Physiology of extracorporeal CO2 removal.

Extracorporeal CO2 removal (ECCO2R) was introduced in 1977 to control arterial CO2 tension and reduce ventilation [1], thus allowing lung rest in patients with acute respiratory failure (ARF) [2].

Its feasibility has been tested in a clinical trial [3], but clear evidence of benefit is lacking. Furthermore, a recent randomized study comparing standard lung protective ventilation versus an ultra-protective strategy with ECCO2R, in moderate-severe ARF, showed no difference in 90-day survival, but greater adverse events and fewer ventilator-free days in the ECCO2R arm [4]. Unfortunately, the relative contribution of ECCO2R on total CO2 clearance and its effects on the natural lung are unexplored. Indeed, the CO2 excretion from artificial and natural lungs is generally not measured, and the ventilatory strategy does not account for the physiological changes due to ECCO2R. In this brief report, we aim to describe the physiological basis of CO2 removal, extensively studied in healthy animal models. To which extent these concepts might be directly translatable to pathological conditions will require further clinical studies. However, a reappraisal of the physiological basis of ECCO2R–natural lung interactions may clarify the rationale behind its clinical application.

Physical–chemical characteristics of ECCO2R

The key concept underlying low-flow ECCO2R is that due to the high CO2 content in the venous blood (45–50 ml/100 ml at venous PCO2 = 45 mmHg), the metabolically produced CO2 (~ 150–200 ml/min) may be theoretically removed from 400 to 500 ml of blood. The amount of CO2 removed—for a given sweep gas flow—increases linearly with the artificial lung surface area and the PCO2 of the pre-membrane blood; and logarithmically with the blood flow [5]. High ventilation/perfusion ratio of the artificial lung is required for an adequate CO2 removal with a post-membrane PCO2 as low as 5–10 mmHg [6].

Artificial and natural lung interactions

Physiology

The ECCO2R was first studied in healthy lambs [1]. The key-finding was that the sum of VCO2 of the natural and artificial lungs remained unchanged when ECCO2R was increased. Consequently, the spontaneously breathing animals maintained a normal arterial PCO2. When 100% of the metabolic VCO2 was removed by the membrane lung, it was possible to maintain the animals “apneic” with normal PCO2, while the oxygenation was maintained through an intratracheal 100% oxygen inflow matching the oxygen consumption (“apneic oxygenation”) [7] (Fig. 1). A similar linear decrease in minute ventilation proportional to the ECCO2-R was described in spontaneously breathing patients with ARF [8].

Fig. 1

Physiology of ECCO2R: The amount of CO2 removed (VCO2) by the membrane lung is proportional to the gas-flow, the logarithm of extra-corporeal blood-flow; the pre-membrane PCO2 and the membrane lung surface. The sum of the VCO2 of the membrane and the natural lungs, at equilibrium, equals the metabolic VCO2. A reduction in the VCO2 of the natural lung decreases the respiratory quotient (RQ) and, therefore, alveolar PO2 (PAO2). The alveolar nitrogen may decrease if the membrane lung is ventilated with fractions of oxygen higher than those delivered to the natural lung. The decrease of VCO2 of the natural lung allows the decrease in tidal volume and mean airways pressure, which can promote lung collapse

Gas exchange

While the amount of oxygen exchanged through the natural lung is unmodified by ECCO2R, as the oxygen added extracorporeally is negligible, the VCO2 eliminated by the natural lung decreased in proportion to the VCO2 eliminated through ECCO2R. Therefore, the respiratory quotient (RQ = VCO2/VO2) decreases. The change in RQ modifies the alveolar PO2 which is function of both FiO2 and the PCO2/RQ ratio, according to the alveolar gas equation. Therefore, during ECCO2R, despite a constant FiO2, the alveolar and arterial PO2 may decrease due to a decrease in RQ [7, 9]). The cardiovascular effects of ECCO2R will depend on the net effect on the pulmonary vascular resistance resulting from the reduction in alveolar and arterial PO2, and hypercapnia (increase in pulmonary arterial pressure); and the PO2 and PCO2 in the mixed venous blood which results from the extracorporeal support.

During apnea, the alveolar gas composition is affected by the nitrogen concentration in the artificial lung, to which the alveolar nitrogen equilibrates. If the nitrogen in the artificial is lower than the natural lung, i.e., if the fraction of oxygen delivered through the membrane lung is greater than FiO2, the natural lung will be progressively depleted of nitrogen [7]. This may favor reabsorption atelectasis in the regions of the natural lung with low ventilation/perfusion ratio, increasing the pulmonary units instability [10]. This phenomenon was proved experimentally in conditions of apnea but may theoretically occur regionally during clinical conditions.

Lung mechanics

As tidal volume is reduced, the mean transpulmonary pressure decreases, and the lung tends to collapse. Experimental data on healthy animals show that the lung volume is halved after 24 h of apnea at 5 cmH2O of positive end-expiratory pressure (PEEP) [7]. To prevent this phenomenon in healthy lungs, two alternatives are possible:

Raising the mean airway pressure. It must be noted, however, that a PEEP of ~ 20–25 cmH2O may be required to preserve lung volumes in lambs during apnea [11], as well as to keep the lungs fully open in patients with acute respiratory distress syndrome (ARDS) [12]. These pressures are generally associated to important hemodynamic consequences, worse fluid balance and kidney function.

Adding an adequate short inflation “sigh”. In healthy animals, it is sufficient to add one sigh of 10–12 ml/kg every 90 s to preserve lung volumes [13]. The role of sigh, in this context, is not to increase gas exchange, but only to preserve lung-volume [14, 15].

Discrepancies between physiology and actual current ECCO2R applications

The effects of the decrease in respiratory quotient (RQ) during ECCO2R is usually ignored in clinical practice. However, this phenomenon may be relevant when FiO2 is reduced, as during weaning. In this phase, the low RQ may cause hypoxemia, which may be incorrectly interpreted as caused by derecruitment.

The reabsorption atelectasis resulting from the lung de-nitrogenization when using 100% oxygen through the artificial lung may  occur in the ARDS lung due higher prevalence of low ventilation/perfusion regions, the higher weight of the lung, and the loss of diaphragmatic tone which favors the formation of compression atelectasis. This problem may be prevented by ventilating the artificial and natural lungs with the same oxygen fraction.

During “ultraprotective” lung strategy and ECCO2R, PEEP is usually increased, and plateau pressure decreased, while the respiratory rate is maintained constant. Actually, in the intervention group of the REST trial, the mechanical ventilation was very similar to the controls [4]. The potential advantages of ECCO2R on mechanical ventilation were, therefore, not exploited, leading only to an increase in the complications associated to ECCO2R and anticoagulation. During ultraprotective ventilation strategy, three conditions may promote atelectasis: (a) lower tidal volume and plateau pressure; (b) lung de-nitrogenization when using 100% oxygen through the artificial lung; c) PEEP levels insufficient to keep the lung open (≥ 20–25 cmH2O). A combination of low frequency plus the addition of sighs and equal FiO2 in the natural and artificial lungs—as suggested by physiology—could enhance lung protection and prevent progressive lung collapse.

Take-home message

Understanding the physiology of ECCO2R and the consequent modification in the natural lung is necessary to optimize the ventilatory management and design stronger future clinical trials.