Extracorporeal carbon dioxide removal (ECCO2R) is a low-flow extracorporeal life support technique used to manage respiratory acidosis1 and to minimize ventilator-induced lung injury in patients with respiratory failure.2 With the currently available technology, a 15 Fr dual lumen catheter and blood flows (BFs) of at least 0.5 L/min are necessary to remove a significant portion (up to 40–50%) of the total CO2 production of adult patients3 and to obtain a clinically relevant reduction in minute ventilation (MV).4 Enhancement of the CO2 removal efficiency of a membrane lung (ML) may permit reduction in catheter sizes and BFs. This would further reduce invasiveness, minimize associated complications, and permit a more widespread application of ECCO2R.
The driving force for ML CO2 removal (VCO2ML) is the transmembrane CO2 partial pressure gradient,5 that is the difference between the partial pressures of CO2 (pCO2) in the blood and the sweep gas of the ML. A possible strategy to enhance VCO2ML relies on increasing the pCO2 in the blood entering the ML. This can be achieved by acidification of the blood at the inlet of the ML. Acid infusion converts bicarbonate ions into dissolved CO2 by moving the Henderson–Hasselbalch equation toward the right, as follows:
Previous studies demonstrated that extracorporeal blood acidification by lactic acid infusion improves VCO2ML.6–8 Lactic acid was chosen because of its low toxicity and fast metabolism and because lactate is easily measurable with point-of-care testing devices. To date, other metabolizable acids have not been tested. Their use may provide additional benefits, such as regional anticoagulation with calcium-binding compounds (e.g., citric acid), or lower impact on systemic metabolism.9
In this preliminary study, performed in healthy sheep, we compared the effects of short-term (2 hours) extracorporeal blood acidification achieved by infusions of 1.5 mEq/min of three different acids: acetic, citric, and lactic acids. Our primary aim was to study their effects on VCO2ML, on ML CO2 removal efficiency, and on extracorporeal blood gas values. We hypothesized that lactic, citric, and acetic acids enhance VCO2ML similarly. In addition, we studied the effects of citric acid infusion on calcium concentration in the extracorporeal blood.
This study was approved by the U.S. Army Institute of Surgical Research Institutional Animal Care and Use Committee and was conducted in compliance with the Animal Welfare Act, the Implementing Animal Welfare Regulations, and in accordance with the principles of the Guide for the Care and Use of Laboratory Animals.
Three healthy ewes (47 ± 10 kg) were instrumented as described previously.10 After surgical preparation and administration of a bolus of unfractioned heparin (100 UI/kg), animals were connected to a custom-made extracorporeal circuit optimized for acid infusion. Afterward, heparin was infused continuously to maintain activated clotting time (ACT) level at approximately 200% of the baseline. The circuit was composed of a commercially available ECCO2R device (Hemolung, Alung Technologies, Pittsburgh, PA), a standard polyethersulfone hemofilter (Purema, NxStage, NxStage Medical, MA) connected in series after the Hemolung ML, and a peristaltic pump for recirculation of ultrafiltrate before the ML. Blood flow was constant at 250 ml/min, sweep GF was 10 L/min of ambient air, and ultrafiltrate flow was 100 ml/min. The acid injection port was located on the ultrafiltrate side of the circuit, as such avoiding direct contact between highly concentrated acids and the cellular components of the blood. Five sampling outlets were arranged in the circuit: four on the blood side (inlet, post-acid, post-ML, and outlet) and one on the ultrafiltrate side before the acid injection port (Figure 1). Extracorporeal BF was measured by the Hemolung flow meter at the circuitry outlet (Figure 1, port 4).
The experiment described here was performed after testing the effect of ultrafiltrate recirculation on CO2 removal of the ML.10 At the end of this test, and after an overnight recovery, reequilibration, and fasting (12 hours), the animals underwent the three acid infusion test. At the beginning of the experiment, animals were provided intravenous buprenorphine (0.01 mg/kg), and then midazolam was continuously infused (0.01 mg/kg/hour). The animals were spontaneously breathing while connected to a mechanical ventilator via a tracheostomy with continuous positive airway pressure (CPAP) of 5 cm H2O and FiO2 of 21%.
The experiment consisted of continuous infusion at a rate of 1.5 mEq/min of acetic (4.4 M, 20.4 ml/hour), citric (0.4 M, 75.0 ml/hour) and lactic (4.4 M, 20.4 ml/hour) acids. During citric acid administration, a continuous infusion of calcium chloride (CaCl2, 1.4 mEq/ml) was carried out to maintain a stable systemic ionized calcium (iCa++) concentration.
Baseline measurements were performed once for each subject, after the aforementioned 12 hours fasting period and before the first acid infusion, with the ECCO2R device set to provide BF at 250 ml/min, ultrafiltrate recirculation flow at 100 ml/min, and GF at 10 L/min of room air. After the baseline phase, acids were infused for 2 hours each, in a randomized fashion. After each acid infusion, a 1 hour equilibration phase was carried out to permit acid clearance.
Membrane lung CO2 removal (VCO2ML) was measured by the Hemolung built-in capnometer. Extracorporeal circuit blood and ultrafiltrate samples for gas analysis and iCa++ concentration were collected at baseline and at 30, 60, and 120 min during each acid infusion. Moreover, arterial and extracorporeal circuit blood and ultrafiltrate samples were collected for gas analyses during the reequilibration phases (i.e., 60 min after stopping acid infusion) to confirm return to baseline. Arterial blood samples were collected at the end of each experimental phase. A capnograph (CO2SMO, Novametrix, CT) was used to record respiratory rate (RR), MV, and natural lung CO2 removal (VCO2NL). Heart rate (HR), arterial and pulmonary artery pressures, and esophageal temperature were continuously monitored.
Membrane lung CO2 removal efficiency ratio was computed as the ratio between VCO2ML and total CO2 content in the inlet blood sample, as previously described.10
Data are expressed as means ± standard deviations (SD). Statistical analysis was accomplished using SigmaPlot 12 statistical program (Systat Software Inc, Chicago, IL). Variables were compared with one-way analysis of variance for repeated measurements with Tukey’s test. The Shapiro–Wilk test was used to test for normality. A p value less than 0.05 was considered statistically significant.
Regional acidification with infusion of equivalent doses (1.5 mEq/min) of acetic, citric, and lactic acids resulted in similar increases in VCO2ML, from a baseline of 37.4 ± 3.6 to 50.6 ± 7.4, 49.8 ± 5.6, and 52.0 ± 8.2 ml/min (around 134% of the baseline values; p < 0.001), respectively (Figure 2). During infusion of each acid, there was no difference in VCO2ML after 30, 60, and 120 min (p = 0.432; Figure 3). Membrane lung CO2 removal efficiency increased from a baseline of 28.6 ± 3.8% to 41.1 ± 6.0%, 43.8 ± 4.2%, and 45.2 ± 5.9% (p < 0.001) during acetic, citric, and lactic acids infusion, respectively (Figure 4). For each infusion, there was no difference in ML CO2 removal efficiency ratio after 30, 60, and 120 min (p = 0.185).
Extracorporeal blood samples are shown in Table 1. During all the experimental phases, injection of the acids resulted in consistent acidification of post-acid blood, coupled with a rise in pCO2 and decrease in HCO3 − (p < 0.001). Likewise, passage of acidified blood through the ML was associated with alkalinization of post-ML blood, combined with a decrease in pCO2 and HCO3 − (p < 0.001). Passage of blood through the hemofilter was never associated with significant changes in extracorporeal blood gas analyses. Absolute pH values of post-acid, post-ML, and outlet blood samples were higher during acetic acid infusion when compared with citric and lactic acids phases. Nevertheless, similar reductions in pH were observed after acetic, citric, and lactic acids infusion (0.217 ± 0.037, 0.246 ± 0.046, and 0.253 ± 0.049, respectively; p = 0.146). Passage of blood through the ML resulted in similar increases in pH after acetic, citric, and lactic acids infusion (0.385 ± 0.058, 0.351 ± 0.047 and 0.323 ± 0.080, respectively; p = 0.073). No statistically significant differences in pCO2 or HCO3 − of inlet, post-acid, and post-ML blood were detected between samples collected during acetic, citric, or lactic acids infusion. HCO3 − in outlet blood samples was lower during lactic acid infusion compared with either acetic or citric acid.
No differences in pH, pCO2, and HCO3 − values were observed between extracorporeal blood obtained at baseline and that obtained during equilibration phases. Nor were such differences observed in the ultrafiltrate. This served as proof of reversal of the effects of acids infusion during the equilibration phases (see Table 1, Supplemental Digital Content, http://links.lww.com/ASAIO/A65).
During citric acid infusion, a significant reduction of ionized calcium concentration (iCa++) was observed in the extracorporeal blood (Figure 5). The iCa++ was significantly reduced (p < 0.001) in post-Acid, post-ML, and outlet samples as well as in ultrafiltrate samples compared with the inlet blood (1.071 ± 0.144 to 0.549 ± 0.139, 0.496 ± 0.095, and 0.511 ± 0.098 mMol/L, respectively). Moreover, iCa++ was lower in ultrafiltrate than in post-acid samples (p < 0.05). In contrast, iCa++ concentration of samples collected from the extracorporeal circuit did not vary after infusion of acetic or lactic acid (p = 0.40 and p = 0.09, respectively; see Table 2, Supplemental Digital Content, http://links.lww.com/ASAIO/A65).
Arterial blood gas analyses and physiologic variables are presented in Table 2. Physiologic variables (to include temperature, HR, mean arterial pressure, and mean pulmonary artery pressure) were not altered significantly during any of the acid infusions. No statistically significant difference was observed between systemic arterial pH at baseline and during any of the acid infusions. Arterial pCO2 during citric acid infusion was lower than at baseline (p < 0.05). There was no statistically significant difference between arterial HCO3 − at baseline and during acid infusion.
No difference was observed between arterial pH, pCO2, or HCO3 − obtained at baseline and during equilibration phases (see Table S3, Supplemental Digital Content, http://links.lww.com/ASAIO/A65). Moreover, there was no statistically significant difference in RR and VCO2NL during acid infusion. Changes in MV were not statistically significant after post-hoc analysis.
No difference in ACT between experimental phases was detected; ACT was 224 ± 12, 218 ± 36, and 219 ± 17 during acetic, citric, and lactic acids infusions, respectively.
We compared the effects of regional extracorporeal acidification with three different metabolizable acids during ECCO2R. Equivalent infusions of acetic, citric, and lactic acids upstream from the ML of an ECCO2R device resulted in similar levels of enhancement of VCO2ML and ML CO2 removal efficiency of approximately 35%. However, we did not observe changes in MV or in systemic arterial blood gas values in these spontaneously breathing sheep.
In previous studies,6,7,11 regional acidification led to a significant increase in CO2 removal with an extracorporeal BF as low as 250 ml/min. Likewise, in the current study, BF of 250 ml/min was used. This should be compared with other studies, not employing acidification, in which BF of 470 ml/min was used to produce a VCO2ML of 70 ml/min.3 With regional acidification as proposed here, ECCO2R may be achieved with smaller sized extracorporeal cannulas (e.g., 13–14 Fr, percutaneously introduced, double-lumen catheters). Consequently, ECCO2R may develop into a procedure with the same footprint and invasiveness of continuous renal replacement therapy (CRRT) making it widely available to larger cohorts of patients. One of the questions that remains to be answered is the choice of optimal acid for regional acidification. In previously published studies,6,7 lactic acid was used. In this study, we evaluated other metabolizable acids as well.
In this study, we demonstrated that equivalent infusions of acetic, citric, and lactic acids are comparably effective in raising VCO2ML. This was subsequent to their similar effects on extracorporeal blood. Indeed, the different acids caused equivalent degrees of acidification; for all the acids, the drop of post-acid extracorporeal blood pH was consistently around 0.25 points. Likewise, reductions in BE and increments in pCO2 (i.e., 15–20 mm Hg) did not differ between the three treatments. Passage of blood throughout the ML affected gas analyses similarly during the different experimental phases. Interestingly, we observed the absolute pH values of all the extracorporeal blood samples to be slightly higher during acetic acid infusion, when compared with citric and lactic acids infusion. Arguably, because sheep metabolize acetate more efficiently than citrate or lactate,12 the pH of venous blood (i.e., inlet blood) may be less impacted during acetic acid infusion than during citric or lactic acid infusions.
We have shown that the enhancement in VCO2ML is dependent on blood acidification, regardless of the compound used, and therefore, identification of the best compound to be utilized requires consideration of their potential risks and benefits (see Table 3).
Lactic acid is an indispensable substrate for the intermediary metabolism of mammalian cells.13 It is nontoxic,14 and its concentration is readily measurable by point-of-care testing devices. Lactic acid metabolism is rapid and well studied in humans.15 These reasons make lactic acid particularly suited for extracorporeal blood acidification in humans. When infused, lactic acid is readily cleared from the bloodstream, undergoing gluconeogenesis or direct oxidation to ATP and CO2.16 In a healthy swine model, lactic acid caused a slight increase in total CO2 production compared with an equicaloric glucose infusion.9 If completely oxidized, compared with acetic and citric acids, lactic acid has a more favorable caloric profile. Indeed, dosages of lactic acid similar to the one used in this experiment (1.5 mEq/min) would provide a significant fraction of a patient’s caloric requirement (up to 700 kcal/day), limiting the necessary caloric input and CO2 production originating from other sources. Consequently, if using lactic acid for regional acidification, a thorough evaluation of energy balance is necessary.
Despite being widely used as a constituent of dialysis replacement fluids and balanced solutions, little is known about metabolism of acetate in humans. Acetic acid does not constitute a common caloric input in humans.17 When infused in high doses (up to 2.5 mmol/min), it is readily oxidized by the liver18 as well as by muscle tissues to CO2 and water,19 supplying as much as 65% of the necessary caloric requirements of an adult.20 Part of the infused acetate is not oxidized and is used for lipid synthesis, leading to thermogenesis.21 This thermal effect is associated with augmented CO2 production and has been demonstrated to be greater than the thermal effect of lactate infusion.22 Efficacy of regional acidification with acetic acid may be influenced by this thermal effect. The possible toxicity associated with long-term acetate infusion23 warrants more in-depth studies.
Citric acid has various interesting characteristics. While acetic and lactic acids are monocarboxylic acids, citric acid is a tricarboxylic one. Therefore, a completely dissociated mole of citric acid provides three equivalents of H+. The finding that pH reduction during infusion of 0.5 mmol/min (i.e., 1.5 mEq/min) of citric acid was similar to that during infusion of 1.5 mmol/min of acetic and lactic acids is suggestive of the complete dissociation of all three citric acid carboxylic moieties. Consequently, the same level of acidification obtained with 1 mole of acetic or lactic acid is attainable with one-third mole of citric acid. Metabolism of citric acid leads to less CO2 production and provides a lower caloric input than the other two acids. In humans, the clearance of citric acid from bloodstream is slow24 and strongly dependent on hepatic function.25 Its use in patients with altered liver function could be prohibitive because of toxicity.26
At the same time, citric acid is a calcium chelator and, as such, has anticoagulant properties. Indeed, citric acid salts (e.g., sodium citrate) are commonly used during CRRT as a locoregional anticoagulant. We infused citric acid at a rate of 0.5 mEq/min, which is well within the range used for locoregional anticoagulation.27 Previously, citrate infusion was tested during ECCO2R. Unfortunately, measurements of iCa++ concentration in the extracorporeal circuitry were not reported.28 In this study, we documented significant iCa++ chelation in blood samples after citric acid infusion. Indeed, iCa++ blood levels were reduced to approximately 0.5 mmol/L, which is at the upper limit for optimal anticoagulation (i.e., 0.25–0.5 mmol/L).29 In light of this consistent reduction in extracorporeal blood levels of iCa++, we speculate that citric acid could be used to achieve regional acidification and anticoagulation. This may enable low-flow ECCO2R without systemic anticoagulation. Techniques such as thromboelastography would be necessary to confirm the effectiveness of citric acid in anticoagulating blood during ECCO2R.30 This goes beyond the scope of this study and further experiments are necessary to confirm this hypothesis.
Infusion of acids may have deleterious effects on blood components. In our work, an innovative technique was utilized to provide regional acidification. A hemofilter was positioned after the ML, and ultrafiltrate was generated with a peristaltic pump. This ultrafiltrate was acidified and then recirculated before the ML. The novel circuit configuration used in this study allowed highly concentrated hyperosmolar acids to be injected into the recirculating ultrafiltrate. This ensured safe extracorporeal blood acidification by avoiding damage of blood components and unnecessary free water infusion. Direct injection of concentrated acids (4.4 M = 8,800 mOsm/L, pH 1) into the blood would have caused hemolysis.31 On the other hand, a high volume of free water (i.e., 600 ml/hour) would have been necessary to infuse isotonic acids (i.e., 300 mOsm/L), causing severe electrolyte derangements. By contrast, our innovative setup allowed for safe infusion of concentrated acids without excessive free water infusion. Such circuit setup was previously tested by us and proved not to alter CO2 removal capabilities of the ML.10 With that experiment, we excluded the possibility of bicarbonate recycling by means of ultrafiltrate recirculation. Notably, introduction of a hemofilter into an extracorporeal circuit may increase the hemostatic and inflammatory responses because of the blood contact with artificial surfaces. Nevertheless, in this circuit setup, hemodilution of the blood subsequent to ultrafiltrate recirculation may mitigate these effects.32 The hemofilter enables renal replacement therapy along with lung support. With this extracorporeal circuit setup, we envision the advent of modular multiorgan support technology (MOST).10
During acid infusion, no major systemic complications were documented. No hemodynamic alterations were observed. No residual effect of the acids on arterial blood gas analyses was observed after the equilibration period, suggesting complete washout of the acids.
This is the first documented experience of the application of regional acidification in spontaneously breathing animals. Despite providing significant enhancements of VCO2ML, none of the acids resulted in a statistically significant reduction in MV, RR, or VCO2NL. Similarly, no reduction in systemic arterial pCO2 was observed. Previously, animals of another species (swine) were paralyzed and sedated while arterial pCO2 was kept constant throughout the experimental phases by changing ventilation settings.6,7
The current study was neither powered nor designed to detect effect of acids infusion on ventilation; however, to explain these findings, several possibilities exist. First, in this experimental setting, the caloric input subsequent to the infusion of the acids may have increased metabolic expenditure and CO2 production when compared with the baseline phase when animals had no caloric input and were fasting for 12 hours. Therefore, the enhanced VCO2ML and expected benefits on ventilation may have been masked by augmented metabolic rate and CO2 production. Use of special techniques (e.g., isotopic carbon-labeled glucose or lactate and direct calorimetry) that go beyond the objectives of this study would be necessary to investigate the metabolic fate of infused acids. Second, infused acids, although metabolized, may cause systemic metabolic acidosis, which may trigger a compensatory respiratory alkalosis, as shown by a reduction in pCO2 during citric acid infusion. Third, ventilation of spontaneously breathing animals may have been influenced by factors other than CO2 clearance (e.g., physical activity). Finally, the absolute augmentation in VCO2ML (+15 ml/min) may have been too small, given their VCO2tot was about 165 ml/min. The absolute VCO2ML during both the baseline and the acidification phases was limited by the low venous content of CO2 of the healthy sheep, rather than by poor device efficiency. Arguably, in a clinical setting, VCO2ML would be higher, and the effects on ventilation would be more pronounced. For instance, hypercapnic patients suffering from chronic obstructive pulmonary disease (COPD) usually have venous HCO3 − and pCO2 much higher than sheep (i.e., 35 mEq/L and 60 mm Hg, respectively).33,34 In this scenario, standard low-flow ECCO2R devices are capable of VCO2ML as high as 80 ml/min with a BF of 350 ml/min.35 Accordingly, we speculate that the rise in efficiency of the ML (+35%) obtained by extracorporeal blood acidification may lead to a VCO2ML of 110 ml/min.
Further limitations of our study are subsequent to the low number of animals used, which restricts the strength of the results, especially with regards to evaluation of respiratory effects of acid infusion. Extrapolation of these results to humans should be done with caution, given that the systemic effect of acid infusion is influenced by the differences in these acids metabolism between ruminants (i.e., sheep) and non-ruminants (e.g., humans).12,17,36–38 Healthy animals were utilized for this experiment. The impact of extracorporeal blood acidification on injured subjects with respiratory or metabolic acidosis must be evaluated as well. The feasibility of extracorporeal acidification at higher blood flow ranges and the effects of recirculation of ultrafiltrate on coagulation need to be further studied. Finally, additional in-depth studies are warranted to assess the effectiveness of citric acid anticoagulation during ECCO2R support.
In conclusion, using extracorporeal infusion of acetic, citric, and lactic acids, we demonstrated comparable significant enhancement of carbon dioxide removal by a ML of 35%. Citric acid also provided consistent calcium chelation, suggesting the possibility of achieving regional anticoagulation as well as acidification. Future studies will be necessary to further evaluate the effects of regional acidification on ventilatory status in spontaneously breathing subjects.
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extracorporeal circulation; carbon dioxide; lactic acid; citric acid; acetic acid
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