive. However, continuous positive airway pressures of 2–6 cm H2O in a lipopolysaccharide-lung injury, spontaneously breathing, rat model increased the inflammatory response in the lungs,31 and sustained alveolar wall tension by high airway pressure might cause structural changes in lung tissue.32 Furthermore, prolonged time without movement of the lungs could theoretically cause stagnation of secretions contributing to infection.
Our study has several important limitations: First, the study was performed in previously healthy animals. Even though we used pigs of a size comparable to human adults, the physiology of a pig is different from a human. Second, lung lavage induces a surfactant depleted, collapse prone lung, but not any severe lung injury. Third, we used FiO2 1.0 in the apneic oxygenation to secure sufficient oxygenation of the blood. Fourth, the arterial blood pressure was high and stable, giving adequate blood flow through the extracorporeal circuit. This could be different in the clinical situation. Fifth, we have just examined the treatment during a relatively short period.
Our study shows that apneic oxygenation using the open lung approach in combination with AVCO2R can provide sufficient gas exchange. We suggest that the method might have potential in the treatment of severe ARDS.
This work was supported by the Danish Medical Research Council Grant (no. 22–04–0420).
Nine membrane ventilator units and accessories were kindly provided by Novalung GmbH, Hechingen, Germany.
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