Abstract

Background: In this study, we aimed to investigate the possible relationship between the venoarterial gradient of carbon dioxide (Dv-a PCO2) and lactate during cardiopulmonary bypass (CPB).

Methods: Sixty consecutive patients (35 males, 53 females; mean age 64 years; range 38 to 78 years) who were scheduled for elective isolated coronary artery bypass graft (CABG) surgery were included in the study after obtaining their informed consent and the approval of the ethics committee of the hospital. All patients were followed up by the same surgical and anesthesia team. The adequacy of tissue perfusion during CPB was evaluated by the venoarterial partial carbon dioxide gradient, lactate level, measurement of arterial and venous blood gas, urinary flow rate, and hemodynamic parameters. The measurements were performed in four periods: before CPB (T1), at the beginning of CPB (T2) at 36 ºC and 32 ºC of hypothermia (T3) and at the end of rewarming (T4) at 37 ºC. The relationship between tissue perfusion parameters was assessed by Pearson’s correlation analysis.

Results: There was a significant correlation between Dv-aPCO2 and the venous lactate level (r=0.54, p=0.046) as well as between Dv-aPCO2 and the arterial lactate level (r=0.55, p=0.042) during the T2 a nd T 4 periods of CPB. There was also a significant correlation between Dv-aPCO2 and arterial base excess (BE) (r=0.64, p=0.013) and between Dv-aPCO2 a nd a rterial H CO3 (r=0.54, p=0.048) during the T3 and T4 periods.

Conclusion: Our study results suggest that in the hypothermia period, the increase in the venoarterial carbon dioxide gradient (Dv-aPCO2) is not inversely associated with insufficient blood flow during CPB and there was a significant correlation between Dv-aPCO2 and the tissue perfusion parameters during the periods other than hypothermia.

Most cardiac surgery is currently being performed under cardiopulmonary bypass (CPB). The purpose of CPB is to supply adequate oxygen (O2) to the tissues and to remove the carbon dioxide (CO2) that is produced in the tissues from the body. The adequate supply of O2 to the tissues during CBP depends on maintaining the parameters of the hematocrit (Hct), partial pressure of oxygen (pO2), mean arterial pressure (MAP), and pump flow values at acceptable limits. However, even when this is possible, sometimes tissue hypoxia occurs during CPB because of the preoperative cardiovascular status and the accompanying preexisting pathologies of other systems.[1,2] Therefore, it is necessary to monitor the adequacy of tissue perfusion using various parameters during CPB and to adjust the hemodynamic parameters according to changing conditions. Blood lactate levels, arterial and venous oxygen saturation, the rate of urinary output, and base excess (BE) have to be monitored during CPB for the adequacy of tissue perfusion. For example, knowing the blood lactate level is vital for monitoring the adequacy of tissue perfusion during CPB.[3,4] However, it is known that changes in the levels of blood lactate are affected by several factors during CPB.[5-8]

Partial pressure of carbon dioxide (pCO2) in venous blood and the partial pressure of veno-arterial carbon dioxide (Dv-apCO2) gradients increase due to cessation of circulation, traumatic shock, or inadequate circulation resulting from severe sepsis or a decrease in systemic or pulmonary circulation.[9] During CPB, similar states in systemic and pulmonary circulation have been encountered, and the term ”sepsis-like syndrome” has been used for CPB.[10]

Other parameters such as lactate, the veno-arterial carbon dioxide (CO2) gradient, and mixed venous oxygen saturation (SvO2) are not accepted as definitive indicators for tissue perfusion, and they all have their own deficiencies. However, they are currently accepted as indirect tissue perfusion indicators. In our study, our aim was to search for any correlations and changes between lactate, the veno-arterial CO2 gradient, and SvO2 during the non-physiological state of circulation, or CPB.

Methods

Sixty consecutive patients (35 males, 53 females; mean age 64 years; range 38 to 78 years) who were scheduled for elective isolated coronary bypass were accepted into the study with the approval of the hospital ethics committee and with the informed consent of the patient. There were no exclusions. The demographic data of the patients is shown in Table 1. All of the patients were premedicated with alprazolam 0.5 mg (Xanax) taken orally the night before surgery. Midazolam 125 mic/kg intramuscular (IM) was given 30 minutes before surgery. A 16 G intravenous (i.v.) cannula was used for the i.v. lines of all of the patients admitted to the operation room, and isotonic saline infusion 100 ml/hour i.v. was started. Hemodynamic monitorization of the patients was done with a two-channel electrocardiogram (ECG) (Siemens 7000 model) DII, V5 derivations, a pulse oximeter, invasive arterial pressure (with a catheter placed in the radial artery by an 18 G cannula and an Edwards Lifesciences TruWave Disposable Pressure Transducer, ICU Medical, Inc. San Clemente, CA 92673 USA), and central venous pressure. Induction of anesthesia was performed with midazolam 50 mic/kg and pancuronium 2 mg, followed by fentanyl 25-35 mic/kg and pancuronium in total 0.1 mg/kg. Endotracheal intubation was done after at least five minutes of mask ventilation. Desflurane 3-4% in oxygen 50% and N2O 50% were used for patients whose hemodynamic parameters were appropriate (systolic blood pressure >120 mmHg, ejection fraction >40%). Anesthesia was maintained using oxygen 50% and air 50% in other patients. Midazolam and vecuronium infusions, both 80 mic/kg/hour, were started. Furosemid 0.5 mg/kg i.v. bolus was given. Beta-blocker agents or vasodilators were used to control hypertension. Heparin 4 mg/kg was given after the left internal thoracic artery had removed, and activated coagulation (ACT) was maintained at between 450-600 seconds. Cardiopulmonary bypass was started following cannulation. The hematocrit values were kept at >18%, with the MAP remaining between 50-80 mmHg, and the pump flow between 2-2.5 L/m²/min throughout the operation. A fresh gas flow was provided at 1.35 L/m2/min in order to remove the carbon dioxide which had accumulated in the reservoir during CPB. Moderate hypothermia (32°) was applied to all patients. Antegrade cold crystalloid cardioplegia (7-10 ml/kg) was used after cross-clamping. When the extracorporeal circulation was terminated, midazolam and vecuronium infusions were set at 50 mic/kg/hour. These infusions were stopped following skin closure. The efficiency of tissue perfusion was monitored throughout the CPB via the Dv-apCO2 gradient (by blood samples from the venous and arterial lines of CPB), lactate levels, blood gas analysis of venous and arterial blood, urinary output, and assessment of hemodynamic parameters.

Measurements were conducted at four periods: before CPB (T1), at the beginning of CPB at 36 °C (T2), at hypothermia at 32 °C (T3), at the end of rewarming at 37 °C (T4).

Table 1: The demographic and operative data of the patients

Data was reported as a percentage or as a mean ± standard deviation (SD), and t-tests were used for continuous variables. The variables were considered significant if p values were less than 0.05. During the assessment of the correlation between the tissue perfusion parameters, the differences between the changes in hemodynamic parameters between the periods were found and compared according to Pearson’s correlation.

Results

The demographic and operative data of our patients is given in Table 1.

There was no significant correlation between the parameters in any of the periods. The values of Dv-aPCO2 were 5.89±2.1 5.74±2 and 7.24±2.6 in the T2, T3, T4 periods, respectively while the lactate values during the same periods were 0.9±0.2 1.02±0.3 and 1.6±0.6. The hemodynamic and blood gas values are given in Table 2.

Table 2: Hemodynamic parameters and blood gas analysis

The T2 a nd T3 periods were compared with regard to the correlation of the change of tissue perfusion parameters between periods, and Table 3 reveals that there was no significant correlation between Dv-aPCO2 and lactate values. The results in which both the changes in venous lactate (r=0.54, p=0.046) and arterial lactate (r=055, p=0.042) values along with those of Dv-aPCO2 showed significant correlation when the T2 a nd T 4 periods were compared. These results are provided in Table 4. A significant correlation was found between Dv-aPCO2 and arterial base excess (BE) values (r=-0.64, p=-0.019) when the T3 and T4 periods were compared, and these results are shown in Table 4.

Table 3: The correlations of changes in the tissue perfusion parameters in between the T2 and T3 of cardiopulmonary bypass

Table 4: The correlations of changes in the tissue perfusion parameters in between T2 and T4 periods of cardiopulmonary bypass

Table 5: The correlations of changes in tissue perfusion parameters in between the periods T3 and T4 of cardiopulmonary bypass

Discussion

The main source of carbon dioxide in our body is CO2, and it is generated as the byproduct of aerobic metabolism and is produced after the buffering process of acids, such as lactic acid, is induced as the result of anaerobic metabolism. The solubility of CO2 is 20 times more than that of O2, so it is more significant for CO2 to be carried in a dissolved state.[11-13] The main route of excretion for CO2 in circulation is the lungs, and under normal conditions, the value for Dv-aPCO2 is 2-5 mmHg. The increased load of CO2 is balanced by the elimination of CO2 through the lungs. However, it is necessary to increase the transfer of CO2 to the lungs in order to be able to increase the elimination of CO2.

In low perfusion states when there is no hypoxia, studies have shown that more CO2 than normal enters the circulation in the peripheral tissue and causes venous hypercapnia due to the increased circulation time. In turn, this causes the Dv-aPCO2 values to increase.[12,13]

In hypoxic situations in which there is insufficient blood flow, CO2 production is a result of the tamponade of the acids coming out. This method has less CO2 production; thus, it is more difficult for the produced CO2 to enter circulation. Because of this, it is takes more effort to detect the CO2 produced under hypoxic conditions. High venous flow is needed to wash out the CO2 produced in the tissue under hypoxic conditions, and it is not possible to detect the produced CO2 under hypoxic conditions by Dv-aPCO2.[14]

The increase in veno-arterial CO2 gradient is not only related to the inadequate blood flow but also to CO2 production and elimination. In septic shock, which is typical in hyperdynamic cardiac failure, the Dv-aPCO2 values have been shown to increase due to systemic hypoperfusion.[15]

The increase in Dv-aPCO2 values in septic shock is due to several factors. First, there is the impairment of ventricular contractility due to the circulating mediators of the patients in septic shock. As a result, there is a decrease in systemic vascular resistance (SVR); consequently the heart cannot supply the increasing demand. The second factor is the rise in production of CO2 due to the hyperdynamic state. In addition, there is the CO2 produced during the buffering of the acids along with the increased need for the buffering of the higher amount of lactic acids during septic shock.[16] Finally, there is the change in CO2 elimination through the lungs because of respiratory failure due to sepsis.

Mecher et al.[9] stated that in 37 patients in septic shock, 19 had Dv-aPCO2 values of > 6 m mHg w ith low cardiac output, but after fluid replacement, the low cardiac output improved, and the Dv-aPCO2 values decreased. Bakker et al.[16] followed 64 septic patients and detected low cardiac output in 15 who had an increase in Dv-aPCO2 and PvCO2 values. The authors deduced that there is a close relationship between the low cardiac output and Dv-aPCO2 a nd P vCO2. Bakker et al.[16] also showed that there was no statistically significant difference between the Dv-aPCO2 values of patients who were ventilated mechanically and those who were breathing spontaneously (p=0.055). The values of Dv-aPCO2 also increased more in patients with high mortality, and this relationship with Dv-aPCO2 is stronger than the parameters related to oxygen and Da-PO2.

Our study was designed to detect inadequate blood flow during CPB with Dv-aPCO2, especially in septic patients, when taking into consideration the efficiency of the use of Dv-aPCO2 for this purpose. When we compared the Dv-aPCO2 values with the other oxygenation parameters and blood lactate levels[3,4] in the normothermic-hypothermic period of CPB (T2 v ersus T 3), no significant correlation was found between the changes in lactate Dv-aPCO2 a nd S vO2 values (Table 3).

The expected correlation between the T2 a nd T 3 periods could not be detected because of the increased solubility of CO2 ( dissolving o f C O2 and becoming a liquid form) attributable to hypothermia and the relationship between the total CO2 content. The PO2 had also been disrupted.[17] Although venous hypercapnia was expected during the hypothermic period of CPB due to inadequate blood flow, it did not occur because of the increased solubility of CO2. This results indirectly in the increase in Dv-aPCO2 not occurring. This physiological change in CO2 due to temperature difference modifies and reduces the efficiency of Dv-aPCO2 to show the inadequate perfusion in the hypothermic period of CPB. Therefore, it is not possible to say that the adequacy of tissue perfusion can be monitored safely only via the monitorization of Dv-aPCO2 during all periods of CPB. Likewise, when evaluating the other indirect parameters of the adequacy of tissue perfusion, such as SvO2, along with the changes in the values of lactate during the hypothermic periods of CPB, the SvO2 and lactate levels changed in parallel directions. However, the decrease in SvO2 was expected to be parallel to the increase in lactate. In order to explain this difference in hypothermia, what the SvO2 reflects and how it works should be precisely known.

Mixed venous oxygen saturation is commonly used to assess the balance of total body oxygen delivery to oxygen demand during cardiopulmonary bypass. Given an adequate and stable arterial oxygen content and metabolic rate, SvO2 of more than 60% implies adequate systemic oxygen delivery.[17] Despite the general acceptance of this fact, major postoperative endorgan complications potentially secondary to undetected regional ischemia during bypass continue to be reported, for example acute mesenteric ischemia, gastrointestinal bleeding, and acute pancreatitis.[18] Mixed venous oxygen saturation may not accurately represent major end-organ venous desaturation and acidemia because it represents pooled venous blood from all organs.[19]

In addition to this deficiency in the ability of SvO2 to detect the adequacy of tissue oxygenation, when CPB and hypothermia are added to the scene, the interpretation of SvO2 becomes even more confusing.

During CPB practice, this change in the redistribution of blood flow along with any associated negative outcomes has led clinicians to prefer to work with the highest blood flow, MAP and hematocrit values during CPB. In addition, with hypothermia, as stated above, the total body O2 consumption (VO2) decreases more than the O2 supply, and an increase in the SvO2 is observed, especially in the hypothermic period of CPB. However, there are regional hypoperfusion areas. This situation decreases the reliability of SvO2.

Lactate is considered to be the gold standard of the tissue perfusion indicators. Microcirculation fails in nonpulsatile flow and during hypothermia, however redistribution occurs, especially during the hypothermic period of CPB, and although tissue hypoxia exists blood lactate levels may stay within normal range similar to other tissue perfusion parameters.[3-8] However, when the regional perfusion improves, there is an increase in blood lactate levels (wash-out). In order to diagnose poor tissue perfusion in time, all of the indirect tissue perfusion parameters should be closely monitored and evaluated during CPB since they work in conjunction with each other.

In conclusion, our results showed that Dv-aPCO2 and the other indirect parameters of tissue perfusion are not adequate if evaluated alone. Every parameter has its own intrinsic value, but each also comes with its own deficiencies. Therefore, monitorization of the adequacy of tissue perfusion should prove to be more accurate when all of the parameters are evaluated together.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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