Extracorporeal Carbon Dioxide Removal Enhanced by Lactic Acid Infusion in Spontaneously Breathing Conscious Sheep

Extracorporeal Carbon Dioxide Removal (ECCO2R): A Potential Perioperative Tool in End-Stage Lung Disease

Extracorporeal carbon dioxide removal through ventilation of acidified dialysate: An experimental study

Extracorporeal carbon dioxide removal (ECCO<inf>2</inf>R) promotes protective ventilation in patients with acute respiratory failure, but devices with high CO<inf>2</inf> extraction capacity are required for clinically relevant impact. This study evaluates three novel low-flow techniques based on dialysate acidification, also combined with renal replacement therapy, and metabolic control. Eight swine were connected to a low-flow (350 mL/min) extracorporeal circuit including a dialyzer with a closed-loop dialysate circuit, and two membrane lungs on blood (ML<inf>b</inf>) and dialysate (ML<inf>d</inf>), respectively. The following 2-hour steps were performed: 1) ML<inf>b</inf>-start (ML<inf>b</inf> ventilated); 2) ML<inf>bd</inf>-start (ML<inf>b</inf> and ML<inf>d</inf> ventilated); 3) HLac (lactic acid infusion before ML<inf>d</inf>); 4) HCl-NaLac (hydrochloric acid infusion before ML<inf>d</inf> combined with renal replacement therapy and reinfusion of sodium lactate); 5) HCl-βHB-NaLac (hydrochloric acid infusion before ML<inf>d</inf> combined with renal replacement therapy and reinfusion of sodium lactate and sodium 3-hydroxybutyrate). Caloric and fluid inputs, temperature, blood glucose and arterial carbon dioxide pressure were kept constant. The total MLs CO<inf>2</inf> removal in HLac (130±25 mL/min), HCl-NaLac (130±21 mL/min) and HCl-βHB-NaLac (124±18 mL/min) were higher compared with ML<inf>bd</inf>-start (81±15 mL/min, P<0.05) and ML<inf>b</inf>-start (55±7 mL/min, P<0.05). Minute ventilation in HLac (4.3±0.9 L/min), HCl-NaLac (3.6±0.8 L/min) and HCl-βHB-NaLac (3.6±0.8 L/min) were lower compared to ML<inf>b</inf>-start (6.2±1.1 L/min, P<0.05) and ML<inf>bd</inf>-start (5.8±2.1 L/min, P<0.05). Arterial pH was 7.40±0.03 at ML<inf>b</inf>-start and decreased only during HCl-βHB-NaLac (7.35±0.03, P<0.05). No relevant changes in electrolyte concentrations, hemodynamics and significant adverse events were detected. The three techniques achieved a significant extracorporeal CO<inf>2</inf> removal allowing a relevant reduction in minute ventilation with a sufficient safety profile.

Livigni and coworkers [1] reported on the safety and efficacy of a venovenous carbon dioxide removal (VVCO2R) circuit in a short-term study (to 12 hours) conducted in healthy sheep. During extracorporeal carbon dioxide removal, carbon dioxide is transferred across a gas exchanger whereas oxygen diffuses across the native lungs. In 1969 Kolobow and coworkers [2] described use of VVCO2R in healthy sheep for 1 week, and they later demonstrated improved survival in injured sheep [3]. Clinical trials, however, failed to show improved outcomes [4]. Arteriovenous carbon dioxide removal (AVCO2R), as a simple arteriovenous shunt, eliminates several circuit components. AVCO2R removes near total carbon dioxide production with only 1 l/min (approximately 15% of cardiac output) blood flow and appears to be effective in acute respiratory distress disorder (ARDS), as shown in prospective randomized large animal and preliminary clinical trials. Our sheep model of severe ARDS is based on a third degree burn to 40% of the total body surface area and 48-breath smoke inhalation injury [5]. Because the median duration of AVCO2R treatment for ARDS is 4.8 days, our model allows comparison of ventilatory techniques over 5 days to evaluate pathophysiology and outcomes [6]. Based on the experience with carbon dioxide removal, two major concerns arise. First, the circuit blood flow employed by Livigni and coworkers is only 5% of the cardiac output, which was inadequate to achieve normalization of arterial carbon dioxide pressure (PaCO2). Use of larger cannulae (12 to 15 Fr) would allow flows up to 1 l/min. Second, studies of such short duration in healthy animals have limited clinical relevance [7]. We wonder whether the methods employed by Livigni and coworkers would have an impact on survival in 5-day large animal studies of lung injury or in clinical application.

Extracorporeal carbon dioxide removal has been proposed to achieve protective ventilation in patients at risk for ventilator-induced lung injury. In an acute study, the authors previously described an extracorporeal carbon dioxide removal technique enhanced by regional extracorporeal blood acidification. The current study evaluates efficacy and feasibility of such technology applied for 48 h. Ten pigs were connected to a low-flow veno-venous extracorporeal circuit (blood flow rate, 0.25 l/min) including a membrane lung. Blood acidification was achieved in eight pigs by continuous infusion of 2.5 mEq/min of lactic acid at the membrane lung inlet. The acid infusion was interrupted for 1 h at the 24 and 48 h. Two control pigs did not receive acidification. At baseline and every 8 h thereafter, the authors measured blood lactate, gases, chemistry, and the amount of carbon dioxide removed by the membrane lung (VCO2ML). The authors also measured erythrocyte metabolites and selected cytokines. Histological and metalloproteinases analyses were performed on selected organs. Blood acidification consistently increased VCO2ML by 62 to 78%, from 79 ± 13 to 128 ± 22 ml/min at baseline, from 60 ± 8 to 101 ± 16 ml/min at 24 h, and from 54 ± 6 to 96 ± 16 ml/min at 48 h. During regional acidification, arterial pH decreased slightly (average reduction, 0.04), whereas arterial lactate remained lower than 4 mEq/l. No sign of organ and erythrocyte damage was recorded. Infusion of lactic acid at the membrane lung inlet consistently increased VCO2ML providing a safe removal of carbon dioxide from only 250 ml/min extracorporeal blood flow in amounts equivalent to 50% production of an adult man.

Essential Topics in the Management of Venovenous Extracorporeal Membrane Oxygenation in COVID-19 Acute Respiratory Distress Syndrome

IN the critically ill patient or patient with hypoventilatory respiratory failure, there have been a number of methods to deal with the complication of hypercarbia. In both of these situations, the idea of tolerating hypercarbia with the label “permissive hypercapnia” has been advocated for over 20 yr.1 In the acutely ill patient, acidosis ensues rapidly and is frequently well tolerated at moderate levels of carbon dioxide. However, at some point, this acidosis becomes profound enough that it must be addressed, and the work presented this month by Dr. Zanella et al.2 represents a substantial potential advance in managing this situation.The method used to address hypercapnia varies depending on the clinical condition of the patient. Typically, the first step is some form of mechanical ventilation (MV). If the patient is extubated, noninvasive positive-pressure ventilation is usually attempted. The patient is frequently kept without oral intake and potentially with bed rest in anticipation of worsening condition, endotracheal intubation, and invasive MV. If this occurs, the managing clinician should provide MV with a lung-protective ventilation strategy, consisting of low tidal volumes, reduced plateau pressures, and an adequate amount of positive end-expiratory pressure in an attempt to prevent ventilator-induced lung injury.3However, as a patient’s pulmonary status continues to deteriorate, the clinician is faced with balancing hypercarbia and acidosis with attempts to maintain lung-protective ventilation. In the modern era of MV, it is not uncommon to see patients with Paco2 values in excess of 80 mmHg. These patients begin to suffer from profound acidosis and the clinician is faced with unfortunate options of increasing tidal volumes and pressures and inducing more lung injury or attempting to chemically buffer the acidosis. The use of buffering agents can introduce a variety of electrolyte disorders. In addition, there exists the theoretical possibility of rebound hypercapnia and acidosis from the metabolism of bicarbonate by carbonic anhydrase if sodium bicarbonate is the chosen buffering agent.To treat hypercarbia, there has been another option available to clinicians for over 30 yr with the use of extracorporeal technology.4 Supplying patients with adequate extracorporeal oxygenation requires several liters of blood flow through a circuit. Distinctly lower flows are required to provide adequate extracorporeal carbon dioxide removal (ECCO2R, pronounced e-kor). However, to date all extracorporeal technologies have required a minimum of approximately 500 to 1000 ml/minof blood flow through some form of an extracorporeal oxygenator to have a substantial clinical impact on carbon dioxide reduction. Systems have used a variety of technologies including venovenous access with mechanical pumps, whereas some commercial systems such as the Novalung iLA (Novalung GmbH, Heilbronn, Germany) in Europe advocate pumpless femoral arteriovenous circulation.Existing systems have two requirements that introduce substantial risk to patients and limit the adoption of the technology. First, even though blood flow rates are substantially lower than 3 to 5 l/min, the 500 to 1000 ml/min flow rates still requires large venous access, substantially larger than a typical acute dialysis catheter. Such cannulae require specialized knowledge, can be challenging to place, and have been associated with substantial bleeding. In the case of arteriovenous cannulation, limb ischemia is a significant potential complication. Second, is the requirement for some form of systemic anticoagulation, which increases the bleeding risk even more, and is frequently contraindicated in critically ill patients.The work presented in this month’s Anesthesiology by Dr. Zanella et al.2 represents a substantial advance in extracorporeal ventilatory support. Through the infusion of lactic acid into the extracorporeal circuit, bicarbonate ion is converted to dissolved carbon dioxide which is almost completely cleared by an oxygenator. With this remarkable clearance of carbon dioxide, the investigators were able to provide a sustained substantial reduction in systemic arterial carbon dioxide with blood flow rates of 250 ml/min. Such rates are routinely used in continuous venovenous hemodialysis technology. This advance should permit carbon dioxide removal to be a far less invasive technology due to the use of a standard acute dialysis catheter and makes regional anticoagulation a viable option for the technology, minimizing the risk of bleeding. Due to the changes in the physical form of the technology, clinicians will no longer view extracorporeal ventilatory support as sophisticated extracorporeal membrane oxygenation (ECMO) or extracorporeal life support requiring a complex procedure, but as a much more manageable version of dialysis that happens to clear carbon dioxide rather than fluids and electrolytes.Applications of this technology are multiple, but will generally fall into three categories: (1) acute ventilatory failure and prevention of MV, (2) lung-protective ventilation in severe respiratory failure, and (3) bridge to lung transplant in hypercarbic patients.For patients with acute respiratory failure due to hypoventilation or asthma, it is conceivable that we may one day be debating the use of noninvasive positive-pressure ventilation, MV, or ECCO2R for support of patients. Such technology will allow ambulation, the organized weaning of support, and virtually eliminate the need for sedation. Historically, each of these measures has been associated with a reduced length of stay and improved outcomes.In the patient with severe hypoxic respiratory failure undergoing advanced MV, the use of low-flow ECCO2R would enable the use of ultra-low tidal volumes. This should reduce the amount of barotrauma, atelectrauma, and subsequent ventilator-induced lung injury. Although exact indications will slowly be developed with the introduction of this technology and its ready accessibility, initial trials will probably address a patient population with severe respiratory acidosis despite the application of an appropriate lung-protective ventilation strategy.Finally, in the carbon dioxide–retaining patient who is awaiting lung transplant, ECCO2R has already been used to bridge patients to their procedure, but usually only when they are nearing a requirement for invasive MV. Existing technology limits this to more advanced centers, typically with extracorporeal membrane oxygenation programs for patients suffering from profound hypoxia. Low-flow ECCO2R offers the potential for early support. With early intervention that does not require MV and bed rest, one anticipates that transplant candidates would be able to undergo physical therapy and rehabilitation before transplant, improving outcomes.The data presented this month by Dr. Zanella et al. are clear step forward in the widespread adoption of ECCO2R. However, support of a porcine model for 2 days with minimal lactic acidosis clearly requires human trials before generalized use. Additionally, this technology would also probably be contraindicated in patients with hepatic insufficiency due to the inability to metabolize the lactic acid load. Despite this limitation, the technology should be applicable to a wide array of patients.In summary, Dr. Zanella et al. in Dr. Pesenti’s lab should be commended for continuing their research in the low-flow ECCO2R domain. With this article, it is time for the technology to move from the animal model to human clinical trials, as low-flow ECCO2R has clear potential to benefit a multitude of patients suffering from respiratory failure.The author is not supported by, nor maintains any financial interest in, any commercial activity that may be associated with the topic of this article.

Patients with acute respiratory distress syndrome and acute kidney injury (AKI) treated by kidney replacement therapy may also require treatment with extracorporeal carbon dioxide removal (ECCO2 R) devices to permit protective or ultraprotective mechanical ventilation. We developed a mathematical model of acid-base balance during extracorporeal therapy using ECCO2 R and continuous venovenous hemofiltration (CVVH) devices applied in series for the treatment of mechanically ventilated AKI patients. Published data from clinical studies of mechanically ventilated AKI patients treated by CVVH at known infusion rates of substitution fluid without ECCO2 R were used to adjust the model parameters to fit plasma levels of arterial partial pressure of carbon dioxide (PaCO2 ), arterial plasma bicarbonate concentration ([HCO3 ]), and plasma pH (as well as certain other unmeasured physiological variables). The effects of applying ECCO2 R at an unchanged and a reduced tidal volume on PaCO2 , [HCO3 ] and plasma pH were then simulated assuming carbon dioxide removal rates from the ECCO2 R device measured in the clinical studies. Agreement of such model predictions with clinical data was good whether the ECCO2 R device was positioned proximal or distal to the CVVH device in the extracorporeal circuit. Although carbon dioxide removal rates from the ECCO2 R device measured in one previous clinical study were higher when it was placed proximal to the CVVH device, suggesting that such in-series positioning was optimal, the current mathematical model demonstrates that proximal positioning of the ECCO2 R device also results in lower bicarbonate (and, therefore, total carbon dioxide) removal from the distal CVVH device. Thus, the removal of total carbon dioxide by such extracorporeal circuits is relatively independent of the position of the in-series devices. It is concluded that the described mathematical model has quantitative accuracy; these results suggest that the overall acid-base balance when using ECCO2 R and CVVH devices in a single extracorporeal circuit will be similar, independent of their in-series position.

During extracorporeal membrane oxygenation (ECMO), oxygen (O2) transfer (V'O2) and carbon dioxide (CO2) removal (V'CO2) are partitioned between the native lung (NL) and the membrane lung (ML), related to the patient's metabolic-hemodynamic pattern. The ML could be assimilated to a NL both in a physiological and a pathological way. ML O2 transfer (V'O2ML) is proportional to extracorporeal blood flow and the difference in O2 content between each ML side, while ML CO2 removal (V'CO2ML) can be calculated from ML gas flow and CO2 concentration at sweep gas outlet. Therefore, it is possible to calculate the ML gas exchange efficiency. Due to the ML aging process, pseudomembranous deposits on the ML fibers may completely impede gas exchange, causing a "shunt effect", significantly correlated to V'O2ML decay. Clot formation around fibers determines a ventilated but not perfused compartment, with a "dead space effect", negatively influencing V'CO2ML. Monitoring both shunt and dead space effects might be helpful to recognise ML function decline. Since ML failure is a common mechanical complication, its monitoring is critical for right ML replacement timing and it also important to understand the ECMO system performance level and for guiding the weaning procedure. ML and NL gas exchange data are usually obtained by non-continuous measurements that may fail to be timely detected in critical situations. A real-time ECMO circuit monitoring system therefore might have a significant clinical impact to improve safety, adding relevant clinical information. In our clinical practise, the integration of a real-time monitoring system with a set of standard measurements and samplings contributes to improve the safety of the procedure with a more timely and precise analysis of ECMO functioning. Moreover, an accurate analysis of NL status is fundamental in clinical setting, in order to understand the complex ECMO-patient interaction, with a multi-dimensional approach.

Diabetes mellitus is associated with important changes in renal hemodynamics. The purpose of this study was to determine whether an increase in blood concentration patterns of ketone bodies and lactic acid, organic acids often elevated in poorly controlled insulin-dependent diabetes mellitus (IDDM), could contribute to increase glomerular filtration rate (GFR) and renal plasma flow (RPF) regardless of changes in circulating levels of glucose and insulin. Six IDDM patients and six normal subjects were given a saline infusion (15 mumol.min-1.kg-1) for 2 h, an acetoacetic acid infusion (15 mumol.min-1.kg-1) for another 2 h, and then a saline infusion after an overnight fast during euglycemic insulin-glucose clamp. Acetoacetic acid infusion resulted in an increase of blood ketone bodies in the range of 0.7-1.5 mM from a basal value of 0.1-0.3 mM. GFR was 125 +/- 16 and 136 +/- 17 ml.min-1.1.73 m-2 in normal and IDDM subjects, respectively, during baseline saline infusion and 138 +/- 21 (P less than .01 vs. basal level) and 158 +/- 15 ml.min-1.1.73 m-2 (P less than .001 vs. basal level) during acetoacetic acid infusion. During the last saline infusion, renal hemodynamic patterns decreased again to baseline levels. Another six IDDM patients and six normal subjects were given saline, lactic acid, and saline infusions at the same rates of infusion after an overnight fast during euglycemic insulin-glucose clamp. Lactic acid concentration increased from approximately 0.5-0.8 to 1.0-1.5 mM in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Extracorporeal carbon dioxide removal means the removal of carbon dioxide from the blood across a gas exchange membrane without substantially improving oxygenation. Carbon dioxide removal is possible with substantially less extracorporeal blood flow than needed for oxygenation. Techniques for extracorporeal carbon dioxide removal include (1) pumpless arterio-venous circuits, (2) low-flow venovenous circuits based on the technology of continuous renal replacement therapy, and (3) venovenous circuits based on extracorporeal membrane oxygenation technology. Extracorporeal carbon dioxide removal has been shown to enable more protective ventilation in acute respiratory distress syndrome patients, even beyond the so-called "protective" level. Although experimental data suggest a benefit on ventilator induced lung injury, no hard clinical evidence with respect to improved outcome exists. In addition, extracorporeal carbon dioxide removal is a tool to avoid intubation and mechanical ventilation in patients with acute exacerbated chronic obstructive pulmonary disease failing non-invasive ventilation. This concept has been shown to be effective in 56-90% of patients. Extracorporeal carbon dioxide removal has also been used in ventilated patients with hypercapnic respiratory failure to correct acidosis, unload respiratory muscle burden, and facilitate weaning. In patients suffering from terminal fibrosis awaiting lung transplantation, extracorporeal carbon dioxide removal is able to correct acidosis and enable spontaneous breathing during bridging. Keeping these patients awake, ambulatory, and breathing spontaneously is associated with favorable outcome. Complications of extracorporeal carbon dioxide removal are mostly associated with vascular access and deranged hemostasis leading to bleeding. Although the spectrum of complications may differ, no technology offers advantages with respect to rate and severity of complications. So called "high-extraction systems" working with higher blood flows and larger membranes may be more effective with respect to clinical goals.

Ventilator-induced Lung Injury

ConclusionsThe tested prototype ECCO 2 R device, enhanced by an electrodialysis unit, proved to be effective in increasing carbon dioxide removal, proportionally to the applied amperage.Future experimental studies are required to evaluate in-vivo this innovative technique.

In the last decade, primarily following the H1N1 pandemics [1], the extracorporeal respiratory assist is increasingly used [2, 3]. The acronym “ECMO”, i.e., ExtraCorporeal Membrane Oxygenation, is, however, somehow misleading as the artificial extracorporeal assist may affect both oxygenation and CO2 removal, as well as the hemodynamics, depending on how it is applied. In this commentary, we will limit our discussion to the respiratory extracorporeal support in veno-venous mode, primarily discussing the aspects, which are usually under-evaluated. Various options for extracorporeal support Table 1 was first published more than 40 years ago [4] and summarizes the main characteristics and options through which the extracorporeal support may be applied. As shown, all the possible application were foreseen and most of them actually tested in the following years. As shown, two main features characterize the extracorporeal support: cannulation (veno-venous vs veno-arterial) and extracorporeal blood flow. In the veno-venous configuration, the artificial and the natural lung are connected in series, as the blood flow entering the membrane lung is re-directed into the natural lung, after the artificial gas exchange. The hemodynamics are not affected by this configuration, which works solely as a respiratory support. In contrast, in the veno-arterial configuration, the artificial and the natural lung are arranged in parallel: the flow leaving the artificial lung is diverted in the arterial section and the natural lung is proportionally under-perfused. The greatest difference between veno-venous and veno-arterial approach is not related to the gas exchange, as the amount of oxygen transferred and CO2 removed are exactly the same (if the operating conditions of the membrane lung are the same), but to the hemodynamic impact, as the veno-arterial configuration provides both respiratory and cardiac support. The second feature is the amount of blood flow and gas flow used to ventilate the artificial lung: to oxygenate venous blood entering the membrane lung, the gas flow required equals the oxygen sufficient to fully saturate the hemoglobin passing through the artificial lung. As an example, if 1 l of venous blood with10 g/dL of hemoglobin and saturation 70% enters the membrane lung every minute, a transfer of 42 ml of 100% oxygen per minute from the gas compartment of the membrane lung would be sufficient to fully saturate the blood leaving the membrane lung. Therefore, being the possibility to “charge” oxygen limited by the hemoglobin concentration and its saturation in the venous blood, the oxygen transfer to the membrane lung is primarily function of the extracorporeal blood flow. In the previous example, 4 l of extracorporeal blood flow, in the absence of re-circulation, would provide fully saturated blood with a gas flow into the membrane lung of only 168 ml/min. All the gas is absorbed, and no gas leaves the membrane lung Table 1 Comparative technical difficulty of hemodialysis, extracorporeal removal of carbon dioxide, and extracorporeal oxygenation

To evaluate the safety and efficacy of pumpless extracorporeal arteriovenous carbon dioxide removal (AVCO2R) in subjects with acute respiratory failure and hypercapnia. A phase I within-group time series trial in which subjects underwent up to 72 h of support with AVCO2R in intensive care units of two university hospitals. Eight patients with acute hypercapnic respiratory failure or hypoxemic respiratory failure managed with permissive hypercapnia. Extracorporeal CO2 removal was achieved through percutaneous cannulation of the femoral artery and vein, and a simple extracorporeal circuit using a commercially available membrane gas exchange device for carbon dioxide exchange. Measurements of hemodynamics, blood gases, ventilatory settings, and laboratory values were made before initiation of AVCO2R, and at subsequent intervals for 72 h. PaCO2 decreased significantly from 90.8+/-7.5 mmHg to 52.3+/-4.3 and 51.8+/-3.1 mmHg at 1 and 2 h, respectively. This decrease occurred despite a decrease in minute ventilation from a baseline of 6.92+/-1.64 l/min to 4.22+/-.46 and 3.00+/-.53 l/min at 1 and 2 h. There was a normalization of pH, with an increase from 7.19+/-.06 to 7.35+/-.07 and 7.37+/-.05 at 1 and 2 h. These improvements persisted during the full period of support with AVCO2R. Four subjects underwent apnea trials in which AVCO2R provided total carbon dioxide removal during apneic oxygenation, resulting in steady-state PaCO2 values from 57 to 85 mmHg. Hemodynamics were not significantly altered with the institution of AVCO2R. There were no major complications attributed to the procedure. Pumpless extracorporeal AVCO2R is capable of providing complete extracorporeal removal of carbon dioxide during acute respiratory failure, while maintaining mild to moderate hypercapnia. Applied in conjunction with mechanical ventilation and permissive hypercapnia, AVCO2R resulted in normalization of arterial PCO2 and pH and permitted significant reductions in the level of mechanical ventilation.