Metabolic Dynamics During Cardiopulmonary Bypass: Oxygen Delivery, Carbon Dioxide Production, and Lactate Response Despite Preserved Global Perfusion

Metabolic Dynamics During Cardiopulmonary Bypass: Oxygen Delivery, Carbon Dioxide Production, and Lactate Response Despite Preserved Global Perfusion | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Metabolic Dynamics During Cardiopulmonary Bypass: Oxygen Delivery, Carbon Dioxide Production, and Lactate Response Despite Preserved Global Perfusion Deepthi J, Joshlin Agnes J, Saranya S, Sreelekha T, Rupika Ekambaram, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9702308/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Objective To analyze intraoperative metabolic parameters from carbon dioxide during cardiopulmonary bypass (CPB) and their association with postoperative hyperlactatemia in elective cardiac surgery. Methods This study observed 26 adult patients undergoing cardiac surgery with CPB. Blood gases were collected at specific times: after cardioplegia and during rewarming at 32°C. It calculated oxygen delivery (DO₂), consumption (VO₂), carbon dioxide production (VCO₂), respiratory quotient (RQ), and the DO₂/VCO₂ ratio. Lactate levels were measured during and up to 24 hours post-surgery. Paired t-tests compared intraoperative data, and repeated-measures ANOVA analyzed lactate and hemoglobin over time. Results Indexed DO₂ stayed above critical thresholds during CPB (265 ± 60 vs. 272 ± 52 mL/min/m², p = 0.48). VO₂ increased during rewarming (36 ± 14 to 52 ± 16 mL/min/m², p < 0.001), while VCO₂ did not change significantly (p = 0.62). RQ decreased from 2.00 ± 0.80 to 1.50 ± 0.50 (p = 0.012). The DO₂/VCO₂ ratio showed a non-significant downward trend (p = 0.18). Lactate levels rose over time, peaking 30 minutes after protamine at 3.9 ± 1.2 mmol/L and remained high at 24 hours. Conclusions Hyperlactatemia occurred despite maintained oxygen delivery during CPB. During rewarming, oxygen consumption rose, and metabolic reactivation was indicated by changes in RQ. While CO₂ variables reflected these changes, they couldn't reliably predict increases in lactate. A multimodal monitoring approach combining oxygen transport and metabolic markers is needed, rather than relying on a single perfusion threshold. Cardiopulmonary bypass Oxygen delivery Carbon dioxide production Respiratory quotient Hyperlactatemia Goal-directed perfusion INTRODUCTION Cardiopulmonary bypass (CPB) enables extracorporeal circulation during cardiac surgery but causes significant changes in systemic hemodynamics, oxygen transport, and cellular functions metabolism. 1 Despite advances in pump technology and membrane oxygenation, CPB remains associated with hemodilution, hypothermia, nonpulsatile flow, systemic inflammatory activation, and microvascular perfusion heterogeneity, all of which may impair effective tissue oxygen utilization. 2 , 3 Postoperative hyperlactatemia is frequently observed after cardiac surgery with CPB and is associated with increased morbidity and mortality, including acute kidney injury, prolonged mechanical ventilation, and extended intensive care unit stay. 4 – 6 Elevated lactate levels have traditionally been interpreted as markers of inadequate oxygen delivery (DO₂) leading to anaerobic metabolism. Consequently, goal-directed perfusion (GDP) strategies have emphasized maintenance of indexed DO₂ (iDO₂) above critical thresholds—commonly 260–280 mL/min/m²—to reduce postoperative organ dysfunction. 7 – 9 Recent systematic reviews confirm that lower intraoperative DO₂ during CPB is consistently associated with higher rates of acute kidney injury and lactate elevation. 9 However, lactate kinetics during and after CPB are multifactorial. Besides the oxygen supply–demand imbalance, factors leading to hyperlactatemia include catecholamine-driven glycolysis, inflammatory responses, mitochondrial dysfunction, reperfusion physiology, and impaired lactate clearance. 5 , 10 Contemporary understanding recognizes that lactate elevation can occur even when overall oxygen delivery is maintained, reducing its specificity as a sole marker of intraoperative hypoxia. 10 Variables derived from carbon dioxide offer a supporting physiological perspective. These include the veno-arterial carbon dioxide gradient (Pv–aCO₂), carbon dioxide production (VCO₂), respiratory quotient (RQ = VCO₂/VO₂), and ratios that combine oxygen delivery with CO₂ production (such as DO₂/VCO₂). These markers have been suggested to indicate tissue hypoperfusion and metabolic stress in critical care settings. 11 – 13 In the context of CPB, recent studies have examined the relationship between CO₂-derived indices and hyperlactatemia, indicating potential usefulness in detecting early metabolic changes imbalance. 14 Nonetheless, emerging data suggest that these parameters may have limited ability to predict major postoperative complications after cardiac surgery. 15 Furthermore, the metabolic transitions occurring during rewarming—a phase characterized by restoration of enzymatic activity and temperature-dependent increases in oxygen consumption—have not been systematically examined in relation to intraoperative CO₂ kinetics and postoperative lactate dynamics. A more integrated evaluation of oxygen- and CO₂-derived variables during CPB may therefore improve the interpretation of metabolic alterations observed in the perioperative period. Study Hypotheses CO₂-derived variables (VCO₂, RQ, DO₂/VCO₂) change significantly during CPB, particularly during rewarming. Alterations in these indices are temporally associated with postoperative lactate elevation. CO₂-derived parameters provide complementary information to indexed DO₂ in detecting intraoperative metabolic imbalance. METHODS Study design and ethical approval: This prospective observational study was conducted within the Department of Cardiothoracic and Vascular Surgery at a tertiary care teaching hospital. In compliance with the Declaration of Helsinki and with authorization from the Institutional Human Ethics Committee (Approval No.; CSP-Ⅲ/24/APR/04/153), the study was executed. Participants were informed in the preoperative area, and written consent was secured from all involved. Patient Population: Adult patients scheduled for elective cardiac surgery with cardiopulmonary bypass were screened over a three-month period. A total of twenty-six patients were included. Inclusion Criteria: Age ≥20 years Elective coronary artery bypass grafting (CABG), valve surgery, or combined procedures Requirement for CPB Exclusion Criteria: Emergency surgery Preoperative lactate >2 mmol/L Hemoglobin <8 g/dL Known renal or hepatic dysfunction Pre-existing metabolic disorders affecting lactate metabolism Preoperative mechanical circulatory support These criteria were used to reduce confounding factors that might affect oxygen transport or lactate kinetics. Anaesthetic management: The administration of general anesthesia was conducted in accordance with institutional protocols. Following induction and tracheal intubation via laryngoscopy, patients were mechanically ventilated using volume-controlled ventilation to sustain normocapnia. Standard monitoring comprised electrocardiography, invasive arterial pressure measurement, pulse oximetry, nasopharyngeal temperature assessment, and urine output monitoring. Systemic anticoagulation was accomplished through the administration of intravenous heparin at a dose of 400 IU/kg to maintain an activated clotting time exceeding 480 seconds prior to the initiation of cardiopulmonary bypass. CPB management: CPB was established using: Non-pulsatile roller pump Hollow-fibre membrane oxygenator Crystalloid-primed circuit Standard arterial line filter Arterial cannulation was performed in the ascending aorta. Venous drainage was achieved via right atrial or bicaval cannulation, depending on the procedure Perfusion targets Indexed pump flow: 2.4 L/min/m² Mean arterial pressure: 60–80 mmHg Hematocrit during CPB: 22–25% Systemic temperature: 28–32°C (moderate hypothermia) Packed red blood cells were administered as required to maintain oxygen-carrying capacity. Hemofiltration was used at the perfusionist's discretion for volume management. Myocardial protection was achieved with intermittent cold-blood cardioplegia. Rewarming was performed gradually to normothermia prior to separation from CPB. Protamine sulfate (1–1.3 mg per 100 IU heparin) was administered following CPB discontinuation. Data collection and sampling protocol Arterial and central venous blood samples were obtained at four predefined time points: 10 minutes after administration of cardioplegia During rewarming at core temperature 32°C 30 minutes after protamine administration 24 hours postoperatively Arterial blood samples were obtained from the indwelling arterial catheter, and venous samples were obtained from the central venous line. Blood gas analysis was performed using a calibrated blood gas analyzer. Calculation of metabolic variables Arterial and venous oxygen contents were calculated using standard equations: CaO₂ = (Hb × 1.36 × SaO₂) + (0.0031 × PaO₂) CvO₂ = (Hb × 1.36 × SvO₂) + (0.0031 × PvO₂) DO₂ = Pump flow × CaO₂ × 10 / Body surface area VO₂ = Pump flow × (CaO₂ − CvO₂) × 10 / Body surface area Carbon dioxide production (VCO₂) was estimated using the veno-arterial pCO₂ gradient: VCO₂ = Pump flow × (PvCO₂ − PaCO₂) Given the near-linear relationship between CO₂ partial pressure and content within physiological ranges, this method was used as a surrogate for CO₂ production during CPB. VCO₂ was estimated indirectly and does not represent direct volumetric carbon dioxide elimination. Respiratory Quotient (RQ): RQ was calculated as VCO₂/VO₂. The DO₂/VCO₂ ratio was calculated as an index of oxygen supply relative to metabolic CO₂ generation. Outcome measures: Primary outcome: Postoperative hyperlactatemia is defined as a blood lactate concentration > 2 mmol/L. Secondary outcomes Intraoperative changes in DO₂, VO₂, VCO₂ Respiratory quotient DO₂/VCO₂ ratio Serial lactate kinetics Statistical analysis: Statistical analysis was performed using SPSS software (27.0). Continuous variables are presented as mean ± standard deviation. Normality was assessed using the Shapiro–Wilk test. Paired t-tests were used to compare intraoperative variables between cardioplegia and rewarming phases. Repeated-measures analysis of variance (ANOVA) assessed temporal trends in lactate and hemoglobin. Bonferroni correction was applied for post hoc comparisons when appropriate. A p-value <0.05 was considered statistically significant. Methodological rigor : To minimize variability between patients and procedures, anesthesia, surgical procedures, and cardiopulmonary bypass (CPB) management were standardized based on institutional protocols. The anesthesia approach—covering induction agents, maintenance, and vasoactive drugs—temperature management, transfusion limits, pump flow rates, and mean arterial pressure targets were predetermined and uniformly implemented. CPB employed a consistent circuit setup and oxygenator system, with pump flows adjusted for body surface area. Hematocrit levels were kept within a predefined range during bypass. Acid–base regulation followed a consistent method (α-stat/pH-stat, as outlined in the full methods). Blood gas samples from arterial and venous blood were collected at specific CPB stages (initiation, cooling, stable hypothermia, rewarming, and pre-weaning) to ensure consistent timing. All samples were analyzed with the same calibrated blood gas analyzer. Key parameters, including oxygen delivery (DO₂), carbon dioxide production (VCO₂), respiratory quotient (RQ), and the DO₂/VCO₂ ratio, were calculated using standardized equations and adjusted for body surface area when needed. By combining directly measured gas exchange data with calculated metabolic indices, this study aimed to comprehensively evaluate oxygen transport and carbon dioxide removal during CPB. RESULTS Study Population Twenty-six adult patients scheduled for elective cardiac surgery with cardiopulmonary bypass were analyzed. The average age was 52 ± 15 years, with 54% being male. The mean duration of CPB was 92 ± 24 minutes. Hematocrit levels during CPB were kept at 23.1 ± 2.4%. Baseline demographic and operative details are summarized in Table 1 . Table 1 Baseline Demographic and Operative Characteristics (n = 26) Variable Value Age (years), mean ± SD 52 ± 15 Sex (Male/Female) 14 / 12 Body Mass Index (kg/m²) 25.8 ± 3.9 Diabetes mellitus, n (%) 7 (27%) Hypertension, n (%) 11 (42%) Preoperative hemoglobin (g/dL) 12.6 ± 1.4 Preoperative LVEF (%) 54 ± 8 CABG 10 (38%) Valve surgery 9 (35%) Combined procedures 7(27%) Cardiopulmonary bypass time (min) 92 ± 24 Aortic cross-clamp time (min) 64 ± 18 Lowest temperature on CPB (°C) 30.8 ± 1.2 Hematocrit during CPB (%) 23.1 ± 2.4 Intraoperative Oxygen Transport and Metabolic Variables Indexed oxygen delivery (DO₂) stayed above standard critical levels throughout CPB. No notable difference in DO₂ was observed between the cardioplegia and rewarming phases (p = 0.48). During rewarming, oxygen consumption (VO₂) rose markedly (p < 0.001), indicating metabolic reactivation. In contrast, carbon dioxide production (VCO₂) remained largely unchanged (p = 0.62). The respiratory quotient (RQ) declined significantly (p = 0.012). The DO₂/VCO₂ ratio showed a downward trend but was not statistically significant (p = 0.18). Notably, the rise in VO₂ during rewarming showed a substantial effect size (Cohen’s d = 0.83), reflecting a significant metabolic shift. ( Table 2 ) The elevated calculated RQ values likely reflect limitations of surrogate VCO₂ estimation during CPB rather than true physiological respiratory quotient values. Table 2 Oxygen Transport and CO₂-Derived Variables During CPB (n = 26) Variable 10 min after Cardioplegia Rewarming (32°C) p-value DO₂ (mL/min/m²) 265 ± 60 272 ± 52 0.48 VO₂ (mL/min/m²) 36 ± 14 52 ± 16 < 0.001* VCO₂ (mL/min/m²) 72 ± 25 75 ± 21 0.62 Respiratory Quotient (RQ) 2.00 ± 0.80 1.50 ± 0.50 0.012* DO₂ / VCO₂ ratio 3.7 ± 1.5 3.3 ± 1.2 0.18 *Statistically significant (p < 0.05) Lactate Kinetics Lactate levels increased progressively during CPB and peaked 30 minutes after protamine administration. Repeated-measures ANOVA showed a significant time effect (F = 18.6, p < 0.001). (Table 3 ) Table 3 Serial lactate levels Time Point Lactate (mmol/L), Mean ± SD 10 min post-Cardioplegia 1.90 ± 0.88 Rewarming (32°C) 2.40 ± 0.93 30 min Post-Protamine (Peak) 3.78 ± 3.43 24 Hours Postoperative 2.08 ± 0.96 Lactate peaked after separation from CPB and partially normalized by 24 hours. Correlation Between Metabolic Reactivation and Hyperlactatemia No significant correlation was found between the rise in oxygen consumption during rewarming (ΔVO₂) and peak postoperative lactate levels (r = − 0.002, p = 0.993). Table 4 . Table 4 Correlation Analysis Variable Pair Pearson r p-value ΔVO₂ vs Peak Lactate −0.002 0.993 This indicates that the level of metabolic reactivation was not a direct factor in the rise of postoperative lactate levels. Predictive Performance of DO₂/VCO₂ Ratio Receiver operating characteristic (ROC) analysis was conducted to evaluate the capacity of the DO₂/VCO₂ ratio at the time of rewarming in predicting clinically significant hyperlactatemia (lactate > 3 mmol/L). Table 5 . Table 5 ROC Analysis for Lactate > 3 mmol/L Predictor AUC Interpretation DO₂/VCO₂ (Rewarming) 0.568 Poor discrimination The AUC was 0.568, which suggests limited ability to distinguish between groups performance. Hemoglobin Trends Hemoglobin levels showed significant variation over time (F = 4.92, p = 0.006), indicating effects of hemodilution and postoperative recovery. (Table 6 ) Table 6 Hemoglobin Levels at Different Study Intervals Time Point Hemoglobin (g/dL), Mean ± SD 10 min Post-Cardioplegia 8.0 ± 1.8 Rewarming 8.3 ± 1.6 30 min Post-Protamine 10.2 ± 2.0 24 Hours Postoperative 10.1 ± 1.4 DISCUSSION This prospective physiological study of adult patients undergoing cardiopulmonary bypass (CPB) found that indexed oxygen delivery (DO₂) consistently remained above critical thresholds throughout the procedure. Rewarming was associated with a notable, clinically meaningful increase in oxygen consumption (VO₂), yet postoperative lactate levels also increased. Importantly, neither VO₂ nor the DO₂/VCO₂ ratio predicted significant hyperlactatemia. These results suggest that the rise in lactate after modern CPB is more likely due to complex metabolic and inflammatory responses rather than an inadequate global oxygen supply. Inadequate oxygen delivery during CPB has been associated with organ dysfunction and hyperlactatemia. Ranucci et al. showed that lower DO₂ levels during bypass are linked to acute renal failure and worse outcomes. More recent research indicates that goal-directed perfusion strategies aiming for higher DO₂ levels can help reduce postoperative kidney injury. 7 , 8 A recent systematic review by Dias et al. also emphasizes the importance of ensuring sufficient oxygen delivery during CPB. 9 In our cohort, DO₂ remained within or above levels generally considered safe. Despite this, lactate levels rose after surgery. This disconnect suggests that mechanisms beyond traditional oxygen debt may be at work. CPB induces a systemic inflammatory response marked by cytokine activation, endothelial dysfunction, and metabolic changes. 2 , 3 These responses might lead to altered substrate use and heightened glycolytic activity, occurring independently of overall oxygen delivery. Hyperlactatemia after cardiac surgery is common and associated with adverse outcomes. 4 – 6 However, elevated lactate levels do not necessarily imply tissue hypoxia. Garcia-Alvarez et al. demonstrated that hyperlactatemia may occur despite adequate oxygen delivery due to metabolic and mitochondrial factors. 10 Our findings are consistent with this paradigm. The absence of correlation between the increases in VO₂ associated with rewarming and peak lactate suggests that lactate elevation may reflect metabolic activation rather than oxygen supply failure. Hypothermia during CPB reduces metabolic rate and oxygen consumption. As temperature normalizes, VO₂ increases accordingly. Leone et al. demonstrated that temperature modulation influences oxygen delivery dynamics during CPB. In the present study, VO₂ increased significantly during rewarming, with a large effect size (Cohen’s d = 0.83), confirming substantial metabolic reactivation. However, this physiologic transition did not translate into proportional changes in lactate kinetics, suggesting that lactate elevation is not simply a consequence of oxygen demand during rewarming. CO₂-derived parameters have been proposed as surrogates of microcirculatory dysfunction and anaerobic metabolism. 12 , 13 Recent cardiac surgery studies have explored their predictive utility during CPB. 14 , 15 In our cohort, ROC analysis demonstrated limited discriminatory performance of DO₂/VCO₂ for predicting lactate > 3 mmol/L (AUC 0.568). This finding aligns with recent data suggesting that CO₂-derived indices may not reliably predict major postoperative complications in cardiac surgery populations. 15 Therefore, although physiologically appealing, CO₂-derived metrics may provide limited standalone utility during elective cardiopulmonary bypass procedures where overall perfusion is sustained. Clinical Implications Our data suggest a nuanced view of lactate during CPB. When DO₂ stays within accepted thresholds, moderate postoperative lactate rises may not always signal insufficient oxygen delivery. These results highlight the need for interpreting lactate levels in context, rather than automatically increasing pump flow or transfusing based solely on lactate values. Limitations This was a single-center observational study with a small sample size. Measurements of microcirculatory and mitochondrial functions were not conducted. Inflammatory mediators and catecholamine levels were also not quantified, so mechanistic explanations are only speculative. CONCLUSIONS During modern CPB with maintained oxygen delivery, rewarming triggers notable metabolic activation. Elevated lactate levels after surgery happen regardless of whether global oxygen delivery (DO₂) is adequate or if VO₂ increases during rewarming. CO₂-based indices are of limited use in predicting these changes. These results indicate that hyperlactatemia during CPB results from complex metabolic and inflammatory processes rather than just insufficient oxygen supply. What This Study Adds This study offers three key insights: 1. Keeping DO₂ above established thresholds does not prevent postoperative lactate levels from rising. 2. Rewarming is a metabolically active and potentially fragile phase of CPB. 3. CO₂-based indices capture physiological changes but may not solely predict lactate kinetics during controlled perfusion. Focusing on intraoperative metabolic dynamics rather than just static thresholds emphasizes the need to consider phase-specific physiology in CPB management. Declarations Ethical approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki and the ethical guidelines of the Indian Council of Medical Research (ICMR). Ethical approval was obtained from the Institutional Human Ethics Committee (Approval No.; CSP-Ⅲ/24/APR/04/153). Written informed consent was obtained from all participants prior to enrolment. Consent for publication: Not applicable. Availability of data and materials The datasets collected during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study received no funding. Authors’ contributions DJ, JAJ and SS conceived the study. ST & RE contributed to data acquisition. DJ supervised. AJ, JAJ & DJ performed statistical analysis. AJ, SS & RE drafted the manuscript. All authors reviewed and approved the final manuscript. Acknowledgements The authors thank the study participants and the cardiology department at Sri Ramachandra Institute of Higher Education and Research. References Sarkar, M. & Prabhu, V. Basics of cardiopulmonary bypass. Indian J Anaesth 61 , 760–767 (2017). Laffey, J. G., Boylan, J. F. & Cheng, D. C. H. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology 97 , 215–252 (2002). Warren, O. J. et al. The inflammatory response to cardiopulmonary bypass: part 1--mechanisms of pathogenesis. J Cardiothorac Vasc Anesth 23 , 223–231 (2009). Hajjar, L. A. et al. High lactate levels are predictors of major complications after cardiac surgery. J Thorac Cardiovasc Surg 146 , 455–460 (2013). Naik, R., George, G., Karuppiah, S. & Philip, M. A. Hyperlactatemia in patients undergoing adult cardiac surgery under cardiopulmonary bypass: Causative factors and its effect on surgical outcome. Ann Card Anaesth 19 , 668–675 (2016). Maillet, J.-M. et al. Frequency, risk factors, and outcome of hyperlactatemia after cardiac surgery. Chest 123 , 1361–1366 (2003). Ranucci, M. et al. Oxygen delivery during cardiopulmonary bypass and acute renal failure after coronary operations. Ann Thorac Surg 80 , 2213–2220 (2005). Ranucci, M. et al. Goal-directed perfusion to reduce acute kidney injury: A randomized trial. J Thorac Cardiovasc Surg 156 , 1918-1927.e2 (2018). Dias, R. D. et al. Delivery of oxygen during cardiopulmonary bypass and associated clinical outcomes among adult cardiac surgery patients: A systematic review. Perfusion 2676591251380659 (2025) doi:10.1177/02676591251380659. Garcia-Alvarez, M., Marik, P. & Bellomo, R. Sepsis-associated hyperlactatemia. Crit Care 18 , 503 (2014). Franchi, F. et al. Oxygen delivery to carbon dioxide production ratio for continuously detecting anaerobic metabolism in trauma patients. Crit Care 11 , P306 (2007). Ospina-Tascón, G. A. et al. Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? Intensive Care Med 42 , 211–221 (2016). Mallat, J. et al. Use of CO2-derived variables in critically ill patients. Ann. Intensive Care 15 , 142 (2025). Kowara, Y. et al. Relation Between Multiplication of Venous Carbon Dioxide Partial Pressure (PvCO2) and the Ratio of Gas Flow to Pump Flow (Ve/Q) with Hyperlactatemia During Cardiopulmonary Bypass. Ann Card Anaesth 27 , 337–343 (2024). Zhou, X.-F. et al. Lactate and CO2-derived parameters are not predictive factors of major postoperative complications after cardiac surgery with cardiopulmonary bypass: a diagnostic accuracy study. Front Cardiovasc Med 12 , 1504431 (2025). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 21 May, 2026 Editor assigned by journal 21 May, 2026 Submission checks completed at journal 21 May, 2026 First submitted to journal 13 May, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9702308","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":639633298,"identity":"2300f8ea-6268-493c-b498-592fbabf49ea","order_by":0,"name":"Deepthi J","email":"","orcid":"","institution":"Sri Ramachandra Institute of Higher Education and Research","correspondingAuthor":false,"prefix":"","firstName":"Deepthi","middleName":"","lastName":"J","suffix":""},{"id":639633299,"identity":"80346e70-0018-47b1-9228-670bafcb8c6f","order_by":1,"name":"Joshlin Agnes J","email":"","orcid":"","institution":"SRM Institute of Science and 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Lactate Response Despite Preserved Global Perfusion","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCardiopulmonary bypass (CPB) enables extracorporeal circulation during cardiac surgery but causes significant changes in systemic hemodynamics, oxygen transport, and cellular functions metabolism.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Despite advances in pump technology and membrane oxygenation, CPB remains associated with hemodilution, hypothermia, nonpulsatile flow, systemic inflammatory activation, and microvascular perfusion heterogeneity, all of which may impair effective tissue oxygen utilization.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePostoperative hyperlactatemia is frequently observed after cardiac surgery with CPB and is associated with increased morbidity and mortality, including acute kidney injury, prolonged mechanical ventilation, and extended intensive care unit stay.\u003csup\u003e\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Elevated lactate levels have traditionally been interpreted as markers of inadequate oxygen delivery (DO₂) leading to anaerobic metabolism. Consequently, goal-directed perfusion (GDP) strategies have emphasized maintenance of indexed DO₂ (iDO₂) above critical thresholds\u0026mdash;commonly 260\u0026ndash;280 mL/min/m\u0026sup2;\u0026mdash;to reduce postoperative organ dysfunction.\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Recent systematic reviews confirm that lower intraoperative DO₂ during CPB is consistently associated with higher rates of acute kidney injury and lactate elevation.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, lactate kinetics during and after CPB are multifactorial. Besides the oxygen supply\u0026ndash;demand imbalance, factors leading to hyperlactatemia include catecholamine-driven glycolysis, inflammatory responses, mitochondrial dysfunction, reperfusion physiology, and impaired lactate clearance.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003eContemporary understanding recognizes that lactate elevation can occur even when overall oxygen delivery is maintained, reducing its specificity as a sole marker of intraoperative hypoxia.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eVariables derived from carbon dioxide offer a supporting physiological perspective. These include the veno-arterial carbon dioxide gradient (Pv\u0026ndash;aCO₂), carbon dioxide production (VCO₂), respiratory quotient (RQ\u0026thinsp;=\u0026thinsp;VCO₂/VO₂), and ratios that combine oxygen delivery with CO₂ production (such as DO₂/VCO₂). These markers have been suggested to indicate tissue hypoperfusion and metabolic stress in critical care settings.\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e In the context of CPB, recent studies have examined the relationship between CO₂-derived indices and hyperlactatemia, indicating potential usefulness in detecting early metabolic changes imbalance.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Nonetheless, emerging data suggest that these parameters may have limited ability to predict major postoperative complications after cardiac surgery.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFurthermore, the metabolic transitions occurring during rewarming\u0026mdash;a phase characterized by restoration of enzymatic activity and temperature-dependent increases in oxygen consumption\u0026mdash;have not been systematically examined in relation to intraoperative CO₂ kinetics and postoperative lactate dynamics. A more integrated evaluation of oxygen- and CO₂-derived variables during CPB may therefore improve the interpretation of metabolic alterations observed in the perioperative period.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStudy Hypotheses\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCO₂-derived variables (VCO₂, RQ, DO₂/VCO₂) change significantly during CPB, particularly during rewarming.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAlterations in these indices are temporally associated with postoperative lactate elevation.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCO₂-derived parameters provide complementary information to indexed DO₂ in detecting intraoperative metabolic imbalance.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy design and ethical approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective observational study was conducted within the Department of Cardiothoracic and Vascular Surgery at a tertiary care teaching hospital. In compliance with the Declaration of Helsinki and with authorization from the Institutional Human Ethics Committee (Approval No.; CSP-Ⅲ/24/APR/04/153), the study was executed. Participants were informed in the preoperative area, and written consent was secured from all involved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Population:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdult patients scheduled for elective cardiac surgery with cardiopulmonary bypass were screened over a three-month period. A total of twenty-six patients were included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion Criteria:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eAge \u0026ge;20 years\u003c/li\u003e\n \u003cli\u003eElective coronary artery bypass grafting (CABG), valve surgery, or combined procedures\u003c/li\u003e\n \u003cli\u003eRequirement for CPB\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion Criteria:\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003eEmergency surgery\u003c/li\u003e\n \u003cli\u003ePreoperative lactate \u0026gt;2 mmol/L\u003c/li\u003e\n \u003cli\u003eHemoglobin \u0026lt;8 g/dL\u003c/li\u003e\n \u003cli\u003eKnown renal or hepatic dysfunction\u003c/li\u003e\n \u003cli\u003ePre-existing metabolic disorders affecting lactate metabolism\u003c/li\u003e\n \u003cli\u003ePreoperative mechanical circulatory support\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThese criteria were used to reduce confounding factors that might affect oxygen transport or lactate kinetics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnaesthetic management:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe administration of general anesthesia was conducted in accordance with institutional protocols. Following induction and tracheal intubation via laryngoscopy, patients were mechanically ventilated using volume-controlled ventilation to sustain normocapnia. Standard monitoring comprised electrocardiography, invasive arterial pressure measurement, pulse oximetry, nasopharyngeal temperature assessment, and urine output monitoring. Systemic anticoagulation was accomplished through the administration of intravenous heparin at a dose of 400 IU/kg to maintain an activated clotting time exceeding 480 seconds prior to the initiation of cardiopulmonary bypass.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCPB management:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCPB was established using:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eNon-pulsatile roller pump\u003c/li\u003e\n \u003cli\u003eHollow-fibre membrane oxygenator\u003c/li\u003e\n \u003cli\u003eCrystalloid-primed circuit\u003c/li\u003e\n \u003cli\u003eStandard arterial line filter\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eArterial cannulation was performed in the ascending aorta. Venous drainage was achieved via right atrial or bicaval cannulation, depending on the procedure\u003c/p\u003e\n\u003cp\u003ePerfusion targets\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eIndexed pump flow: 2.4 L/min/m\u0026sup2;\u003c/li\u003e\n \u003cli\u003eMean arterial pressure: 60\u0026ndash;80 mmHg\u003c/li\u003e\n \u003cli\u003eHematocrit during CPB: 22\u0026ndash;25%\u003c/li\u003e\n \u003cli\u003eSystemic temperature: 28\u0026ndash;32\u0026deg;C (moderate hypothermia)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003ePacked red blood cells were administered as required to maintain oxygen-carrying capacity. Hemofiltration was used at the perfusionist\u0026apos;s discretion for volume management.\u003c/p\u003e\n\u003cp\u003eMyocardial protection was achieved with intermittent cold-blood cardioplegia. Rewarming was performed gradually to normothermia prior to separation from CPB.\u003c/p\u003e\n\u003cp\u003eProtamine sulfate (1\u0026ndash;1.3 mg per 100 IU heparin) was administered following CPB discontinuation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and sampling protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eArterial and central venous blood samples were obtained at four predefined time points:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003e10 minutes after administration of cardioplegia\u003c/li\u003e\n \u003cli\u003eDuring rewarming at core temperature 32\u0026deg;C\u003c/li\u003e\n \u003cli\u003e30 minutes after protamine administration\u003c/li\u003e\n \u003cli\u003e24 hours postoperatively\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eArterial blood samples were obtained from the indwelling arterial catheter, and venous samples were obtained from the central venous line. Blood gas analysis was performed using a calibrated blood gas analyzer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCalculation of metabolic variables\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eArterial and venous oxygen contents were calculated using standard equations:\u003c/p\u003e\n\u003cp\u003eCaO₂ = (Hb \u0026times; 1.36 \u0026times; SaO₂) + (0.0031 \u0026times; PaO₂)\u003cbr\u003e\u0026nbsp;CvO₂ = (Hb \u0026times; 1.36 \u0026times; SvO₂) + (0.0031 \u0026times; PvO₂)\u003c/p\u003e\n\u003cp\u003eDO₂ = Pump flow \u0026times; CaO₂ \u0026times; 10 / Body surface area\u003c/p\u003e\n\u003cp\u003eVO₂ = Pump flow \u0026times; (CaO₂ \u0026minus; CvO₂) \u0026times; 10 / Body surface area\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCarbon dioxide production (VCO₂) was estimated using the veno-arterial pCO₂ gradient:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVCO₂ = Pump flow \u0026times; (PvCO₂ \u0026minus; PaCO₂)\u003c/p\u003e\n\u003cp\u003eGiven the near-linear relationship between CO₂ partial pressure and content within physiological ranges, this method was used as a surrogate for CO₂ production during CPB. VCO₂ was estimated indirectly and does not represent direct volumetric carbon dioxide elimination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRespiratory Quotient (RQ):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRQ was calculated as VCO₂/VO₂. The DO₂/VCO₂ ratio was calculated as an index of oxygen supply relative to metabolic CO₂ generation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary outcome:\u003c/p\u003e\n\u003cp\u003ePostoperative hyperlactatemia is defined as a blood lactate concentration \u0026gt; 2 mmol/L.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecondary outcomes\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eIntraoperative changes in DO₂, VO₂, VCO₂\u003c/li\u003e\n \u003cli\u003eRespiratory quotient\u003c/li\u003e\n \u003cli\u003eDO₂/VCO₂ ratio\u003c/li\u003e\n \u003cli\u003eSerial lactate kinetics\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using SPSS software (27.0).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eContinuous variables are presented as mean \u0026plusmn; standard deviation. Normality was assessed using the Shapiro\u0026ndash;Wilk test.\u003c/p\u003e\n\u003cul class=\"decimal_type\"\u003e\n \u003cli\u003ePaired t-tests were used to compare intraoperative variables between cardioplegia and rewarming phases.\u003c/li\u003e\n \u003cli\u003eRepeated-measures analysis of variance (ANOVA) assessed temporal trends in lactate and hemoglobin.\u003c/li\u003e\n \u003cli\u003eBonferroni correction was applied for post hoc comparisons when appropriate.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;A p-value \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethodological rigor\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eTo minimize variability between patients and procedures, anesthesia, surgical procedures, and cardiopulmonary bypass (CPB) management were standardized based on institutional protocols. The anesthesia approach\u0026mdash;covering induction agents, maintenance, and vasoactive drugs\u0026mdash;temperature management, transfusion limits, pump flow rates, and mean arterial pressure targets were predetermined and uniformly implemented.\u003c/p\u003e\n\u003cp\u003eCPB employed a consistent circuit setup and oxygenator system, with pump flows adjusted for body surface area. Hematocrit levels were kept within a predefined range during bypass. Acid\u0026ndash;base regulation followed a consistent method (\u0026alpha;-stat/pH-stat, as outlined in the full methods).\u003c/p\u003e\n\u003cp\u003eBlood gas samples from arterial and venous blood were collected at specific CPB stages (initiation, cooling, stable hypothermia, rewarming, and pre-weaning) to ensure consistent timing. All samples were analyzed with the same calibrated blood gas analyzer. Key parameters, including oxygen delivery (DO₂), carbon dioxide production (VCO₂), respiratory quotient (RQ), and the DO₂/VCO₂ ratio, were calculated using standardized equations and adjusted for body surface area when needed. By combining directly measured gas exchange data with calculated metabolic indices, this study aimed to comprehensively evaluate oxygen transport and carbon dioxide removal during CPB.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eTwenty-six adult patients scheduled for elective cardiac surgery with cardiopulmonary bypass were analyzed. The average age was 52\u0026thinsp;\u0026plusmn;\u0026thinsp;15 years, with 54% being male. The mean duration of CPB was 92\u0026thinsp;\u0026plusmn;\u0026thinsp;24 minutes. Hematocrit levels during CPB were kept at 23.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4%. Baseline demographic and operative details are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eBaseline Demographic and Operative Characteristics (n\u0026thinsp;=\u0026thinsp;26)\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (Male/Female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 / 12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody Mass Index (kg/m\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (27%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (42%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative hemoglobin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative LVEF (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCABG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (38%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValve surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (35%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombined procedures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(27%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiopulmonary bypass time (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92\u0026thinsp;\u0026plusmn;\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAortic cross-clamp time (min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLowest temperature on CPB (\u0026deg;C)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematocrit during CPB (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eIntraoperative Oxygen Transport and Metabolic Variables\u003c/h2\u003e \u003cp\u003eIndexed oxygen delivery (DO₂) stayed above standard critical levels throughout CPB. No notable difference in DO₂ was observed between the cardioplegia and rewarming phases (p\u0026thinsp;=\u0026thinsp;0.48).\u003c/p\u003e \u003cp\u003eDuring rewarming, oxygen consumption (VO₂) rose markedly (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating metabolic reactivation. In contrast, carbon dioxide production (VCO₂) remained largely unchanged (p\u0026thinsp;=\u0026thinsp;0.62). The respiratory quotient (RQ) declined significantly (p\u0026thinsp;=\u0026thinsp;0.012). The DO₂/VCO₂ ratio showed a downward trend but was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.18).\u003c/p\u003e \u003cp\u003eNotably, the rise in VO₂ during rewarming showed a substantial effect size (Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.83), reflecting a significant metabolic shift. \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e The elevated calculated RQ values likely reflect limitations of surrogate VCO₂ estimation during CPB rather than true physiological respiratory quotient values.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOxygen Transport and CO₂-Derived Variables During CPB (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 min after Cardioplegia\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRewarming (32\u0026deg;C)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDO₂ (mL/min/m\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e265\u0026thinsp;\u0026plusmn;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e272\u0026thinsp;\u0026plusmn;\u0026thinsp;52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVO₂ (mL/min/m\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e36\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e52\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVCO₂ (mL/min/m\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e72\u0026thinsp;\u0026plusmn;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e75\u0026thinsp;\u0026plusmn;\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory Quotient (RQ)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e1.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.012*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDO₂ / VCO₂ ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e3.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*Statistically significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eLactate Kinetics\u003c/h2\u003e \u003cp\u003eLactate levels increased progressively during CPB and peaked 30 minutes after protamine administration. Repeated-measures ANOVA showed a significant time effect (F\u0026thinsp;=\u0026thinsp;18.6, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerial lactate levels\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime Point\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLactate (mmol/L), Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10 min post-Cardioplegia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e1.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRewarming (32\u0026deg;C)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30 min Post-Protamine (Peak)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.78\u0026thinsp;\u0026plusmn;\u0026thinsp;3.43\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24 Hours Postoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eLactate peaked after separation from CPB and partially normalized by 24 hours.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation Between Metabolic Reactivation and Hyperlactatemia\u003c/h2\u003e \u003cp\u003eNo significant correlation was found between the rise in oxygen consumption during rewarming (ΔVO₂) and peak postoperative lactate levels (r\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.002, p\u0026thinsp;=\u0026thinsp;0.993). Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelation Analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable Pair\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePearson r\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔVO₂ vs Peak Lactate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026minus;0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThis indicates that the level of metabolic reactivation was not a direct factor in the rise of postoperative lactate levels.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003ePredictive Performance of DO₂/VCO₂ Ratio\u003c/h2\u003e \u003cp\u003eReceiver operating characteristic (ROC) analysis was conducted to evaluate the capacity of the DO₂/VCO₂ ratio at the time of rewarming in predicting clinically significant hyperlactatemia (lactate\u0026thinsp;\u0026gt;\u0026thinsp;3 mmol/L). Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eROC Analysis for Lactate\u0026thinsp;\u0026gt;\u0026thinsp;3 mmol/L\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePredictor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAUC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDO₂/VCO₂ (Rewarming)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.568\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePoor discrimination\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe AUC was 0.568, which suggests limited ability to distinguish between groups performance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eHemoglobin Trends\u003c/h2\u003e \u003cp\u003eHemoglobin levels showed significant variation over time (F\u0026thinsp;=\u0026thinsp;4.92, p\u0026thinsp;=\u0026thinsp;0.006), indicating effects of hemodilution and postoperative recovery. (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHemoglobin Levels at Different Study Intervals\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime Point\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHemoglobin (g/dL), Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10 min Post-Cardioplegia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRewarming\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e8.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30 min Post-Protamine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24 Hours Postoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis prospective physiological study of adult patients undergoing cardiopulmonary bypass (CPB) found that indexed oxygen delivery (DO₂) consistently remained above critical thresholds throughout the procedure. Rewarming was associated with a notable, clinically meaningful increase in oxygen consumption (VO₂), yet postoperative lactate levels also increased. Importantly, neither VO₂ nor the DO₂/VCO₂ ratio predicted significant hyperlactatemia. These results suggest that the rise in lactate after modern CPB is more likely due to complex metabolic and inflammatory responses rather than an inadequate global oxygen supply.\u003c/p\u003e \u003cp\u003eInadequate oxygen delivery during CPB has been associated with organ dysfunction and hyperlactatemia. Ranucci et al. showed that lower DO₂ levels during bypass are linked to acute renal failure and worse outcomes. More recent research indicates that goal-directed perfusion strategies aiming for higher DO₂ levels can help reduce postoperative kidney injury.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e A recent systematic review by Dias et al. also emphasizes the importance of ensuring sufficient oxygen delivery during CPB.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn our cohort, DO₂ remained within or above levels generally considered safe. Despite this, lactate levels rose after surgery. This disconnect suggests that mechanisms beyond traditional oxygen debt may be at work.\u003c/p\u003e \u003cp\u003eCPB induces a systemic inflammatory response marked by cytokine activation, endothelial dysfunction, and metabolic changes.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e These responses might lead to altered substrate use and heightened glycolytic activity, occurring independently of overall oxygen delivery.\u003c/p\u003e \u003cp\u003eHyperlactatemia after cardiac surgery is common and associated with adverse outcomes.\u003csup\u003e\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e However, elevated lactate levels do not necessarily imply tissue hypoxia. Garcia-Alvarez et al. demonstrated that hyperlactatemia may occur despite adequate oxygen delivery due to metabolic and mitochondrial factors.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur findings are consistent with this paradigm. The absence of correlation between the increases in VO₂ associated with rewarming and peak lactate suggests that lactate elevation may reflect metabolic activation rather than oxygen supply failure.\u003c/p\u003e \u003cp\u003eHypothermia during CPB reduces metabolic rate and oxygen consumption. As temperature normalizes, VO₂ increases accordingly. Leone et al. demonstrated that temperature modulation influences oxygen delivery dynamics during CPB.\u003c/p\u003e \u003cp\u003eIn the present study, VO₂ increased significantly during rewarming, with a large effect size (Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.83), confirming substantial metabolic reactivation. However, this physiologic transition did not translate into proportional changes in lactate kinetics, suggesting that lactate elevation is not simply a consequence of oxygen demand during rewarming.\u003c/p\u003e \u003cp\u003eCO₂-derived parameters have been proposed as surrogates of microcirculatory dysfunction and anaerobic metabolism.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Recent cardiac surgery studies have explored their predictive utility during CPB.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn our cohort, ROC analysis demonstrated limited discriminatory performance of DO₂/VCO₂ for predicting lactate\u0026thinsp;\u0026gt;\u0026thinsp;3 mmol/L (AUC 0.568). This finding aligns with recent data suggesting that CO₂-derived indices may not reliably predict major postoperative complications in cardiac surgery populations.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTherefore, although physiologically appealing, CO₂-derived metrics may provide limited standalone utility during elective cardiopulmonary bypass procedures where overall perfusion is sustained.\u003c/p\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eClinical Implications\u003c/h2\u003e \u003cp\u003eOur data suggest a nuanced view of lactate during CPB. When DO₂ stays within accepted thresholds, moderate postoperative lactate rises may not always signal insufficient oxygen delivery. These results highlight the need for interpreting lactate levels in context, rather than automatically increasing pump flow or transfusing based solely on lactate values.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis was a single-center observational study with a small sample size. Measurements of microcirculatory and mitochondrial functions were not conducted. Inflammatory mediators and catecholamine levels were also not quantified, so mechanistic explanations are only speculative.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eDuring modern CPB with maintained oxygen delivery, rewarming triggers notable metabolic activation. Elevated lactate levels after surgery happen regardless of whether global oxygen delivery (DO₂) is adequate or if VO₂ increases during rewarming. CO₂-based indices are of limited use in predicting these changes. These results indicate that hyperlactatemia during CPB results from complex metabolic and inflammatory processes rather than just insufficient oxygen supply.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat This Study Adds\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study offers three key insights:\u003c/p\u003e\n\u003cp\u003e1. Keeping DO₂ above established thresholds does not prevent postoperative lactate levels from rising.\u003c/p\u003e\n\u003cp\u003e2. Rewarming is a metabolically active and potentially fragile phase of CPB.\u003c/p\u003e\n\u003cp\u003e3. CO₂-based indices capture physiological changes but may not solely predict lactate kinetics during controlled perfusion.\u003c/p\u003e\n\u003cp\u003eFocusing on intraoperative metabolic dynamics rather than just static thresholds emphasizes the need to consider phase-specific physiology in CPB management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and the ethical guidelines of the Indian Council of Medical Research (ICMR). Ethical approval was obtained from the Institutional Human Ethics Committee (Approval No.; CSP-Ⅲ/24/APR/04/153). Written informed consent was obtained from all participants prior to enrolment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets collected during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received no funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDJ, JAJ and SS conceived the study. \u0026nbsp;ST \u0026amp; RE contributed to data acquisition. \u0026nbsp;DJ supervised. \u0026nbsp;AJ, JAJ \u0026amp; DJ performed statistical analysis. AJ, SS \u0026amp; RE drafted the manuscript. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the study participants and the cardiology department at Sri Ramachandra Institute of Higher Education and Research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSarkar, M. \u0026amp; Prabhu, V. Basics of cardiopulmonary bypass. \u003cem\u003eIndian J Anaesth\u003c/em\u003e \u003cstrong\u003e61\u003c/strong\u003e, 760\u0026ndash;767 (2017).\u003c/li\u003e\n\u003cli\u003eLaffey, J. G., Boylan, J. F. \u0026amp; Cheng, D. C. H. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. \u003cem\u003eAnesthesiology\u003c/em\u003e \u003cstrong\u003e97\u003c/strong\u003e, 215\u0026ndash;252 (2002).\u003c/li\u003e\n\u003cli\u003eWarren, O. J. \u003cem\u003eet al.\u003c/em\u003e The inflammatory response to cardiopulmonary bypass: part 1--mechanisms of pathogenesis. \u003cem\u003eJ Cardiothorac Vasc Anesth\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 223\u0026ndash;231 (2009).\u003c/li\u003e\n\u003cli\u003eHajjar, L. A. \u003cem\u003eet al.\u003c/em\u003e High lactate levels are predictors of major complications after cardiac surgery. \u003cem\u003eJ Thorac Cardiovasc Surg\u003c/em\u003e \u003cstrong\u003e146\u003c/strong\u003e, 455\u0026ndash;460 (2013).\u003c/li\u003e\n\u003cli\u003eNaik, R., George, G., Karuppiah, S. \u0026amp; Philip, M. A. Hyperlactatemia in patients undergoing adult cardiac surgery under cardiopulmonary bypass: Causative factors and its effect on surgical outcome. \u003cem\u003eAnn Card Anaesth\u003c/em\u003e \u003cstrong\u003e19\u003c/strong\u003e, 668\u0026ndash;675 (2016).\u003c/li\u003e\n\u003cli\u003eMaillet, J.-M. \u003cem\u003eet al.\u003c/em\u003e Frequency, risk factors, and outcome of hyperlactatemia after cardiac surgery. \u003cem\u003eChest\u003c/em\u003e \u003cstrong\u003e123\u003c/strong\u003e, 1361\u0026ndash;1366 (2003).\u003c/li\u003e\n\u003cli\u003eRanucci, M. \u003cem\u003eet al.\u003c/em\u003e Oxygen delivery during cardiopulmonary bypass and acute renal failure after coronary operations. \u003cem\u003eAnn Thorac Surg\u003c/em\u003e \u003cstrong\u003e80\u003c/strong\u003e, 2213\u0026ndash;2220 (2005).\u003c/li\u003e\n\u003cli\u003eRanucci, M. \u003cem\u003eet al.\u003c/em\u003e Goal-directed perfusion to reduce acute kidney injury: A randomized trial. \u003cem\u003eJ Thorac Cardiovasc Surg\u003c/em\u003e \u003cstrong\u003e156\u003c/strong\u003e, 1918-1927.e2 (2018).\u003c/li\u003e\n\u003cli\u003eDias, R. D. \u003cem\u003eet al.\u003c/em\u003e Delivery of oxygen during cardiopulmonary bypass and associated clinical outcomes among adult cardiac surgery patients: A systematic review. \u003cem\u003ePerfusion\u003c/em\u003e 2676591251380659 (2025) doi:10.1177/02676591251380659.\u003c/li\u003e\n\u003cli\u003eGarcia-Alvarez, M., Marik, P. \u0026amp; Bellomo, R. Sepsis-associated hyperlactatemia. \u003cem\u003eCrit Care\u003c/em\u003e \u003cstrong\u003e18\u003c/strong\u003e, 503 (2014).\u003c/li\u003e\n\u003cli\u003eFranchi, F. \u003cem\u003eet al.\u003c/em\u003e Oxygen delivery to carbon dioxide production ratio for continuously detecting anaerobic metabolism in trauma patients. \u003cem\u003eCrit Care\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, P306 (2007).\u003c/li\u003e\n\u003cli\u003eOspina-Tasc\u0026oacute;n, G. A. \u003cem\u003eet al.\u003c/em\u003e Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? \u003cem\u003eIntensive Care Med\u003c/em\u003e \u003cstrong\u003e42\u003c/strong\u003e, 211\u0026ndash;221 (2016).\u003c/li\u003e\n\u003cli\u003eMallat, J. \u003cem\u003eet al.\u003c/em\u003e Use of CO2-derived variables in critically ill patients. \u003cem\u003eAnn. Intensive Care\u003c/em\u003e \u003cstrong\u003e15\u003c/strong\u003e, 142 (2025).\u003c/li\u003e\n\u003cli\u003eKowara, Y. \u003cem\u003eet al.\u003c/em\u003e Relation Between Multiplication of Venous Carbon Dioxide Partial Pressure (PvCO2) and the Ratio of Gas Flow to Pump Flow (Ve/Q) with Hyperlactatemia During Cardiopulmonary Bypass. \u003cem\u003eAnn Card Anaesth\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 337\u0026ndash;343 (2024).\u003c/li\u003e\n\u003cli\u003eZhou, X.-F. \u003cem\u003eet al.\u003c/em\u003e Lactate and CO2-derived parameters are not predictive factors of major postoperative complications after cardiac surgery with cardiopulmonary bypass: a diagnostic accuracy study. \u003cem\u003eFront Cardiovasc Med\u003c/em\u003e\u003cstrong\u003e12\u003c/strong\u003e, 1504431 (2025).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cardiopulmonary bypass, Oxygen delivery, Carbon dioxide production, Respiratory quotient, Hyperlactatemia, Goal-directed perfusion","lastPublishedDoi":"10.21203/rs.3.rs-9702308/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9702308/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo analyze intraoperative metabolic parameters from carbon dioxide during cardiopulmonary bypass (CPB) and their association with postoperative hyperlactatemia in elective cardiac surgery.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study observed 26 adult patients undergoing cardiac surgery with CPB. Blood gases were collected at specific times: after cardioplegia and during rewarming at 32\u0026deg;C. It calculated oxygen delivery (DO₂), consumption (VO₂), carbon dioxide production (VCO₂), respiratory quotient (RQ), and the DO₂/VCO₂ ratio. Lactate levels were measured during and up to 24 hours post-surgery. Paired t-tests compared intraoperative data, and repeated-measures ANOVA analyzed lactate and hemoglobin over time.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIndexed DO₂ stayed above critical thresholds during CPB (265\u0026thinsp;\u0026plusmn;\u0026thinsp;60 vs. 272\u0026thinsp;\u0026plusmn;\u0026thinsp;52 mL/min/m\u0026sup2;, p\u0026thinsp;=\u0026thinsp;0.48). VO₂ increased during rewarming (36\u0026thinsp;\u0026plusmn;\u0026thinsp;14 to 52\u0026thinsp;\u0026plusmn;\u0026thinsp;16 mL/min/m\u0026sup2;, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while VCO₂ did not change significantly (p\u0026thinsp;=\u0026thinsp;0.62). RQ decreased from 2.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.80 to 1.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50 (p\u0026thinsp;=\u0026thinsp;0.012). The DO₂/VCO₂ ratio showed a non-significant downward trend (p\u0026thinsp;=\u0026thinsp;0.18). Lactate levels rose over time, peaking 30 minutes after protamine at 3.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 mmol/L and remained high at 24 hours.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eHyperlactatemia occurred despite maintained oxygen delivery during CPB. During rewarming, oxygen consumption rose, and metabolic reactivation was indicated by changes in RQ. While CO₂ variables reflected these changes, they couldn't reliably predict increases in lactate. A multimodal monitoring approach combining oxygen transport and metabolic markers is needed, rather than relying on a single perfusion threshold.\u003c/p\u003e","manuscriptTitle":"Metabolic Dynamics During Cardiopulmonary Bypass: Oxygen Delivery, Carbon Dioxide Production, and Lactate Response Despite Preserved Global Perfusion","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-18 06:35:50","doi":"10.21203/rs.3.rs-9702308/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-05-21T13:48:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-21T08:52:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-21T06:43:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"SN Comprehensive Clinical Medicine","date":"2026-05-13T10:10:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"c9851785-4653-4179-907e-d14d3e98cdea","owner":[],"postedDate":"May 18th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewersInvited","content":"19","date":"2026-05-21T13:48:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-21T08:52:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-21T06:43:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"SN Comprehensive Clinical Medicine","date":"2026-05-13T10:10:19+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-21T13:55:21+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-18 06:35:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9702308","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9702308","identity":"rs-9702308","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}