Expert consensus on perioperative inflammation management in cardiac surgery involving cardiopulmonary bypass

Introduction

Cardiopulmonary bypass (CPB) is a medical technique used during certain types of heart surgery, where the patient’s heart and lungs are temporarily bypassed by a machine. This machine takes over the role of pumping blood and oxygen throughout the body while the heart is being operated on. CPB allows surgeons to perform complex cardiac procedures while keeping the body’s circulation stable. Cardiac and vascular surgeries, particularly those involving CPB, are frequently accompanied by a perioperative inflammatory response. This complex pathophysiological phenomenon, characterized by systemic activation of inflammatory pathways, poses significant challenges to perioperative management (1,2). Systemic inflammatory response syndrome (SIRS) is a prevalent complication following CPB, with reported incidence rates ranging from 20% to 58.7% (3). Left unmanaged, SIRS can progress to multi-organ dysfunction syndrome (MODS), a critical condition that significantly impacts patient outcomes and contributes to increased morbidity and mortality.

Despite advancements in surgical and perioperative care, the management of inflammation remains inconsistent, reflecting a lack of standardized diagnostic criteria and therapeutic strategies (4). Existing approaches vary widely across institutions, and there is limited consensus on the optimal methods to mitigate inflammatory complications associated with CPB. This variability underscores the urgent need for a unified framework to guide clinicians in diagnosing and managing perioperative inflammation effectively.

The variability in the management of inflammation post-CPB is further reflected in the existing guidelines from key professional organizations, such as the Society of Thoracic Surgeons (STS), the Society of Cardiovascular Anesthesiologists (SCA), and the American Society of Extra-Corporeal Technology (AmSECT). While these guidelines provide important general recommendations on reducing perioperative complications, they do not offer standardized approaches for managing the inflammatory response that often follows CPB. This lack of consensus is evident in clinical practice, where institutions adopt varying protocols, ranging from the use of anti-inflammatory medications like corticosteroids to more conservative approaches that avoid pharmacological interventions altogether. Recent studies highlight this gap by illustrating the inconsistent use of therapies to mitigate SIRS, with no single treatment proving universally effective (5,6). This variability further underscores the need for a cohesive, evidence-based consensus to guide clinicians in managing perioperative inflammation more effectively and improve patient outcomes. Therefore, this consensus aimed to establish standardized, evidence-based recommendations for managing perioperative inflammation in cardiac surgeries involving CPB to improve patient outcomes and reduce mortality. By synthesizing current literature and leveraging multidisciplinary expertise, the consensus aims to establish a practical and standardized approach that enhances patient care and outcomes.

Methods

Literature search and selection

A systematic review of the literature was conducted to establish the foundation for this expert consensus. Four major databases—PubMed, Embase, CNKI, and Wanfang—were comprehensively searched for relevant studies. The search strategy incorporated a combination of keywords and Medical Subject Headings (MeSH) terms, including “Cardiac Surgery”, “Inflammation”, “Cardiopulmonary Bypass”, and related concepts. Boolean operators were employed to optimize search specificity and sensitivity [supplementary file (Appendix 1)]. Searching was performed in July 2023. To ensure a comprehensive literature search, we included gray literature by searching OpenGrey, ProQuest Dissertations, and clinical trial registries (ClinicalTrials.gov, WHO ICTRP), as well as conference abstracts from major cardiology meetings. For non-English/Chinese studies, we considered publications with English abstracts and used translation tools when necessary. Database searches were expanded with terms like “unpublished data” and “conference abstract”, and we consulted experts to identify additional relevant studies. Two independent evaluators performed literature reviews in accordance with a predefined search strategy. The initial review of the identified publications was carried out independently by both evaluators. In instances of disagreement, a third expert was consulted. The articles selected through the literature search were subsequently analyzed and synthesized to extract relevant evidence, which underpinned the formulation of consensus statements, accompanied by a comprehensive narrative synthesis of the available data.

Inclusion and exclusion criteria

Articles were selected based on their relevance to the intersection of cardiac surgery, inflammation, and CPB. Eligible studies included original research, meta-analyses, systematic reviews, and clinical guidelines published in English or Chinese. Studies were excluded if they lacked direct relevance to the research question, contained incomplete data, or failed to meet predefined methodological quality criteria. Evidence searches were conducted with a focus on retrieving the highest-quality evidence available for each outcome and research question, in alignment with GRADE guidelines. Case series were excluded, unless they represented the only available source of evidence for a specific question or outcome, or were considered a valid form of evidence for particular outcomes (e.g., safety). Additionally, studies with a sample size of ≤10 were excluded.

Data extraction and analysis

The literature screening process followed a structured, multi-phase approach. First, duplicate records were removed using automated deduplication in EndNote X20 followed by manual verification. The remaining studies underwent sequential screening: (I) title/abstract review applying predefined exclusion criteria (incomplete data, small sample size ≤10 patients), followed by (II) full-text assessment to exclude non-comparative designs and irrelevant outcomes. A total of 102 articles were deemed eligible after the initial screening process. Data relevant to clinical outcomes, inflammatory markers, and perioperative management in the context of cardiac surgery were extracted and synthesized. The extracted evidence served as the basis for the development of consensus recommendations. Data extraction was performed by two independent reviewers with expertise in the field. Both reviewers followed a standardized protocol to ensure consistency and accuracy in the data collection process. Once the evidence addressing a specific question was finalized, a single reviewer extracted all relevant data and recorded it in a pre-formatted data abstraction form. Team leaders, section members, and methodologists then participated in discussions to interpret specific data extraction issues. The secondary reviewer for the question subsequently reviewed the database containing the data extracted by the primary reviewer to ensure accuracy and completeness. Any discrepancies between the reviewers were resolved through discussion, and, when necessary, a third reviewer was consulted to reach a final consensus (Figure 1).

Figure 1 Flowchart of literature screening.

Consensus development process

A group of 23 experts, representing multiple specialties involved in the treatment of (5 from Anesthesiology, 11 from Cardiothoracic Surgery, 2 from Intensive Care Medicine, and 5 from Extracorporeal Circulation). The panelists disclosed potential conflicts of interest and did not receive financial compensation for their participation. The expert panel, comprising specialists in cardiac surgery, perioperative care, and inflammation research, reviewed the synthesized evidence during structured discussions. A Delphi method was employed to achieve consensus, involving multiple rounds of anonymous voting to refine and finalize the recommendations. For the few items without consensus after two rounds, an independent arbitrator made evidence-based decisions using predefined criteria. Two rounds of consensus seminars were held in Shanghai. At least 70% of panelists had to vote in order for a decision on the recommendation to be made. Panelists were asked to vote to rate their agreement with the statements based on the evidence available, on a scale of A to E, where A = accept completely, B = accept with some reservation, C = accept with major reservation, D = reject with some reservation, E = reject completely. Consensus for each statement was defined as having agreement (A + B) from at least 80% of panelists.

Following discussion and voting, evidence supporting the statements that achieved 80% agreement or higher was categorized according to the GRADE system for grading quality of evidence. The quality of evidence scale ranged from ‘high’ (high confidence in the correlation between true and estimated effect), ‘moderate’ (moderate confidence in the estimated effect. It is possible that the true effect is very different from the estimated effect), ‘low’ (limited confidence in the estimated effect. The true effect may be very different from the estimated effect) and ‘very low’ (very little confidence in the estimated effect. The true effect is very probably different from the estimated effect). The strength of each recommendation was then recorded as ’strong’ or ‘conditional’. Panelists assigned proposed recommendation strengths to each consensus statement according to the GRADE grid.

Results

Factors contributing to excessive inflammatory response

Preoperative factors

Body mass index (BMI)

BMI is an internationally recognized objective indicator used to assess body fat. The standard BMI range in China is 18.5–23.9 kg/m², with BMI <18.5 kg/m² indicating underweight and BMI ≥24 kg/m² indicating overweight. Studies have shown that overweight and obese patients have a higher risk of postoperative infection compared to those with a normal BMI (22.22% vs. 17.42%, P<0.001) (7,8). However, the generalizability of these thresholds to non-Asian populations may be limited, as they do not account for the differences in body composition and associated health risks in individuals from other ethnic groups. Therefore, caution should be taken when applying these thresholds to populations outside of China or other Asian countries.

Blood glucose

Hyperglycemia is a triggering factor that exacerbates the perioperative inflammatory response in CPB cardiac surgery (9). Research has demonstrated that higher fasting blood glucose levels [odds ratio (OR) =1.32, P=0.02] are an independent predictor of elevated systemic immune inflammation index in patients (10).

Fibrinogen-to-albumin ratio (FAR)

FAR is an important marker reflecting inflammation. Research findings indicate a positive correlation between FAR and inflammatory indicators such as the systemic immune inflammation index and platelet-to-lymphocyte ratio (PLR) (P<0.05). This suggests that a high FAR level may lead to an intensified systemic inflammatory response. FAR serves as an independent risk factor for all-cause mortality following off-pump coronary artery bypass grafting, exhibiting a positive correlation with a median value 8.9 (interquartile range, 7.3–11.0) (11,12).

Neutrophil-to-lymphocyte count ratio (NLR)

NLR is a sensitive indicator for assessing infection and inflammation (13). In cardiac surgery, NLR is closely associated with the systemic inflammation induced by CPB and can serve as a postoperative marker (14).

PLR

PLR is an important inflammatory marker and a predictive factor for postoperative SIRS and sepsis (15). It is reported that PLR is an independent risk factor for predicting postoperative SIRS (16). In this study, the critical value for PLR predicting SIRS was 114.1. Patients with PLR >114.1 had a higher risk of developing SIRS (P=0.02), with a sensitivity of 80.4%, specificity of 60.2%, positive predictive value of 35.4%, and negative predictive value of 91.9%.

Intraoperative factors

Surgical factors

Non-specific adaptive responses caused by surgical trauma may lead to SIRS characterized by hypermetabolism and hyper catabolism (17). The inflammatory state further induces vascular endothelial injury, and the endothelial glycocalyx can be rapidly degraded by endogenous enzymes (e.g., heparanase, hyaluronidase), resulting in impaired vascular endothelial integrity and increased vascular permeability, thereby inducing or exacerbating organ dysfunction (18). Prondzinsky et al. (19) found that both surgical trauma and CPB can lead to cytokine release in cardiac surgery patients postoperatively, with surgical trauma having a more significant impact on the expression of inflammatory factors.

Autologous/allogeneic blood product transfusion

Blood transfusion can rapidly alter the proportions of various cells in the circulatory system, and the presence of exogenous blood cells poses a risk of stimulating the recipient’s immune system, potentially causing a systemic inflammatory response. A higher volume of perioperative blood transfusion is a risk factor for postoperative SIRS (OR =2.2, P<0.001) (20). The method of blood transfusion also significantly impacts the patient’s inflammatory response. Studies have shown that, compared to allogeneic transfusion, intraoperative autologous blood transfusion can avoid immune system stimulation and suppress the inflammatory response (21). Therefore, the transfusion of autologous/allogeneic blood products during surgery is a risk factor for postoperative SIRS.

Temperature management

During CPB, body temperature is lowered to reduce oxygen demand in vital organs such as the heart and brain, thereby preventing hypoxia and organ dysfunction. Hypothermia can also reduce the patient’s inflammatory response. Mild hypothermia ranges between 32–35 ℃, moderate hypothermia between 28–32 ℃, and deep hypothermia is defined as temperatures below 28 ℃. The ideal cooling and rewarming rate is 0.5 ℃ per minute, When the body temperature exceeds 30°C, the temperature gradient between arterial outflow and venous inflow should not exceed 4 ℃ (22). Rewarming rates ≤0.5 ℃/min during CPB are essential for minimizing neurovascular and coagulopathy risks while protecting organ function. Gradual rewarming helps prevent cerebral hyperperfusion, which can lead to reperfusion injury and neurological damage, ensuring neuroprotection. Rapid rewarming can also destabilize coagulation, increasing the risk of bleeding or thrombosis. A slower rewarming process promotes more stable blood flow, reducing the chances of disseminated intravascular coagulation (DIC). Moreover, controlled rewarming ensures a safer transition from hypothermic conditions to normothermia, minimizing ischemia-reperfusion injuries in vital organs like the heart and kidneys.

CPB

CPB creates a non-physiological blood circulation state where blood comes into contact with air, tubing, and artificial lungs, which are non-physiological materials. This contact activates Factor XII, initiating the intrinsic coagulation pathway and accelerating the activation of plasma kallikrein, thereby activating the fibrinolytic system and causing the degradation of Factor XII, which activates the complement system. The primary pathway for complement activation during CPB is the alternative pathway, resulting in the formation of the membrane attack complex that damages endothelial cells and myocardial cells, exacerbating the inflammatory response. Activation of the fibrinolytic system leads to plasmin formation, which cleaves fibrin chains, causing thrombolysis. The continuous generation of degradation products reduces platelet adhesion and aggregation capabilities, becoming a significant cause of postoperative bleeding.

As plasma proteins cover non-endothelial surfaces, the blood contact with non-physiological materials decreases, and the later stages of CPB-associated inflammation are mainly related to ischemia-reperfusion injury (IRI) and endotoxemia. Ischemia and hypoxia induce the upregulation of adhesion molecules and pro-inflammatory factors through mechanisms involving hypoxia-inducible factor and nuclear factor kappa-B (NF-κB). Reperfusion generates high concentrations of reactive oxygen species (ROS), damaging endothelial cells and surrounding tissue structures, or entering the circulation to further stimulate the inflammatory response, leading to its exacerbation. Additionally, endotoxins act as potent activators of the inflammatory cascade during the later stages of CPB, stimulating the release of pro-inflammatory cytokines [such as tumor necrosis factor (TNF)-α] and nitric oxide (NO), enhancing neutrophil oxygen radical production. The concentration of endotoxins is positively correlated with CPB time and aortic cross-clamp time, with the production of peroxynitrite metabolites increasing vascular permeability and causing tissue damage. Inflammatory mediators in CPB-associated inflammation have diverse sources and targets, forming an inflammatory network that collectively exerts pro-inflammatory effects.

Postoperative factors

After CPB surgery, the patient’s systemic inflammatory response should be assessed. Through a series of optimized postoperative interventions, excessive inflammatory responses and their damage to the body can be mitigated, protecting the function of vital organs and improving patient outcomes. Postoperative interventions, such as mechanical ventilation, may aggravate the inflammatory response. However, most postoperative interventions could manage or prevent existing inflammatory responses.

Consensus on the management of perioperative inflammation

Preoperative management

Consensus 1: preoperative control of blood glucose, BMI, FAR, and NLR plays a significant role in modulating the perioperative inflammatory response. It is recommended that healthcare providers implement appropriate interventions aimed at optimizing these parameters based on the individual patient’s clinical profile. These interventions are crucial for minimizing perioperative inflammation and improving postoperative outcomes (recommendation level: I, evidence level: B).

Intraoperative management

Surgical trauma and stress response

Consensus 2: surgical trauma is a key risk factor for exacerbating the perioperative inflammatory response. Enhanced recovery after surgery (ERAS) strategies, which include modified routine treatment protocols, can help reduce intraoperative trauma and stress response, thereby decreasing the inflammatory response (recommendation level: I, evidence level: B).

Compared with traditional open surgery, minimally invasive procedures, such as laparoscopic surgery, significantly reduce the levels of inflammatory factors like interleukin-6 (IL-6) postoperatively (23). Minimizing surgical trauma can significantly lower the systemic inflammatory response, thus reducing the risk of SIRS. ERAS involves applying a series of evidence-based measures during the perioperative period to optimize recovery and potentially reduce stress and inflammatory responses. In a randomized controlled trial (RCT), patients in the ERAS group had significantly lower IL-6 and IL-10 levels on postoperative days 1, 3, and 5 compared to the non-ERAS group (P<0.05). CRP and WBC levels on days 3 and 5 were also lower in the ERAS group (P<0.05) (24). These findings suggest that ERAS strategies play a positive role in reducing intraoperative trauma and inflammation.

Anesthesia methods and anesthetics

Consensus 3: during the perioperative period, general anesthesia is recommended, with the consideration of risk-benefit analysis. Neural blockade can be used in conjunction to control the stress response (recommendation level: IIA, evidence level: B).

Neural blockade combined with general anesthesia can reduce the perioperative inflammatory response. Opioids remain the cornerstone of perioperative anesthesia management and stress response control in cardiac surgery. However, the role of neural blockade combined with general anesthesia in ERAS has become increasingly important. Thoracic epidural anesthesia combined with general anesthesia can reduce perioperative stress and inflammatory responses, thereby improving patient outcomes (25). However, when applied in CPB cardiac surgery, the risks and benefits need to be weighed. Paravertebral nerve blockade has a higher safety profile and provides analgesia comparable to epidural anesthesia, making it recommended for use in intraoperative or postoperative analgesia in CPB, especially in minimally invasive cardiac surgeries with lateral incisions (26,27).

Consensus 4: the release of mitochondrial metabolites into the cytoplasm or extracellular environment can induce an exacerbation of the inflammatory response. Alpha-2 adrenergic receptor agonists and opioid anesthetics can reduce this exacerbation by inhibiting mitochondrial metabolism and adaptive immunity, respectively (recommendation level: IIA, evidence level: C).

The release of mitochondrial metabolites into the cytoplasm or extracellular environment can induce an exacerbation of the inflammatory response (28). Alpha-2 adrenergic receptor agonists (e.g., dexmedetomidine) can inhibit mitochondrial metabolism, thereby reducing the release of metabolites and the subsequent increase in inflammation (29,30). Opioid drugs (e.g., morphine) have inhibitory effects on both the innate and adaptive immune systems, and can reduce the exacerbation of inflammation by suppressing adaptive immunity (31).

Volume management and autologous/allogeneic blood product transfusion

Consensus 5: the use of goal-directed perfusion principles is beneficial for reducing tissue reperfusion injury and lowering perioperative inflammatory responses (recommendation level: IIA, evidence level: A).

Goal-directed perfusion principles are based on evidence to guide CPB perfusion flow and blood pressure management, using indicators such as oxygen partial pressure, carbon dioxide partial pressure, mixed venous oxygen saturation, oxygen delivery, oxygen consumption, and carbon dioxide production index (32). A meta-analysis showed that, compared with standard CPB management, goal-directed perfusion strategies significantly reduce the risk of acute kidney injury (AKI) in patients undergoing cardiac surgery with CPB [relative risk (RR) =0.52, P<0.001] (33). A similar conclusion was drawn in another randomized controlled study (34).

Consensus 6: proper control of perioperative allogeneic blood transfusion helps reduce the perioperative inflammatory response (recommendation level: IIA, evidence level: B).

Perioperative blood transfusion increases the inflammatory response and the risk of organ dysfunction after CPB. It is recommended to maintain optimal oxygen delivery and tissue perfusion while minimizing inflammation, preserving the coagulation cascade, maintaining colloid osmotic pressure, and fluid balance. In patients undergoing CPB cardiac surgery, a restrictive perioperative allogeneic red blood cell transfusion strategy is suggested. This restrictive strategy lowers the transfusion rate and volume of allogeneic red blood cells without increasing mortality or morbidity risks. A restrictive transfusion strategy is recommended when hemoglobin concentration is below 7 g/dL (35). For patients with preoperative anemia, those who refuse transfusion, or those at high risk of postoperative anemia, preoperative administration of erythropoietin and iron supplementation several days before cardiac surgery can be considered to increase hemoglobin levels.

Temperature management

Consensus 7: during the perioperative period of CPB, closely monitor the patient’s temperature changes. The cooling rate should generally be 0.5 ℃/min, and the rewarming rate should be less than 0.5 ℃/min (recommendation level: IIB, evidence level: C). Ensure gradual and uniform temperature changes during cooling and rewarming, with the oxygenator outlet blood temperature not exceeding 37 ℃.

Maintaining hypothermia during CPB can reduce the metabolic rate of tissues and organs, providing organ protection and reducing the inflammatory response. Hence, hypothermia techniques are widely used in CPB cardiac surgery. Temperature management during CPB cardiac surgery should be adjusted in synchrony with local tissue perfusion to maintain normal cellular metabolism and mitigate the inflammatory response. Proper temperature management strategies must be employed during extracorporeal circulation surgery to ensure slow and uniform cooling and rewarming. The target values for cooling in mild hypothermia are nasopharyngeal temperatures between 32–35 ℃, moderate hypothermia between 26–31 ℃, and deep hypothermia between 18–20 ℃. The cooling rate is generally 0.5 ℃/min, and the rewarming rate should be less than 0.5 ℃/min, with continuous temperature monitoring after cardiac resuscitation (22). Studies have shown that oxygenated blood temperatures >37 ℃ at the oxygenator outlet are associated with the occurrence of postoperative AKI. For every 10-minute increase in oxygenator outlet blood temperature >37 ℃, the incidence of AKI increases by 34%. Therefore, it is recommended that the oxygenator outlet blood temperature during CPB not exceed 37 ℃ (36). With the widespread use of CPB in cardiac surgery, the side effects of hypothermia have also received increasing attention. Hypothermia may reduce the oxygen-carrying capacity of the blood and may cause coagulation dysfunction, leading to increased perioperative bleeding and transfusion requirements (37,38). In contrast, normothermic CPB can avoid these side effects and the risks associated with improper rewarming during extracorporeal circulation. However, there is currently limited clinical research on normothermic CPB. Its potential for widespread clinical application needs further confirmation through large-scale, multicenter RCTs.

Lung protective ventilation

Consensus 8: during CPB, adopting a lung-protective ventilation strategy with positive end-expiratory pressure (static PEEP) of 5 cmH₂O can prevent lung collapse and reduce systemic inflammatory responses (recommendation level: IIB, evidence level: C).

It is recommended to use lung-protective ventilation strategies during CPB cardiac surgery, as they can improve intraoperative oxygenation, avoid lung overdistension or atelectasis, and mitigate the inflammatory response. The main methods include individualized moderate PEEP, intermittent lung recruitment, and low inspired oxygen concentration. During CPB, the lungs are not actively ventilated, leading to lung collapse and potentially exacerbating inflammation in lung tissue. Therefore, it is recommended to use continuous positive airway pressure ventilation during CPB to maintain a pressure of 5 cmH₂O, which helps to prevent lung collapse and reduce systemic inflammation (39,40).

CPB management

Consensus 9: using coating materials that improve biocompatibility can mitigate the inflammatory response caused by contact activation (recommendation level: IIB, evidence level: B).

Applying biomolecular coatings on blood-contacting surfaces to reduce contact activation responses includes heparin-coated surfaces (HBCs), poly-2-methoxyethyl acrylate (PMEA), or polycaprolactone coatings, and phosphocholine coatings. Heparin coatings possess anticoagulant properties and can inhibit the activation of the contact system, complement system, and neutrophils, thereby reducing the release of pro-inflammatory cytokines and improving platelet function. A meta-analysis by Mangoush et al. (41) confirmed that using a heparin-coated system significantly decreased postoperative mechanical ventilation time, the incidence of blood transfusion required and re-sternotomy, and hospital and intensive care unit (ICU) stay duration. Using HBCs can also safely reduce systemic heparinization levels, thus decreasing postoperative drainage. PMEA forms an amphiphilic blood-contact surface with good biocompatibility, which can reduce perioperative inflammation and improve clinical outcomes.

CPB broadly activates coagulation, necessitating systemic anticoagulation to prevent thrombosis. Heparin anticoagulation has been in use for nearly 70 years and remains the first choice for CPB. It works by enhancing the activity of antithrombin III to inhibit thrombin. Activated coagulation time (ACT) is the gold standard for monitoring CPB anticoagulation. Young et al. (42) observed fibrin formation in CPB circuits microscopically and clinically validated that the safe ACT value should be maintained above 400 seconds. The 2018 STS/SCA/AmSECT CPB anticoagulation guidelines recommend an initial loading dose of 300 IU/kg before CPB, maintaining ACT >480 seconds during CPB (IIa/C) (43). Many factors affect ACT, so regular monitoring is necessary to keep ACT within a safe range. Antithrombin III deficiency can lead to heparin resistance, where ACT is less than 400 seconds despite standard heparin dosing, requiring fresh plasma infusion for supplementation. Postoperatively, protamine is used for heparin neutralization. Due to heparin’s distribution and metabolism characteristics, small doses of protamine may need to be given intermittently or continuously to prevent heparin rebound, but the total amount should not exceed twice the total heparin dose. Heparin can cause complications such as heparin-induced thrombocytopenia (HIT), hyperkalemia (secondary to aldosterone inhibition), and allergic reactions.

Consensus 10: use of miniaturized CPB systems and blood salvage devices can reduce blood contact with foreign materials and air, thereby reducing activation (recommendation level: IIB, evidence level: B).

The miniaturized CPB system is a semi-closed system comprising a centrifugal pump, membrane oxygenator, cardioplegia perfusion system, air-bubble capturing device, and blood salvage management system. In the inflammatory response associated with open CPB, blood contact with air plays an important role in addition to foreign material contact. Air-blood contact leads to increased cytokines, C-reactive protein (CRP), neutrophil elastase, and upregulation of granulocyte integrin CD11, with a more significant increase observed during the use of intracardiac suction for blood recovery. The miniaturized CPB system reduces the foreign surface area and uses a closed system to decrease air-blood contact, which can lower levels of creatine kinase-MB and troponin I (44).

Consensus 11: application of ultrafiltration (UF) during CPB helps reduce volume overload, improve microcirculation, enhance oxygen delivery, and improve tissue perfusion, contributing to the reduction of systemic inflammatory responses (recommendation level: IIB, evidence level: B).

Blood dilution during CPB leads to a decrease in intravascular colloid osmotic pressure, and the increase in vascular permeability due to the inflammatory response can cause tissue edema and further affect organ function. Excessive blood dilution increases complications and mortality. Maintaining a higher colloid osmotic pressure has anti-inflammatory characteristics, such as reducing postoperative plasma lactate levels and shortening mechanical ventilation time. Multiple studies have shown that using UF during CPB can remove excess free water and low-molecular-weight substances from the plasma, including complements, inflammatory cytokines, and cell adhesion molecules, thereby increasing postoperative hematocrit, reducing postoperative transfusion, and improving organ function (45-47). These findings suggest that while UF can be beneficial for certain patients, particularly those with acquired cardiac defects, its use should be individualized based on the patient’s condition, surgical procedure, and the type of CPB system employed. UF may improve outcomes in selected cases but is not universally advantageous. Excessive UF, however, can lead to hypovolemia, impairing renal perfusion and potentially resulting in postoperative AKI and a higher transfusion requirement. Therefore, it is crucial to carefully balance UF volumes to maintain an adequate circulating volume and prevent these adverse outcomes.

Postoperative management

Evaluation of postoperative systemic inflammatory response

Consensus 12: when a patient exhibits a systemic inflammatory response postoperatively, it is important to distinguish between infectious and non-infectious causes, ensuring timely identification and control of infection (recommendation level: IIA, evidence level: B).

The systemic inflammatory response state following CPB surgery should be comprehensively evaluated based on clinical presentation, laboratory tests, and organ damage. SIRS can be diagnosed when at least two of the following criteria are present and persist for at least 6 hours (48): (I) body temperature >38 ℃ or <36 ℃; (II) heart rate >90 beats per minute; (III) rapid breathing (>20 breaths per minute) or hyperventilation (PaCO₂ <32 mmHg); (IV) peripheral white blood cell count >12×10⁹/L or <4×10⁹/L, or immature neutrophils >10%.

In addition to SIRS, cardiac surgery patients may develop systemic infections, including sepsis. Early differential diagnosis between systemic infection and SIRS based on clinical presentation alone remains challenging. A study analyzing urine and serum samples from patients in sepsis, SIRS, and healthy control groups found that the levels of CRP, leucine-rich alpha-2 glycoprotein-1 (LRG1), and serum amyloid A (SAA) were higher in the sepsis group compared to the SIRS group (P<0.001). The combined use of these biomarkers had a sensitivity of 0.906 and specificity of 0.896 in differentiating sepsis from SIRS (49). The prognosis and treatment strategies differ between patients with infectious and non-infectious SIRS, making this differentiation clinically valuable for improving outcomes.

Analgesia and sedation strategy

Consensus 13: early goal-directed analgesia and sedation strategies are recommended. In patients requiring prolonged mechanical ventilation due to hemodynamic or respiratory instability, particularly during the rescue and optimization phase of circulatory shock, an appropriate depth of sedation should be selected (recommendation level: I, evidence level: A).

A reasonable analgesia and sedation strategy after CPB can reduce cardiac and systemic oxygen consumption and alleviate the stress response. This approach facilitates hemodynamic stability and cardiac function recovery while reducing excessive inflammatory responses. For routine short-term postoperative sedation, early goal-directed sedation (EGDS) is recommended. EGDS involves titrating sedation depth to achieve a light sedation state, defined as a Riker Sedation-Agitation Scale score of 3–4 or a Richmond Agitation-Sedation Scale score of −2 to +1, based on adequate analgesia (50). For patients with hemodynamic or respiratory instability who require delayed mechanical ventilation, particularly those in the rescue and optimization phase of circulatory shock, prolonged sedation therapy with an appropriate sedation depth may be employed. Dexmedetomidine, an α2 receptor agonist with both sedative and analgesic effects, has been shown in a meta-analysis to reduce postoperative inflammatory markers (IL-6, TNF-α) and myocardial injury markers after CPB, as well as shorten ICU stay duration (51).

Improving cardiac function and ensuring tissue perfusion

Consensus 14: the use of serine protease inhibitors in cardiac surgery under CPB can reduce systemic inflammatory responses and improve myocardial IRI, contributing to the maintenance of hemodynamic stability and perfusion of tissues and vital organs (recommendation level: IIA, evidence level: B).

Ulinastatin, a broad-spectrum serine protease inhibitor, has been shown to improve cardiac function, maintain hemodynamic stability, and ensure perfusion of tissues and vital organs during the perioperative period of CPB. This results in a reduction of systemic inflammatory responses and provides organ protection (52). Multiple clinical studies have demonstrated that ulinastatin significantly improves cardiac function in patients undergoing cardiac surgery with CPB, reduces levels of pro-inflammatory cytokines, and maintains organ function stability (53-59). Administering ulinastatin during CPB can significantly inhibit perioperative inflammatory responses (60) and reduce the risk of MODS (52). Additionally, the use of ulinastatin in cardiac surgery under CPB can shorten mechanical ventilation time (61,62), reduce postoperative bleeding and allogeneic red blood cell transfusion (63,64) and decrease hospital stay duration (65,66).

Blood glucose management

Consensus 15: for non-diabetic critically ill patients after major surgery, it is recommended to maintain blood glucose levels between 7.8 and 10.0 mmol/L. For critically ill diabetic patients, a more lenient blood glucose control of 6.1 to 11.1 mmol/L is suggested (recommendation level: IIB, evidence level: C).

The 2022 guidelines for “Blood Glucose Management in Critically Ill Patients” recommend maintaining blood glucose levels between 7.8 and 10.0 mmol/L for non-diabetic critically ill patients after major surgery (Grade 1+, strongly recommended). This relatively strict range balances the effectiveness and safety of blood glucose management after major surgery. For critically ill diabetic patients, a more lenient blood glucose control range of 6.1 to 11.1 mmol/L is suggested (grade 2+, weak recommendation) (67). It is important to note that critically ill diabetic patients are more prone to hypoglycemia than non-diabetic patients, so close monitoring of blood glucose levels is crucial.

Nutritional support therapy

Perioperative nutritional intervention has become an important strategy to mitigate metabolic stress and excessive inflammatory responses, regulate immune function, and improve outcomes in CPB surgery patients. For patients exhibiting systemic inflammatory responses postoperatively, active nutritional support therapy can facilitate recovery. Early enteral nutrition (EEN) postoperatively can reduce the expression of inflammatory markers such as IL-6 and CRP, thereby improving patient outcomes (68).

Pharmacological treatment of excessive inflammatory response in CPB

Protease inhibitors

Proteases are a class of inflammatory mediators, and their upregulation can lead to tissue damage and an exacerbated inflammatory response (69). Protease inhibitors effectively inhibit target proteases by binding to their active centers, forming “inhibitor-enzyme complexes”. This binding prevents the cleavage of the peptide chain at the active center of the target protease, rendering the protease inactive, thereby inhibiting tissue damage and excessive inflammation. Ulinastatin is a serine protease inhibitor with a broad inhibitory spectrum. It stabilizes lysosomal membranes, inhibits the release of lysosomal hydrolases, suppresses the generation of myocardial depressant factors, reduces the production of oxygen free radicals, and inhibits the excessive release of various inflammatory mediators, offering protective effects on vital organs such as the heart, liver, lungs, and kidneys (70). Multiple studies have confirmed that intraoperative and postoperative use of ulinastatin in CPB surgery can inhibit the production of inflammatory cytokines IL-6, IL-8, and TNF-α while promoting the release of the anti-inflammatory cytokine IL-10, effectively reducing systemic inflammatory responses and improving patient outcomes (71,72).

Glucocorticoids

The application of glucocorticoids in CPB surgery can alleviate systemic inflammatory responses by inhibiting endotoxin release and complement system activation, reducing inflammatory cytokines, and decreasing leukocyte activation and neutrophil adhesion molecule upregulation. However, the impact of glucocorticoids on CPB surgery outcomes remains controversial. A meta-analysis that included 31 randomized double-blind trials indicated that intraoperative use of glucocorticoids in CPB could reduce the risk of postoperative atrial fibrillation but had no significant effect on postoperative mortality, mechanical ventilation time, bleeding, or infection risk (73). An RCT showed that high-dose dexamethasone (1 mg/kg) during CPB could suppress SIRS but could also lead to significant pulmonary dysfunction, prolonged extubation time, and postoperative hyperglycemia (74). Based on the available evidence, routine glucocorticoid use to control inflammatory responses during CPB surgery is not recommended. While glucocorticoids have been shown to reduce certain morbidities, such as postoperative atrial fibrillation and blood loss, their use is associated with significant risks. Specifically, dexamethasone, though effective in modulating systemic inflammation, can lead to pulmonary dysfunction, prolonged extubation times, and hyperglycemia, all of which may contribute to renal and intestinal complications. Consequently, the application of glucocorticoids should be carefully considered on a case-by-case basis, taking into account both the potential benefits and the risk of adverse outcomes.

Statins

Statins have multiple non-lipid-lowering effects, including anti-inflammatory properties. Studies have found that preoperative use of statins can reduce the expression of inflammatory cytokines such as TNF, IL-6, and IL-8 in patients after CPB surgery, suggesting a positive role of statins in suppressing inflammatory responses (75). However, due to the limited clinical validation of these findings, further research is needed to confirm the effectiveness of statins in suppressing inflammatory responses and to establish their role in perioperative care for CPB surgery.

Antioxidants

During CPB-induced ischemia-reperfusion, activated neutrophils release large amounts of oxygen free radicals, exacerbating the inflammatory response, while CPB itself consumes endogenous free radical scavengers. The use of exogenous antioxidants (e.g., vitamin C, vitamin E, N-acetylcysteine) can scavenge oxygen free radicals, reducing inflammation and cellular damage (76). However, the aforementioned effects of antioxidants have not been confirmed in clinical studies, so the use of antioxidants to control inflammatory responses in CPB surgery is not recommended. Given the limited clinical validation of the effects of exogenous antioxidants in CPB-induced ischemia-reperfusion, further research is needed to confirm their efficacy in reducing inflammation and cellular damage before they can be recommended for routine use in CPB surgery.

Complement and inflammatory factor inhibitors (monoclonal antibodies)

Complement activation plays a key role in the early stages of CPB-induced inflammation. Pexelizumab, a complement inhibitor, can specifically bind to complement C5, blocking the cleavage into C5a and C5b-9, thereby inhibiting the inflammatory response. However, the PRIMO-CABG study failed to show that pexelizumab reduces mortality in coronary artery bypass grafting (CABG) under CPB (77). Other complement and inflammatory factor inhibitors include anti-C1 antibodies, anti-C3 antibodies, anti-TNF-α antibodies, anti-IL-1 antibodies, and anti-adhesion molecule antibodies, but their roles in CPB-induced inflammation remain unclear.

Phosphodiesterase inhibitors

Phosphodiesterase inhibitors increase intracellular cyclic adenosine monophosphate (cAMP) concentrations by inhibiting its degradation, enhancing Ca²⁺ influx, and exerting a positive inotropic effect on the myocardium. An increase in cAMP in vascular smooth muscle can improve cardiac output, protect cardiac function, and treat post-CPB ventricular dysfunction. Studies have shown that administering phosphodiesterase inhibitors during CPB can lower postoperative inflammatory cytokine levels compared to the saline control group (78).

Angiotensin-converting enzyme inhibitors (ACE inhibitors)

ACE inhibitors are commonly used antihypertensive drugs in clinical practice. They reduce postoperative inflammatory responses and oxidative stress in cardiac surgery under CPB by inhibiting the renin-angiotensin-aldosterone system, thereby slowing the progression of myocardial fibrosis. A prospective study involving 69 patients undergoing CPB cardiac surgery showed that ACE inhibitor treatment significantly reduced the expression of serum inflammatory cytokines postoperatively (79).

Conclusions

This consensus introduces innovative strategies for perioperative inflammation management in CPB cardiac surgery, including personalized glycemic control protocols tailored for diabetic and non-diabetic patients, and advanced CPB techniques such as miniaturized systems, biocompatible coatings, and goal-directed UF. It further incorporates novel pharmacologic approaches like alpha-2 adrenergic agonists and serine protease inhibitors, establishing an evidence-based, multidimensional framework for inflammatory response modulation. By integrating these optimized interventions across preoperative, intraoperative, and postoperative phases, the consensus provides actionable guidelines to standardize care, mitigate CPB-related inflammatory complications, and ultimately enhance patient outcomes and recovery trajectories.

However, several important considerations merit attention. First, while providing specific clinical thresholds (e.g., BMI <24 kg/m², FAR >7.6%), their generalizability to non-Asian populations may be limited by ethnic variations in body composition and inflammatory physiology. Second, implementation may be constrained by unequal access to specialized CPB technologies across healthcare settings. Third, certain recommendations (e.g., statins, antioxidants) require further validation through multicenter trials to strengthen the evidence base. These limitations highlight the need for both contextual adaptation in clinical practice and continued research to optimize inflammatory management strategies globally.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2024-213/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2024-213/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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