Expert consensus on the use of human serum albumin in adult cardiac surgery

Introduction Albumin, which is a 65-kDa liver-synthesized protein, accounts for nearly 50% of total plasma protein and contributes to approximately 80% of intravascular oncotic pressure. Albumin helps maintain microvascular integrity, functions as an antioxidant, and transports hormones, fatty acid, bile salts, bilirubin, electrolytes (e.g., calcium, magnesium, copper, zinc, et al.), and drugs.[1–3] Human serum albumin (HSA) is a sterile, liquid albumin product derived from large pools of human plasma by fractionation and pasteurization. The medical use of HAS could date back to approximately the time of World War II.[4] Cardiac surgery inevitably causes major changes, such as surgical trauma, blood loss, hemodilution, and a systemic inflammatory response, in patients.[5–7] HSA has been widely used in adult patients undergoing cardiac surgery for fluid resuscitation, pump priming, or correction of hypoalbuminemia, etc.[8,9] However, evidence and practice guidelines are still lacking regarding the use of HSA in cardiac surgical patients. There is notable interhospital variation in terms of how HSA is used. Inappropriate clinical use of HSA is not uncommon, which may cause enormous waste, and increases the burden of healthcare.[3] Our goal was to develop an expert consensus on the use of HSA in adult patients who underwent cardiac surgery. We aimed to help understand the roles of HSA infusion in perioperative treatment and improve patients' care by systemically evaluating available evidence in the literature. This consensus was written collaboratively by a multidisciplinary team consisting of cardiac surgeons, anesthesiologists, intensivists, perfusionists, and other healthcare providers who care for cardiac surgical patients. Methodology According to the recommendation of developing expert consensus statements,[10] a committee was initiated in August 2022 and consisted of 25 experts in cardiac surgery, anesthesiology, critical care, and perfusion. Three sections were developed, including volume replacement, pump priming, and correction of hypoalbuminemia. We searched the PubMed, Ovid, MEDLINE, and Cochrane Library databases from 1990 until August 2022, and reviewed the retrieval results. After the review, drafted recommendations were proposed on the basis of existing evidence in the literature, and by discussion and consensus among the experts. The class of recommendation and the level of evidence of each recommendation were weighed and graded according to predefined scales[11] [Tables 1 and 2]. The class of recommendation (COR) specified the strength of recommendation, including the estimated magnitude and certainty of benefit compared with risk. The level of evidence (LOE) was used to assess the quality of scientific evidence supporting the recommendation, graded by the type, quantity, and consistency of the data from clinical trials and other researches. Table 1 - Class of recommendations (COR) and corresponding definition. COR Definition Class I (strong) Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective, (Benefit far outweights Risk) Class II Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure. Class IIa (moderate) Weight of evidence/opinion is in favor of usefulness/efficacy. (Benefit > Risk) Class IIb (weak) Usefulness/efficacy is less well established by evidence/opinion. (Benefit ≥ Risk) Class III Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. Class III: No benefit Benefit = Risk Class III: Harm Benefit 5 mmHg, pulmonary artery diastolic pressure >20 mmHg, and pulmonary edema). A study from this center compared 440 patients who received restricted albumin use with 961 patients in whom albumin was used without restriction. This study showed that a significant reduction in albumin use (mean: 101 doses monthly vs. 280 doses monthly, P <0.001) after albumin restriction resulted in similar mortality and morbidity. This study suggested that albumin restriction in postoperative care of cardiac surgical patients is feasible and safe.[69] Therefore, considering the high cost and limited availability of albumin, it is not recommended as the first-line choice for fluid replacement. Recommendation 6: Using HSA for fluid resuscitation in patients with hemorrhagic shock and uncontrolled bleeding is not recommended (COR III: No Benefit, LOE C-EO). The strategy to manage cardiac surgical patients with active bleeding and hemorrhagic shock should focus on timely control of surgical bleeding, targeted correction of coagulopathy, and adequate fluid resuscitation. In patients who are complicated with massive bleeding or hemodynamically unstable, appropriate blood products such as red blood cells, fresh frozen plasma, platelets, and cryoprecipitate should be initially provided to replace blood components on the basis of hemodynamic parameters, the rate of bleeding, and point-of-care hemostasis testing.[39] In addition, balanced crystalloid should serve as the first-line choice after blood products for fluid resuscitation owing to its availability and safety profile on coagulation. To date, no studies have investigated the safety and effectiveness of albumin use in cardiac surgical patients complicated by hemorrhagic shock and uncontrolled bleeding. However, avoiding albumin and choosing a safer fluid, such as crystalloids, are reasonable choices in hemorrhagic shock because of its possible effect on coagulation. Recommendation 7: HSA infusion is reasonable to supplement prior volume and albumin loss in patients with bleeding-controlled hemorrhagic shock (COR IIa, LOE C-EO). Patients in hemorrhagic shock during or after cardiac surgery will usually have been resuscitated with crystalloids and blood transfusion. After the active bleeding has been controlled, these patients often require ongoing volume resuscitation and have an intravascular oncotic deficit from prior bleeding-caused albumin loss. In addition, postoperative bleeding and blood transfusion usually exacerbate the systemic inflammation and damage of the endothelial glycocalyx in cardiac surgical patients.[20,42] In this situation, HSA infusion is indicated to help with volume replacement, limit positive fluid balance, restore microvascular integrity, and reduce systemic inflammation. SECTION 2: Pump Priming Regarding CBP, HSA is currently used for pump priming, replacing volume loss, and relieving a drop in oncotic pressure. Recommendation 8: Pump priming with HSA for optimizing blood management might be reasonable (COR IIb, LOE B-NR). Recommendation 9: Pump priming with HSA might be considered in specific cardiac surgical populations, such as those undergoing heart transplantation, pulmonary thromboembolectomy, and deep hypothermic circulatory arrest (COR IIb, LOE C-EO). Pump priming usually takes approximately 1.0 L to 1.5 L of fluid and induces considerable hemodilution.[38] This priming may lead to a fall in colloid oncotic pressure (COP) and extravascular fluid shift, which further cause interstitial salt and water overload, as well as postoperative weight gain.[70] Colloids are usually used as priming fluid to help maintain oncotic pressure. However, because of the concern regarding AKI and the bleeding risk mentioned above, the use of synthetic colloids has declined over the last decade. Fresh frozen plasma is also not recommended as priming fluid in the adults because of the risk of blood transfusion.[39] However, some centers commonly use HSA as a pump priming fluid. According to two surveys, HSA is used for CPB priming by approximately 30% of healthcare responders in the United States and approximately 8.7% in European countries.[61,71] Studies have shown that priming with HSA attenuates an on-pump fall in COP and reduces positive fluid balance.[72,73] In addition, shear stress and a pressure drop across the pump boot may release inflammatory mediators and initiate a systemic inflammatory response, which may further cause the breakdown of endothelial permeability.[74] HSA has been postulated to help protect the endothelial glycocalyx and microvascular integrity.[9] Furthermore, blood contact with roller pumps and the foreign inner surface of oxygenator and extracorporeal circuits induces bound fibrinogen, which may cause platelet adhesion on fibrinogen via glycoprotein IIb/IIIa receptor, fibrin deposition, and platelet consumption.[75,76] Albumin from pump priming coats the surface of the circuit and oxygenator, which prevents fibrinogen binding during bypass and helps protect from platelet adhesion and likely the consumption of other coagulation factors.[9,77] A meta-analysis of 1346 patients from 21 studies compared platelet counts, COP, on-bypass fluid balance, and postoperative weight gain. Compared with crystalloid priming, albumin priming significantly reduced the drop in the postoperative platelet count (-23.8×109/L; 95% CI, -42.8×109/L to -4.7×109/L), minimized the decline in COP (-3.6 mmHg; 95% CI, -4.8 mmHg to -2.3 mmHg) during bypass, and caused a less positive fluid balance (-584 mL, 95% CI: -819 mL to -348 mL) and less postoperative weight gain (-1.0 kg; 95% CI, -1.3 kg to -0.6 kg).[37] Despite the benefits mentioned above, pump priming with HSA has failed to translate into an improvement in the outcome in the general cardiac surgery population.[9,32] In the ALBICS trial, the group with pump priming of 60 g of HSA did not show reduced morbid outcomes compared with the group of priming with crystalloid.[32] However, HSA is currently widely used for high-risk patient populations, such as those with a low body weight, heart transplantation, pulmonary thromboembolectomy, deep hypothermic circulatory arrest, advanced age, reoperations, thrombocytopenia, impaired heart function, and a long pump run. Future studies should investigate the benefit of HSA priming in these patients and provide evidence for this practice. SECTION 3: Correction of Hypoalbuminemia Recommendation 10: HSA infusion is reasonable to correct preoperative hypoalbuminemia in normovolemic patients (COR IIb, LOE B-NR). Hypoalbuminemia is defined as serum albumin concentrations <35 g/L. Preoperative hypoalbuminemia is common among cardiac surgical patients, and is usually caused by cardiac-related malnutrition, liver dysfunction, and chronic consumption.[78] Preoperative hypoalbuminemia is strongly associated with early and late adverse outcomes,[79–82] especially infection,[81] AKI,[27] and delirium.[83] Baseline albumin concentrations have been used to help assess the operative risk in cardiac surgical patients. However, whether exogenous HSA supplementation can improve operative outcomes is still controversial. A meta-analysis of nine controlled, clinical trials on critically ill non-cardiac surgical patients was performed. This analysis showed that HSA infusion significantly reduced the incidence of postoperative complications in patients whose preoperative albumin concentration was corrected to higher than 30 g/L.[84] However, limited evidence is available in cardiac surgical patients. A single-center, parallel-arm RCT of 220 patients who underwent off-pump coronary artery bypass grafting with preoperative albumin concentrations <4.0 g/L showed that preoperative administration of 20% albumin solution reduced the risk of postoperative AKI (albumin vs. control group: 13.7% vs. 25.7%, P =0.048), but there was no significant effect on mortality or other major morbidities.[31] Notably, hypoalbuminemia often occurs in preoperative patients with congestive heart failure, and HSA infusion, especially hypertonic HSA, should be avoided in such patients who are intolerant of hypervolemia. Recommendation 11: Correcting postoperative hypoalbuminemia by HSA infusion in normovolemic patients might be beneficial (COR IIb, LOE C-EO). In cardiac surgical patients, baseline hypoalbuminemia, operative loss, leakage to the extravascular space, and considerable hemodilution often lead to postoperative hypoalbuminemia. An observational study of 2818 patients who underwent cardiac surgery showed that 61.5% of patients had serum albumin concentrations <30 g/L postoperatively.[85] Studies have shown that postoperative hypoalbuminemia is associated with adverse outcomes.[85,86] HSA is commonly used to replace an albumin deficit during the postoperative period, aiming to maintain oncotic pressure, relieve tissue edema, and maintain microvascular integrity and metabolism, etc. In the future, studies should be carried out to determine whether exogenous HSA improves the clinical outcome of patients who have postoperative hypoalbuminemia, but do not require volume replacement.[87] Conclusions HSA can be used for volume replacement, pump priming, and correcting hypoalbuminemia in cardiac surgical patients. We summarized the recommendations for use of human serum albumin (HSA) in adult cardiac surgery in Table 3. However, more evidence is required to justify this practice, especially regarding the improvement of clinical outcomes. This expert consensus will serve to guide the decisions regarding the use of HSA during and after cardiac surgery. Table 3 - Recommendations for use of human serum albumin (HSA) in adult cardiac surgery. No. Recommendations COR LOE References Section 1. Volume Replacement 1 A comprehensive multimodality approach by a multidisciplinary team is recommended to minimize hemodilution during cardiac surgery. I C-EO 5, 39–45- 2 Goal-directed fluid therapy is recommended to assess the volume status and optimize fluid resuscitation during and after cardiac surgery. I B-NR 46–50- 3 It is reasonable to administer HSA following crystalloid resuscitation in patients who needs further volume replacement during and after cardiac surgery to avoid excessive positive fluid balance. IIb B-NR 13, 19, 21–23-, 32, 51–59-, 61 4 HSA infusion might be helpful to maintain intravascular volume and arterial pressure when aggressive diuresis is given to relieve fluid overload and interstitial edema after cardiac surgery. Hypertonic (20% or 25%) HSA is preferred in this setting. IIb C-LD 19,20,62–66- 5 HSA is not routinely recommended as the first-line choice of fluid resuscitation during and after cardiac surgery. III: No Benefit B-R 32, 58, 60,67–69- 6 Using HSA for fluid resuscitation in patients with hemorrhagic shock and uncontrolled bleeding is not recommended. III: No Benefit C-EO None 7 Recommendation 7: HSA infusion is reasonable to supplement prior volume and albumin loss in patients with bleeding-controlled hemorrhagic stroke, IIa C-EO None Section 2. Pump Priming 8 Pump priming with HSA for optimizing blood management might be reasonable. IIb B-NR 9, 32, 37–39-, 61, 70–76- 9 Pump priming with HSA might be considered in specific cardiac surgical populations, such as those undergoing heart transplantation, pulmonary thromboembolectomy, and deep hypothermia circulatory arrest. IIb C-EO None Section 3. Correction of Hypoalbuminemia 10 HSA infusion is reasonable to correct preoperative hypoalbuminemia in normovolemic patients. IIb B-NR 31, 77–83- 11 Correcting postoperative hypoalbuminemia by HSA infusion in normovolemic patients might be beneficial. IIb C-EO None COR: Class of recommendations; EO: Expert opinion; LD: Limited data; LOE: Level of evidence; NR: Nonrandomized; R: Randomized. Acknowledgments We thank Ellen Knapp, PhD, from Liwen Bianji (Edanz) (www.liwenbianji.cn/), for editing the English text of a draft of this manuscript. Conflicts of interest This consensus was sponsored by the CSL Behring. The funders had no role in the consensus development process or in the writing and preparation of the manuscript or the decision to publish.