Abstract

Background: This study aims to investigate the effects of partial pressure of venous-arterial carbon dioxide changes in the early period after cardiopulmonary bypass in patients who did or did not receive inotropic support therapy and the effect of these changes on tissue perfusion.

Methods: A total of 100 consecutive patients (70 males, 30 females; mean age 61.8±2.3 years; range, 20 to 75 years) who underwent open heart surgery were divided into two groups as those who did not receive any inotropic agent (group 1, n=50) and those who received at least one inotropic agent (group 2, n=50) during the early postoperative period. Heart rate, blood oxygen saturation level, mean arterial pressure, central venous pressure and urine volume, lactate and base excess levels were recorded during the postoperative first 24 hours. At the same timeframe, partial pressure of venous-arterial carbon dioxide level was calculated from central venous and peripheral blood samples.

Results: In both groups, partial pressure of venous-arterial carbon dioxide were significantly higher in the postoperative fourth hour compared with basal values. This significant difference continued for the postoperative first 24 hours. Partial pressure of venous-arterial carbon dioxide in group 2 was significantly higher at the 12th-hour measurement (p=0.002). Lactate levels at zeroth and eighth hours were significantly higher in group 2 (p=0.012 and p=0.017, respectively). Fourthhour urine excretion volumes were significantly lower in group 1 (p=0.010). Mean arterial pressure at zeroth, 12th and 20th hours was significantly higher in group 2 (p=0.001, p=0.016, and p=0.027, respectively). At the eighth-hour measurement, a positive weak relationship was detected between partial pressure of venousarterial carbon dioxide and lactate levels (r=0.253 and p=0.033).

Conclusion: This study demonstrated that partial pressure of venous-arterial carbon dioxide increased in the first few hours and remained to be high for 24 hours after cardiopulmonary bypass independently of the use of inotropic support. However, in the postoperative period, even after lactate and base excess levels return to baseline values, partial pressure of venous-arterial carbon dioxide may continue to remain at high values, which may indicate impaired perfusion in some tissues.

Deterioration in cardiac performance, decreased cardiac output, and need for inotropic support are frequent conditions after open heart surgery. Hypoperfusion, which can lead to multiple organ failure in open heart surgery patients, is a preventable cause of morbidity and mortality.[1] Previous studies have shown that central venous oxygen saturation measured from the superior vena cava (ScvO₂) can be an indirect indicator of mixed venous oxygen saturation (SvO₂) and cardiac output, and hence it has indicated the tissue perfusion under certain conditions.[2-4] Low perfusion pressure, even in the absence of hypoxia, leads to increased carbon dioxide in the peripheral tissues and venous hypercarbia by incorporation of the carbon dioxide into the circulation. This leads to increased difference between the partial pressure of carbon dioxide (ScvCO₂) measured in venous blood and partial pressure of venous-arterial carbon dioxide (ΔPCO₂).[5] Partial pressure of venous-arterial carbon dioxide may be considered to be a good indicator of the adequacy of blood flow to remove total CO₂ produced by peripheral tissues. Previous studies reported that a ΔPCO₂ value higher than 6 mmHg in patients with high-risk surgery or in patients with sepsis might identify adequately untreated patients.[2,6,7] In this study, we aimed to investigate the effects of ΔPCO₂ changes in the early period after cardiopulmonary bypass (CPB) in patients who did or did not receive inotropic support therapy and the effect of these changes on tissue perfusion.

Methods

This study was conducted at Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital between January 2013 and September 2013. A total of 100 consecutive patients (70 males, 30 females; mean age 61.8±2.3 years; range, 20 to 75 years) who underwent elective open heart surgery were divided into two groups as those who did not receive any inotropic agent (group 1, n=50) and those who received at least one inotropic agent and/or vasopressor support to maintain the mean arterial pressure (MAP) above 65 mmHg (group 2, n=50) during the early postoperative period. Patients with preoperative low cardiac ejection fraction (<40%), history of cerebrovascular disease, chronic renal insufficiency, chronic obstructive pulmonary disease, peripheral arterial occlusive disease, postoperative intra-aortic balloon pump need or those reoperated at first six hours after primary surgery were excluded. The study protocol was approved by the Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital Ethics Committee (approval number 28001928-051.99). A written informed consent was obtained from each patient. The study was conducted in accordance with the principles of the Declaration of Helsinki.

On arrival to the operating room, a peripheral intravenous catheter was inserted. A 20-gauge cannula was inserted in the contralateral radial artery for invasive arterial blood pressure measuring. Other monitoring included five-lead electrocardiography and pulse oximetry. The induction of anesthesia was established with 2 mg/kg propofol, 15 µg/kg fentanyl, 0.5 mg/kg rocuronium intravenously with 100% oxygen inhalation. Anesthesia was maintained with 50% air and 5-6% desflurane in oxygen with positive pressure ventilation in a circle system. End-tidal CO₂ was maintained between 30 and 35 mmHg. An esophageal temperature probe and a urine catheter were also placed. After induction of anesthesia, a central venous catheter was inserted in the right internal jugular vein.

After the sternotomy incision, 300 U/kg heparin was administered to provide an activated coagulation time >400 sec. Membrane oxygenators (Medtronic, Inc., Minneapolis, USA) were primed with 1,000-1,500 mL of Ringer's solution. A non-pulsatile pump flow was set at with 2.2-2.4 L/min/m2 to maintain MAP between 50 and 70 mmHg. Mild hypothermia with a core temperature of 33°C was provided during CPB. Intermittent antegrade cardioplegia was used for myocardial protection. Protamine sulfate was used to antagonize the heparin.

Postoperative care in the intensive care unit (ICU) was provided according to the institutional standard of care. After surgery, patients were transferred to the ICU for full monitoring, where they were monitored with electrocardiography, MAP, pulse oximetry, central venous pressure (CVP) and were mechanically ventilated with synchronized intermittent-mandatory ventilation plus pressure support mode with fraction of inspired oxygen of 0.6, respiratory rate of 10-14, and a positive end-expiratory pressure of 5-8. Low cardiac output was considered in those who met the following criteria before discharge from the first hospitalization in ICU immediately after surgery: need for inotropic support with vasoactive drugs (dopamine 4 ?g/kg/min at least for 12 h and/or dobutamine and/or norepinephrine) to maintain systolic blood pressure above 90 mmHg or need for mechanical circulatory support with intra-aortic balloon pump to maintain systolic blood above 90 mmHg and signs of impairment of body perfusion, hypothermia, hypotension, oliguria/anuria, lowered level of consciousness or a combination of these signs.[8,9] The dose was determined according to the patient's body weight. Doses of dopamine or dobutamine were increased or decreased by 2 µg/kg/min and doses of norepinephrine by 0.02 µg/kg/min to maintain the target MAP (>65 mmHg).[10]

Extubation criteria for the patients were adequate neurologic response, sufficient muscle strength, hemodynamic stability without high dose inotropic/vasoactive support, and an arterial PO₂>60 mmHg with an inspired oxygen fraction ?40%. Criteria for discharge from the ICU were that patients must be awake, cooperative, and hemodynamically stable (without inotropes), while having an acceptable respiratory pattern, blood gas analysis (arterial PO₂ >70 mmHg, PCO₂ <50 mmHg), and visual analog scale score ≥5.

End of surgery was accepted as a zero-hour point, and, during the postoperative first 24 hours, heart rate, blood oxygen saturation level, MAP, CVP and urine volume, lactate, glucose, and base excess levels in arterial blood gas were recorded in every four hours. At the same timeframe, P(v-a) CO₂=(ƒpCO₂) level was calculated from central venous and peripheral blood samples.

Statistical analysis
Statistical analysis was performed with Number Cruncher Statistical System 2007 & Power Analysis and Sample Size 2008 Statistical Software (NCSS, Kaysville, UT, USA). Student"s t-test was used for comparison of parametric variables and Mann- Whitney U was used for nonparametric variables. Qualitative variables were compared with Yates continuity correction test (Yates corrected chi-square).

The relationship between parameters was determined with Pearson"s correlation analysis and Spearman"s correlation analysis. A p value of <0.05 was considered to indicate statistical significance.

Results

There were no significant differences between study groups in terms of gender, age, or body mass index. Cross-clamping time, CBP time, ICU stay and hospital stay were significantly longer in group 2 (p=0.001, p=0.001, p=0.003, and p=0.001, respectively) (Table 1).

Table 1: Patients" characteristics and perioperative data

The mean ΔPCO₂ were 5.9±1.9 in group 1 and 5.5±1.6 in group 2 during admission to ICU (baseline) (p=0.330). Partial pressure of venousarterial carbon dioxide levels increased significantly in both groups at the postoperative fourth hour and this rate remained for 24 hours postoperatively. Fourth-, eighth-, 16^th-, and 24^th-hour ΔPCO₂ value measurements were similar in both groups. Partial pressure of venous-arterial carbon dioxide level in group 2 was significantly higher at the 12^th-hour measurement (p=0.002) (Figure 1).

Figure 1: Comparison of partial pressure of venous-arterial carbon dioxide levels by groups.
ΔpCO₂: Partial pressure of venous-arterial carbon dioxide.

Lactate levels at zeroth- and at eighth-hours were significantly higher in group 2 (p=0.012 and p=0.017, respectively), but no difference was detected in fourth-, 12^th-, 16^th-, 20^th-, or 24^th-hours. Fourth-hour urine excretion volumes were significantly lower in group 1 (p=0.010). There were no statistical differences in terms of urine excretion in other time points. Although a statistical difference was found in terms of BE levels in zeroth hour (p=0.002), no statistical difference was found in other time points. Heart rate measurements showed statistically significant difference at zeroth- and fourth-hours (p=0.001 and p=0.017, respectively) in favor of group 2. There were no significant differences in terms of heart rate at eighth-, 12^th-, 16^th-, 20^th-, or 24^th-hours. Mean arterial pressure at zeroth-, 12^th-, and 20^th-hours were significantly higher in group 2 (p=0.001, p=0.016, and p=0.027, respectively). No statistical difference was detected in terms of central venous pressure values or glucose levels in any time point (Table 2).

Table 2: Comparisons for different time points

Table 2: Continued

There was no statistically significant relationship between ΔPCO₂ and lactate levels at the zeroth-, fourth-, 12^th-, 16^th-, 20^th-, or 24^th-hour measurements. Meanwhile, in eighth-hour measurement, a positive weak relationship was detected (r=0.253, p=0.033). No significant relationship was found between ΔPCO₂, urine excretion, BE, MAP, and CVP (Table 3).

Table 3: Relationship between partial pressure of venous-arterial carbon dioxide and other parameters

Discussion

The current study demonstrated that ΔPCO₂ increased in the first few hours and remained to be high for 24 hours in the postoperative period after CPB independently of the use of inotropic support. However, in the postoperative period, even after lactate and BE levels returned to baseline values, ΔPCO₂ may continue to remain at high values, which may indicate impaired perfusion in some tissues.

Monitoring tissue perfusion is among the main aims after cardiac surgery in postoperative care units. Increase of ΔPCO₂ in response to alterations in systemic and pulmonary blood flow in cardiac and CPB surgery patients was shown in previous studies.[11,12] Toraman et al.[13] reported that during the hypothermic period of CBP, the increase in ΔPCO₂ was not inversely associated with insufficient blood flow and there was a significant correlation between ΔPCO₂ and tissue p erfusion parameters. Moreover, Takami and Masumoto[11] showed that increased ΔPCO₂ was associated with decreased cardiac index, SvO₂, arterial bicarbonate (HCO₃), and high lactate levels and elevation of ΔPCO₂ related to surgical invasiveness and CPB and cross-clamping time. In the current study, the highest level of ΔPCO₂ after CPB in both inotropic agent administered and nonadministered groups was reached at postoperative fourth hour and the high levels of ΔPCO₂ remained for the first 24 hours postoperatively. The increase of ΔPCO₂ was not different between the two groups until the 12^th hour, whereas at 12^th-hour measurement, ΔPCO₂ was higher in inotropic agent administered group. Similar to the previous studies,[11] the lactate and BE levels were higher, MAP was lower, CBP and cross-clamping time were longer in inotropic agent administered group in the postoperative period. Utoh et al.[14] reported that ΔPCO₂ was correlated with cardiac index, oxygen delivery, minimum rectal temperature, and duration of CPB while increased ΔPCO₂ decreased to within normal ranges at 12 hours postoperatively. In our study, except for the postoperative 12^th hour, similar ΔPCO₂ values in both inotropic agent administered and non-administered groups may be an indication that ΔPCO₂ is unrelated to inotropic support.

It was shown that SvO₂ was superior than MAP and heart rate in cardiac surgery patients as a hemodynamic measurement.[15] However, the clinically predictable threshold of SvO₂ has been differently presented. Pölönen et al.[16] showed that ScvO₂ values higher than 70% and lactate values lower than 2 mmol improved treatment targets in the early postoperative period. Meanwhile, the negative predictive value of high initial ScvO₂ levels in septic patients was also stated in other studies.[15,16] The reliability of the ScvO₂ in association with tissue perfusion markers such as lactate and ΔPCO₂ was also shown in previous studies.[17-19] Although ΔPCO₂ is not an excellent marker for tissue hypoxia, it may show that venous blood flow is not sufficient to remove carbon dioxide produced in peripheral tissues.[17] Habicher et al.[18] stated that although oxygen delivery and consumption balance might be assumed as normal with ScvO₂ level and cardiac index interpretation, this fact was insufficient to show the hypoperfused regions of the body.

Several studies have reported different results regarding lactate changes and its association with ΔPCO₂ after CPB. Habicher et al.[18] reported that the high level of ΔPCO₂ was related to hyperlactatemia and this relationship was associated with splanchnic perfusion alteration after CPB. They also found a high complication rate and long length of ICU stay. However, Okten et al.[20] reported that although blood lactate levels provided information on the adequacy of tissue perfusion, changes in lactate levels did not correlate with mixed venous oxygen saturation. Furthermore, Guinot et al.[21] stated that ΔPCO₂ was associated weakly with arterial lactate. Although serum lactate levels have been used as a marker of global tissue hypoxia in circulatory shock, hyperlactatemia after cardiac surgery may occur depending on other mechanisms such as stress response to surgery and the use of beta-adrenergics.[22,23] Therefore, early after CPB, hyperlactatemia may reflect intraoperative factors rather than anaerobic metabolism, which may not be reliable for evaluating the adequacy of tissue oxygenation. Gasparovic et al.[23] reported that pulmonary lactate levels rise significantly after CPB and may contribute significantly to circulating lactate levels up to six hours postoperatively. In addition, Naik et al.[24] reported that serum lactate levels increased from the onset of CPB to peak and remained high up to six hours in the ICU and returned to normal by 24 hours. In a study on infants and neonates undergoing cardiac surgery, Rhodes et al.[25] reported that ΔPCO₂ continued to increase within the first 24 hours after admission to ICU compared with admission levels, while patients remaining on inotropes at 24 hours showed a trend toward higher 24-hour ΔPCO₂ compared with patients who were weaned off inotropes. Changes in ΔPCO₂ over time could be related to high CO₂ production or changes in each factor determining the relationship between partial CO₂ pressure and CO₂ content. Cardiopulmonary bypass may increase CO₂ tissue production as a result of increased metabolic needs, redistribution of blood flow to peripheral tissues, and changes in hepatosplanchnic perfusion; which may result in increased ΔPCO₂.[18] In addition, extubation and rewarming in cardiac surgical patients may contribute to increased ΔPCO₂. Extubation is associated with redistribution of systemic blood flow from peripheral tissues to respiratory muscles.[26] Hypothermia during surgery and rewarming in the ICU may affect both CO₂ production and the relationship between CO₂ content and partial CO₂ pressure.[27] In the current study, lactate level was found significantly increased at eighth-hour measurement in inotropic agent administered group, which had a tendency to decrease afterward. On the other hand, the decreased lactate, MAP, and ΔPCO₂ levels at 12th-hour measurement approved impaired perfusion. However, lactate level was not assessed after the 24th-hour period in the current study.

Futier et al.[19] suggested that measurement of ScvO₂ complementary to Δ PCO₂ might be applied for assessment of intravascular volume sufficiency and hypoperfusion in target treatment for high-risk surgery. Moreover, it was stated that if ΔPCO₂ was measured to be higher than 6 mmHg, care to keep adequate fluid levels and increased cardiac output should be given in sepsis patients.[28] Studies in the literature stating the simplicity, usefulness, and accessibility of ΔPCO₂ measurement to follow the tissue perfusion after cardiac surgery are limited and, to our knowledge, have not investigated the inotropic agents in these groups.[11,12]

The current study does, however, have several limitations. Firstly, PCO₂ was measured from central venous blood instead of mixed venous blood which could lead to under-estimation of CO₂ exchanges. However, previous studies demonstrated good correlation between central ΔPCO₂ and mixed ΔPCO₂.[19] Secondly, the study population was a cohort of relatively older patients. Therefore, our findings may not be generalizable to other populations. Finally, in the current study, ΔPCO₂ within the first 24 hours after cardiac surgery were evaluated while changes in ΔPCO₂ after the first 24 hours of surgery are unclear and merit further investigation.

In conclusion, although there is an increase in partial pressure of venous-arterial carbon dioxide in the postoperative period after cardiopulmonary bypass, partial pressure of venous-arterial carbon dioxide is insufficient to guide inotropic support therapy when evaluated alone. Even if indirect parameters of tissue perfusion return to baseline values, partial pressure of venous-arterial carbon dioxide can continue to remain high for the first 24 hours postoperatively. Further prospective studies are needed to confirm the results.

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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