Carbon dioxide production during cardiopulmonary bypass: pathophysiology,measure and clinical relevance

Introduction

Carbon dioxide (CO₂) removal monitoring during cardiopulmonary bypass (CPB) is considered a recommended guideline for practice by the American Society of Extracorporeal Technology and a standard of practice by the Australian New Zealand College of Perfusion.^1,2 This monitoring is usually performed through capnometric analysis of gases from the exhaust port of the oxygenator. Despite its relative easiness, this practice is not routinely applied; recent data are lacking in the literature, but a French survey in 2001 reported only 25% of the perfusionists using on-line capnography during CPB. ³

CO₂ tension (PCO₂) as measured by capnometry is representative of the complex interaction of CO₂ production by cells and its elimination by the natural or artificial lung. Therefore, this technique may provide important information, not only on the efficacy of CO₂ removal, but even on the metabolic status of the peripheral organs and on the adequacy of their perfusion with respect to their oxygen (O₂) needs. ⁴ The present review article addresses the pathophysiological meaning of CO₂ production during CPB, the technical aspects of CO₂ kinesis measurement on CPB and the clinical relevance of this monitoring. Table 1 reports the nomenclature and abbreviations used throughout this article.

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Table 1.

Nomenclature.

Physiological variable	Abbreviation
Arterial carbon dioxide tension (mmHg)	PaCO2
Cardiac output or pump flow during CPB (L/min)	Qc
Carbon dioxide expired fraction (%)	FECO2
Exhaled carbon dioxide tension (mmHg)°	ePCO2
Mixed venous carbon dioxide tension (mmHg)	PvCO2
Pulmonary ventilation or sweep gas flow on CPB (L/min)	VE
Respiratory quotient (VCO2/VO2)	RQ
Systemic oxygen delivery (mL/min)	DO2
Systemic O2 consumption (mL/min)	VO2
Systemic CO2 production (mL/min)	VCO2

°: end tidal during normal or mechanical ventilation or at the exhaust port of the oxygenator during cardiopulmonary bypass.

Physiology and pathophysiology of CO₂ production

The sources of CO₂

Carbon dioxide and water are end products of energy production pathways. Carbohydrates and lipids are the substrates of the energy production; they are oxidized by O₂ in aerobic conditions in the mitochondria, producing high-energy phosphate compounds and CO₂. Six molecules of CO₂ are produced and six molecules of O₂ are consumed when the energy substrates are carbohydrates, with an RQ of 1.0; when lipids are oxidized, the ratio is 16 CO₂ molecules produced per 23 O₂ molecules consumed, with an RQ of 0.71.

An essential mechanism of this energy production pathway is the “proton shuttle” which carries protons from the cytosol into the mitochondria (Figure 1). Oxygen availability at the cellular level is the limiting factor of this process and, whenever the O₂ flow to the mitochondria is inadequate, the NADH + H⁺ is re-oxidized to NAD through a different, so-called “anaerobic” pathway. This pathway is located at the level of the cytosol and is based on pyruvate re-oxidization of NADH + H⁺ and lactic acid production at a rate of two molecules per each glucose molecule undergoing anaerobic glycolysis.

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Figure 1.

Aerobic and anaerobic carbon dioxide (CO₂) production. Oxidative mechanisms are responsible for aerobic CO₂ production. Anaerobic energy production results in excess protons which are buffered to H₂O and CO₂, leading to anaerobic CO₂ production.

Lactic acid is a strong acid with a pK of approximately 3.9, being totally dissociated at the normal pH of 7.4; buffering of lactic acid is essential in order to preserve the cell pH. The buffering mechanisms of lactic acidosis have been studied extensively in sport physiology and to a minor degree in critically ill patients. The commonly accepted model^5–7 is shown in Figure 1. Bicarbonate is the main buffer of lactic acid, with intracellular production of CO₂ that flows into the circulation to be finally eliminated by the lung. So, in the presence of anaerobic energy production, there is an “extra CO₂” production on top of the aerobic CO₂ production. For each mmol of lactic acid buffered, 1 mmol (22.3 mL) of extra CO₂ is produced ⁸ and the total VCO₂ results from VCO₂ (aerobic) + VCO₂ (extra, anaerobic). The bicarbonate buffering of lactic acid is not the only buffering mechanism. Actually, during exercise, it has been calculated that about 40% of lactic acid production is buffered by non-bicarbonate systems whereas bicarbonate-dependent buffers account for the remaining 60%. ⁹ Even if the theory of bicarbonate-based buffering of lactic acidosis has been challenged, ¹⁰ it remains accepted as the primary mechanism for extra CO₂ production under hypoxic conditions in the critically ill patient.^11,12

The two energy production pathways (aerobic – anaerobic) are not alternative, as they may simultaneously occur in energy production when the DO₂ is inadequate to meet the oxygen needs (VO₂). In turn, these conditions, which are labelled by hyperlactataemia and extra CO₂ production may belong to different scenarios (Figure 2); on one side, the anaerobic energy production may be triggered by a high work rate during strenuous physical exercise when the energy demand exceeds the maximum aerobic energy delivery (DO₂max). At the opposite side, in critically ill patients, the DO₂ may be inadequate to support even the basic energy requirements (critical DO₂) and, to preserve the metabolic needs of the peripheral organs, the anaerobic metabolism is activated and produces additional energy at the expense of lactate accumulation and extra CO₂ production.

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Figure 2.

Anaerobic carbon dioxide (CO₂) production in different scenarios. DO₂: oxygen delivery; VCO₂: CO₂ production; VO₂: oxygen consumption. Anaerobic CO₂ production may be triggered by strenuous physical work, exceeding the energy production of the aerobic metabolism (right side of X-axis) or by a poor DO₂, below the critical value needed to maintain the basic O₂ needs (left side of X-axis).

Carbon dioxide production and its measurement during normal conditions and CPB

VCO₂ assessment in natural lung-ventilating patients

CO₂ production (VCO₂) may be assessed according to the equation:

VCO 2 ( mL / min ) = V E ( mL / min ) × F E CO 2 . .

(1)

If V_E (sweep gas during CPB) is expressed as L/min and exhaled CO₂ as tension (mmHg), the equation becomes:

VCO₂ (mL/min) = 1,000 x V_E (L/min) x ePCO₂ (mmHg)/760(mmHg), that is

VCO 2 ( mL / min ) = V E ( L / min ) × ePCO 2 × 1 . 315

This equation makes the assumption that the inspiratory CO₂ fraction is negligible and that both VCO₂ and V_E are measured under standard temperature, pressure, dry (STPD) conditions. Conversion into body temperature, pressure, saturated (BTPS) conditions requires a conversion factor which varies according to the patient temperature and the ambient temperature and dryness. For a patient temperature of 32°C, an ambient temperature of 18°C and a water vapour pressure of 18 mmHg, the conversion coefficient is 0.874 and the final equation becomes:

VCO 2 ( mL / min ) = V E ( L / min ) × ePCO 2 × 1 . 15

The physiological concept underlying the above equations can be better understood considering that the F_ECO₂ is directly related to the alveolar and arterial PCO₂. Since the PaCO₂ is a direct determinant of arterial pH, the equation may be seen as an expression of the goal of maintaining a stable pH. When the VCO₂ increases, the ventilation must increase to maintain a stable pH, otherwise the pH will decrease (respiratory acidosis).

This approach to the relationship between VCO₂, V_E, and PaCO₂ is actually correct in many physiological conditions. When the VO₂ increases (as during physical exercise), the V_E increases in a linear fashion to allow oxygen input and aerobically produced CO₂ clearance. When the anaerobic energy production is triggered, then the V_E increases at a higher rate to guarantee the additional clearance of excess CO₂ produced through the anaerobic pathway (Figure 2). Measurement of F_ECO₂ offers a reliable approximation of the PvCO₂ and, therefore, of the peripheral organs’ (during exercise, basically muscles) VCO₂ production, because the concomitant increase in the Qc guarantees an increased lung perfusion to match the increased lung ventilation.

However, things are different when the anaerobic CO₂ production to buffer lactic acid is not physiologically coming from strenuous exercise, conversely being driven by an inadequate DO₂ as it happens in the case of a low cardiac output (cardiogenic shock). In this clinical setting, the Qc is reduced and lung perfusion is consequently poor, with an overall increased pulmonary ventilation/perfusion ratio. This phenomenon is known as “venous blood CO₂ stagnation” ¹³ and the excess CO₂ produced to buffer lactic acid is accumulated on the venous side of the circulation, as reflected by an increase in the PvCO₂. Conversely, given the low pulmonary perfusion, the CO₂ elimination is reduced and the ePCO₂ does not follow the PvCO₂, creating the conditions for an ePCO₂ – PvCO₂ gradient. When this condition takes course, equation (1) provides a false underestimation of the VCO₂ and cannot be applied.

Clinicians in charge of critically ill patients, where hyperlactatemia and the consequent excess CO₂ production are common, are well aware of this problem and have searched for alternative measures of VCO₂, considering this index as a valuable indicator of an inadequate DO₂ due to a low Qc.

Unfortunately, assessing the VCO₂ with equations not based on the measure of the FeCO₂ is far from being an easy task. A theoretical alternative could be based on Fick’s principle, which is based on the assessment of the Qc and the arterial and mixed venous CO₂ content:

VCO 2 = Qc × ( Mixed venous CO 2 content – arterial CO 2 content )

(2)

Fick’s principle works nicely for the determination of the VO₂ because the arterial and mixed venous O₂ contents can be reliably calculated based on the pO₂, the haemoglobin concentration and the haemoglobin O₂ saturation, given the fact that the great majority of the O₂ is carried by the haemoglobin.

Conversely, CO₂ in blood is carried by different systems: dissolved CO₂ (about 10%), bicarbonates (about 60%) and associated with proteins (about 30%). Therefore, a calculation of the CO₂ content based only on the PCO₂ (equation 2) is not possible, because the relationship between PCO₂ and CO₂ content is not linear (Figure 3) and varies depending on the pH status. Therefore, surrogates of VCO₂ measurement have been proposed to assess cardiovascular failure. These include the measurement of the PvCO₂ – PaCO₂ gradient ¹¹ based on the fact that, under conditions of stable VO₂ and VCO₂, this gradient increases along with the decrease of Qc.^14,15 Alternative surrogates include the ratio between veno-arterial PCO₂ difference and arterio-venous oxygen content. ¹⁶

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Figure 3.

Relationship between carbon dioxide (CO₂) pressure and content. Acidosis decreases and alkalosis increases the CO₂ content at the same PCO_2.

Technical aspects of CO₂ monitoring during CPB

The partial pressure of carbon dioxide (pCO₂₎ may be measured by serial samples from the venous and arterial lines of the CPB circuit and modern monitoring devices allow a continuous, on-line measurement of both. However, due to the already mentioned non-linearity of the relationship between CO₂ tension and content, these parameters cannot be used for a reliable VCO₂ calculation.

Infra-red (IR) spectography is the most popular means currently used to monitor CO₂. The wavelength of IR rays is >1.0 µm while that of visible light lies between 0.4 and 0.8 µm. Infra-red rays are absorbed by polyatomic gases (e.g. N₂O and CO₂), but water vapour also absorbs IR light. Carbon dioxide selectively absorbs specific wavelengths (4.3 µm) of IR light. Since the amount of light absorbed is proportional to the concentration of the absorbing molecules, the concentration can be determined by comparing the absorbance with that of a known standard. The CO₂ concentration measured by the monitor is usually expressed as partial pressure in mmHg although some capnographs display percentage CO₂ (FCO₂) by dividing CO₂ partial pressure by the atmospheric pressure. ¹⁹

Two types of capnograph are used for measuring CO₂ in the gas exhaust of an oxygenator (ePCO₂): mainstream and sidestream devices. In the mainstream devices, the CO₂ sensor is mounted directly in the gas exhaust of the oxygenator. In order to prevent condensation of water vapour, which will give false high CO₂ readings, mainstream sensors are heated above body temperature. The major advantages of mainstream devices are: no need for a sampling line, no risk for obstruction, not affected by changes in water vapour pressure, no delay in recording and can be used with low gas flows as encountered during neonatal and pediatric CPB. The main disadvantages are the weight of the sensor and the difficulty to insert the sensor into the oxygenator gas exhaust port which has typical a diameter of 1/4 inch or 3/8 inch. Sidestream capnographs have the CO₂ sensor built into the console (away from the oxygenator) and a tiny pump aspirates gas samples from the oxygenator gas exhaust through long capillary tubing into the capnograph. The sampling tube is connected to a female Luer in the gas exhaust or to a large bore needle inserted in a piece of tubing connected to the gas exhaust port. The sampling flow rate can be set high or low. The latter is important because, if the ventilating gas flow is equal or lower than the sampling flow, room air can be aspirated and mixed with ventilating gas, resulting in artificially low ePCO₂ values.

Most centres that use oxygenator exhaust capnography routinely use sidestream devices because of their ease of use. The exact position of the sample line connection in the gas exhaust is important as all microporous hollow-fibre membrane oxygenators are protected against accidental blockage of the gas exhaust port and the risk to transfer microemboli into the blood stream ²⁰ by one or more vent ports. If the sampling is located too close to the vent ports, the sample can be diluted with room air. ²¹

The accuracy of IR spectroscopy during CPB can be influenced by the presence of water vapour. The difference in water vapour pressures between blood and gas will lead to condensation in the inner lumen of the gas fibres. To avoid interference in the measuring cell, as water vapour will absorb part of the IR rays, Nafion (a sulfonated tetrafluoroethylene-based fluoropolymer-copolymer) tubing in combination with a water trap should be used, virtually eliminating this source of analyzer failure.

Initially, capnography was mainly used to measure metabolic CO₂ production and to estimate PaCO₂. Many studies show a good correlation between ePCO₂ and uncorrected PaCO₂ during clinical cases,^22-24 making it easier to maintain a specific target PaCO₂ during CPB. Although there is a good linear correlation between ePCO₂ and uncorrected PaCO₂, there is some deviation, especially during the rewarming phase. This deviation is the same for oxygenators of the same type and brand, but can differ between types and brands. These differences are most likely due to differences in fibre bundle design, with countercurrent design having the best overall correspondence. ²¹

More recent research showed that VCO₂ is a good predictor of anaerobic metabolism ²⁵ and, as such, can help to reduce CPB-related morbidity. Indeed, CO₂-derived parameters are more rapid and sensitive than O₂-derived parameters in detecting anaerobic metabolism. ¹⁶ A combination of DO₂, VO₂ and VCO₂ parameters was significantly associated with the risk of postoperative renal insufficiency. ²⁶

Beside technical errors, clinical practice can also influence ePCO₂ readings. In order to facilitate de-airing of cardiac cavities and to improve neurological outcome, surgical programmes start to use CO₂ flooding of the operating field.^27–29 However, the use of this technique has some major disadvantages as huge quantities of CO₂ will enter the systemic circulation, leading to severe hypercarbia and acidosis during CPB. ³⁰ As it is difficult to predict how much CO₂ will enter the CPB circuit, it was suggested that capnography was used to monitoring ePCO₂. ²⁷ Under the guidance of ePCO₂, the non-metabolic CO₂ will be instantaneously detected and can be removed by increasing the oxygenator sweep gas flow, thus, maintaining a physiological acid-base status. However, it is important to understand that, when CO₂ flooding is used, the ePCO₂ values will no longer reflect metabolic CO₂ production as it will be the combination of the metabolic CO₂ production and the removed amount of non-metabolic CO₂. This latter contribution may be limited, but not totally eliminated, using controlled CO₂ flooding of the surgical field (i.e. not exceeding 1 L/min).

Clinical relevance of CO₂ monitoring

The potential clinical relevance of VCO₂ monitoring goes far beyond the safety control of the maintenance of an adequate PaCO₂ of the patient throughout the CPB procedure. Certainly, the on-line measurement of ePCO₂ at the exhaust port of the oxygenator may prompt sweep gas adjustments to rapidly adjust the systemic PaCO₂ during the different phases of CPB. Increased values of ePCO₂ as an expression of increased VCO₂ can be found at the release of the cross-clamp, due to the reperfusion of the heart (anaerobic CO₂) or during the rewarming phases after deep hypothermia, as an expression of the increasing VO₂ (aerobic CO₂) and of the decreased solubility of CO₂. This last mechanism should be considered when assessing VCO₂ during CPB cooling and rewarming phases, where the changes in CO₂ solubility respectively decrease and increase the ePCO₂. Nowadays, the routine use of low temperatures on CPB has been replaced by moderate hypothermia or normothermia in many institutions. However, CPB temperatures <28°C may still be used in congenital heart surgery and for specific interventions of high complexity. Within the setting of profound hypothermia, the changes in CO₂ solubility result in corresponding changes in pH, with a reflection on cerebral blood flow. To compensate for the low values of CO₂ at low temperatures, the pH-stat strategy considers the addition of exogenous CO₂ to the sweep gas. Another exogenous source of CO₂ may come from the flooding of the surgical field to prevent the formation of large air bubbles inside the heart chambers. In this case, adequate adjustments of the sweep gas may be prompted by the increase in ePCO₂ due to the additional CO₂ entering the venous line (exogenous CO₂). The finding of elevated values of ePCO₂ is rarely attributable to a failure of the oxygenator, which is much more often manifested by a poor blood oxygenation.

Apart from this, the measurement of the VCO₂ may offer important information on the adequacy of the perfusion in terms of DO₂ (pump flow x arterial O₂ content). As outlined in the pathophysiology of CO₂ production, under conditions of inadequate DO₂, there is an excess CO₂ production as a result of lactic acid buffering. Therefore, VCO₂ may be considered as an indirect marker of lactate increase.

In 2006, Ranucci and associates ²⁵ investigated the association between CO₂-related parameters and arterial blood lactates in 54 adult patients during CPB. They found that the VCO₂ and the DO₂/VCO₂ ratio were significantly associated with the arterial blood lactate concentration (Figure 4). With adequate statistical tests, cut-off values for the prediction of hyperlactataemia (>3 mmol/L) were found at a VCO₂ of 60 mL/min/m² and a DO₂/VCO₂ ratio of 5.0. The DO₂/VCO₂ was introduced to stress the role of an increased VCO₂ due to a low DO₂. Below the critical DO₂, the VO₂ becomes dependent on the DO₂ and decreases. Simultaneously, aerobic CO₂ production decreases and anaerobic CO₂ production starts. However, anaerobic CO₂ production only partially compensates for the decreased aerobic CO₂ production ¹¹ and, therefore, the absolute value of VCO₂ may not be representative of a hypoxic peripheral tissue condition. Analogously, during the rewarming phases of CPB, the aerobic production of VCO₂ is increased due to the increased VO₂; however, the DO₂ is increased as well by increasing the pump flow and the DO₂/VCO₂ ratio remains constant or, in any case, >5.0. Conversely, when the DO₂ decreases below the critical threshold, the DO₂/VCO₂ ratio represents the combined effects of an inadequate DO₂ and increased anaerobic CO₂ production.

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Figure 4.

Panel A: Relationship between carbon dioxide production (VCO₂) and arterial lactate concentration. Panel B: Relationship between oxygen delivery (DO₂)/VCO₂ ratio and arterial lactate concentration. Data from Ranucci and associates ²⁴ during cardiopulmonary bypass (reproduced with permission).

In a recent study, ²⁶ de Somer and associates confirmed the relevance of the DO₂/VCO₂ ratio on CPB as a predictor of postoperative acute kidney injury, with a cut-off value at 5.3, therefore, similar to the value of 5.0 identified as associated with hyperlactatemia. The use of DO₂ and VCO₂ to guide the perfusion management are now included in the concept of the “Goal Directed Perfusion (GDP)”.^31–33 The GDP concept considers that the goal of perfusion is to maintain an adequate oxygen supply to all the organs, avoiding the patient entering into the anaerobic zone. To achieve this goal, the pump flow is adjusted according to the haematocrit value in order to reach and maintain a DO₂ above the critical value of 270 mL/min/m². ³³ Within this context, the VCO₂ should not exceed 60 mL/min/m² and the DO₂/VCO₂ ratio should be higher than 5.0.

Of course, other measures to check the adequacy of perfusion with respect to the metabolic needs are available in daily clinical practice. The central venous oxygen saturation (SvO₂) represents the O₂ extraction from the peripheral organs and, therefore, increases when the DO₂ decreases. However, during CPB, this measurement may be misleading: the SvO₂ is measured at the level of the systemic venous return and represents a mixture of all the regional SvO₂ values coming from the different organs. Since much of the venous return is coming from organs at a very low metabolic rate (i.e. muscles), the systemic SvO₂ may appear normal, even if some peripheral organ (namely the splanchnic district) has a low regional SvO₂. This concept has been demonstrated by McDaniel and associates ³⁴ in an animal model, observing that the systemic SvO₂ on CPB was normal despite very low values of regional SvO₂ values from the cerebral and splanchnic districts. From a clinical perspective, a recent study demonstrated that acute kidney injury following cardiac surgery is associated with low levels of nadir DO₂ on CPB, but not with the corresponding value of SvO₂. ³⁵ Additionally, another recent study found that the SvO₂ values on CPB were not associated with the arterial blood lactate levels. ³⁶

Arterial blood lactates are certainly a valuable measure of the adequacy of perfusion on CPB. Increased levels of arterial blood lactates on CPB have been associated with bad outcomes in both adult ³⁷ and pediatric ³⁸ heart surgery. However, the measurement of arterial blood lactates is not continuous and suffers from a number of limitations.

Once lactates are formed, they must be cleared by the liver and this process requires a variable, but considerable time. Therefore, a hyperlactataemia on CPB may reflect a condition of peripheral dysoxia occurring at any time before its detection and is not necessarily an expression of an inadequate perfusion. Additionally, after hyperlactatemia is established, blood lactates may remain high, even if the perfusion pattern is adequate.

A typical case is represented by patients under unstable haemodynamic conditions before the onset of CPB (Figure 5, a case from the series published by deSomer and associates ²⁶ ). Hyperlactataemia is already present and the CO₂-derived parameters are normal during the initial phases of CPB; a subsequent increase in arterial blood lactates due to inadequate perfusion is detected by the CO₂-derived parameters.

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Figure 5.

A representative case of carbon dioxide production (VCO₂) and oxygen delivery (DO₂)/VCO₂ ratio monitoring during cardiopulmonary bypass (CPB). Data from de Somer and associates. ²⁶ Hyperlactataemia developed before the onset of CPB is not associated with increased VCO₂ or decreased DO₂/VCO₂. New onset hyperlactataemia is detected by CO₂-related parameters.

Conclusions

Despite the many possible applications of CO₂-derived parameters during CPB, very few studies have been published in this area. The expanding concept of GDP will probably increase the interest of clinicians and researchers in these measurements. Further studies on the clinical relevance of CO₂ production monitoring are warranted.