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 <Risk Table 2 - Level of evidence (LOE) and corresponding definition. LOE Definition Level A • High quality evidence from more than one randomized controlled trial (RCT) • Meta-analysis of high-quality RCTs • One or more RCTs corroborated by high-quality registry studies Level B-R (randomized) • Moderate quality evidence from one or more RCTs • Meta-analysis of moderate quality RCTs Level B-NR (nonrandomized) • Moderate quality evidence from one or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies • Meta-analysis of such studies Level C-LD (limited data) • Randomized or nonrandomized observational or registry studies with limitations of design or execution • Moderate quality of such studies • Physiological or mechanistic studies in human subjects Level C-EO (expert opinion) • Consensus of expert opinion based on clinical experience A draft of the recommendations was then submitted for voting among committee members. To approve a specific recommendation, a 75% consensus rate was required with 80% participation to ensure the validity of voting. This process was repeated for each section. Controversies were discussed and resolved by regular online video meetings and re-voting, following the Delphi method process.[12] The final draft was approved with high levels of consistency achieved for each recommendation. SECTION 1: Volume Replacement Volume replacement is a crucial component of perioperative cardiac surgical care. Volume replacement is often initiated in response to signs of inadequate tissue perfusion or intravascular volume, such as hypotension, oliguria, or hyperlactatemia. Balanced crystalloids, synthetic colloids, and HSA are the most frequently used fluids to maintain or restore circulating plasma volume during and after cardiac surgery.[13,14] Recently published data from randomized, clinical trials (RCTs), meta-analyses, and observational studies have shown that synthetic colloids, particularly hydroxyethyl starches, increase the risk of death, acute kidney injury (AKI), and excess bleeding in cardiac surgical patients.[15–18] Therefore, the U.S. Food and Drug Administration and European Medicine Agency recommend suspending all hydroxyethyl starches products unless adequate alternative treatment is unavailable. HSA remains in the intravascular space for a more extended period than crystalloids when the endothelial glycocalyx is intact because of its large molecular weight.[19,20] With regard to the colloid oncotic effect of albumin, it is believed to provide intravascular volume expansion more sustainably and efficiently than crystalloids. Larger volumes of crystalloids are required to create similar changes in hemodynamic parameters during resuscitation compared with albumin.[21–24] Yanase et al[21] monitored hemodynamic parameters (cardiac index, mean arterial pressure, and central venous pressure) after administering 20 g of albumin or 500 ml of crystalloid as fluid bolus therapy after cardiac surgery. They found that both of these achieved a similar immediate increase in the cardiac index and mean arterial pressure, but the improvement in mean arterial pressure was maintained longer by albumin than by crystalloids. HSA and kidney function AKI is one of the most common complications after cardiac surgery,[25,26] and preoperative hypoalbuminemia is a risk factor for developing AKI.[27,28] However, the effect of exogenous albumin on renal function is still largely unknown. Frenette et al[29] showed a dose-dependent effect of albumin administration on AKI, which raised concern about the safety of albumin on kidney function in patients undergoing cardiac surgery. However, in this study, preoperative albumin concentrations were not matched, and a majority of patients in the albumin group also received other colloids. Therefore, the study's validity is limited by its design, and its results should be interpreted with caution.[30] A prospective, single-center, randomized, controlled study evaluated the effect of preoperative 20% albumin administration on postoperative AKI in 220 patients with preoperative hypoalbuminemia (<4.0 g/dL) undergoing off-pump coronary artery bypass grafting.[31] This study showed that the postoperative incidence of AKI in the albumin group was lower than that in the group without preoperative albumin supplementation (13.7% vs. 25.7%, P =0.048), but there was no difference in new-onset dialysis-dependent renal failure.[31] The first large interventional RCT, Albumin in Cardiac Surgery (ALBICS) trial, showed that pump priming and fluid resuscitation with albumin did not increase the risk of AKI compared with crystalloids (3.3% vs. 2.6%, P =0.43).[32] The ALBICS trial randomly assigned 1386 patients into 2 groups who received 4% albumin solution or Ringer acetate for cardiopulmonary bypass (CPB) priming and perioperative 24-h intravenous volume replacement. The investigators examined the incidence of operative complications in the two groups and found that 4% albumin solution did not significantly reduce the risk of major adverse events over 3 months following cardiac surgery. In detail, patients in the albumin group received less volume of fluid replacement (median: 2150 mL vs. 3298 mL, P <0.001), had a lower incidence of myocardial injury (risk ratio [RR] 0.44; 95% confidence interval [CI], 0.28–0.68; P <0.001), but had a higher incidence of bleeding (RR, 1.73; 95% CI, 1.12–2.68; P =0.01), re-exploration (RR, 1.85; 95% CI, 1.28–2.68; P =0.001), and infection (RR, 1.45; 95% CI, 1.07–1.97; P =0.02) than the Ringer's group.[32] However, this trial has some limitations. First, the patients in this study had a median EuroSCORE of 1.7, which indicated that only low-risk patients were included, and this trial did not represent the high-risk population who might benefit the most from HSA use. Second, the concentration/dose of HSA used and the criteria for switching from crystalloids to albumin during resuscitation followed in this trial are different from routine practice, which might affect the interpretation of the results. HSA and coagulation Besides the hemodilution effect from albumin infusion, studies have shown mixed results regarding the effect of albumin on coagulation function and bleeding in patients undergoing cardiac surgery. Albumin inhibits platelet aggregation in vitro.[33,34] Niemi et al[16] performed thromboelastography (TEG) in patients who underwent cardiac surgery and found that maximum clot firmness, fibrin formation, and fibrinogen-dependent clot strength did not change after albumin infusion. Another RCT showed that albumin infusion during cardiac surgery resulted in weaker clot strength (TEG-maximal amplitude [MA]: 59±6 mm vs. 67±6 mm, P <0.001) and slower clot growth in thromboelastography (TEG angle: 69°±5° vs. 74°±3°, P <0.01) than those with crystalloids.[35] However, there was no significant difference in postoperative blood loss between these treatments (P =0.45).[35] Skhirtladze et al[36] evaluated the effects of 5% albumin solution and lactate Ringer's solution on blood loss and coagulation function in 240 patients after cardiac surgery. Albumin did not increase chest drainage at 24 h after cardiac surgery (835 mL vs. 670 mL, P =0.085), but increased the requirement of red blood cell infusion (300 mL vs. 0 mL, P =0.0015) at 24h after cardiac surgery compared with lactate Ringer's solution.[36] A meta-analysis from 21 studies of 1346 patients who underwent cardiac surgery also showed no significant effect of albumin infusion on postoperative blood loss or blood transfusion.[37] However, the ALBICS trial showed a higher risk of major postoperative bleeding in the albumin group than in the crystalloid group (7.5% vs. 4.3%; RR, 1.73; 95% CI, 1.12–2.68).[32] Recommendation 1: A comprehensive multimodality approach by a multidisciplinary team is recommended to minimize hemodilution during cardiac surgery (COR I, LOE C-expert opinion [EO]). Although hemodilution during CPB was routinely applied to reduce blood viscosity and improve tissue perfusion during hypothemia,[38] current evidence has shown that excessive hemodilution increases the risk of receiving allogenic blood transfusion, AKI, and positive fluid balance, and thus should be well controlled.[5,39–41] To effectively minimize hemodilution, a multimodality approach is recommended,[42] which should include the following items: (1) restricting intravenous fluid administration before CPB when acute normovolemic hemodilution is not applied; (2) minimizing the circuit prime volume;[43] (3) applying autologous priming techniques, such as retrograde autologous priming and/or venous antegrade priming;[44] and (4) ultrafiltration techniques.[45] This approach has also been recommended by the recent Society of Thoracic Surgeons (STS)/Society of Cardiovascular Anesthesiologists (SCA)/American Society of ExtraCorporeal Technology (AmSECT)/Society for the Advancement of Blood Management (SABM) and European Association for Cardio-Thoracic Surgery (EACTS) clinical practice guidelines regarding blood management in patients with cardiac surgery.[39,43] Recommendation 2: Goal-directed fluid therapy (GDFT) is recommended to assess the volume status and optimize fluid resuscitation during and after cardiac surgery (COR I, LOE B-nonrandomized [NR]). GDFT uses comprehensive measures of organ perfusion, such as hemodynamic parameters (e.g., blood pressure, central venous pressure, and the cardiac index), metabolic parameters (e.g., urine output, serum lactate concentrations, and mixed venous oximetry), and monitoring systems (e.g., Vigileo, pulse-induced contour cardiac output [PiCCO], and LiDCO) during and after cardiac surgery. With this approach, intravascular fluid volume, vascular resistance, and cardiac output can be dynamically assessed and addressed. This helps determine the timing and dose of albumin infusion and achieve adequate resuscitation but not over-resuscitation (positive fluid balance).[46–48] A meta-analysis on 5 studies of patients showed that the use of GDFT the postoperative rate ratio 95% CI, P and the of 95% CI, P without a significant in et showed that GDFT was with a significantly risk of AKI after cardiac surgery 95% CI, Recommendation is to HSA following crystalloid resuscitation in patients who volume replacement during and after cardiac surgery to excessive positive fluid (COR LOE Volume replacement in cardiac surgical patients is because hemodynamic parameters during and after cardiac surgery can be by such as blood loss, and cardiac output In intravascular volume is Therefore, over-resuscitation is common in patients undergoing cardiac studies have shown that volume is with an increased risk of (e.g., AKI, and and in patients who cardiac a HSA is believed to in the intravascular space for a more extended period and thus provide intravascular volume expansion more efficiently than volume of HSA can achieve more hemodynamic improvement than crystalloids during and after cardiac In a study, et patients who required fluid resuscitation during the first 24 h after cardiac surgery. They the first patients with crystalloid fluid bolus and the following patients with to ml of 20% which were followed by crystalloid fluid bolus required The group was with a less positive fluid (median: mL vs. P =0.001), of fluid bolus therapy (median: 3 vs. P and a lower volume of fluid bolus therapy (median: mL vs. mL, than the The was also with a median dose of (median: vs. P and a median time to of (median: h vs. P Another study by et cardiac surgical patients and showed that patients who received HSA during the first 24 h of care had significantly lower than patients who did not 95% CI, P a there is a in the of HSA to over-resuscitation and an excessive positive fluid in patients undergoing cardiac Recommendation HSA infusion might be to maintain intravascular volume and arterial pressure when is given to fluid and after cardiac surgery. or HSA is in this (COR LOE data the acute of fluid resuscitation is patients often a positive fluid and with and (e.g., and or The of excessive and by is the first of and in patients who cardiac However, these patients may also have an inadequate intravascular can often the of intravascular volume and cause systemic In this HSA infusion helps by the circulating plasma volume to maintain adequate In HSA is also believed to help of the endothelial which an that fluid to from the space to the intravascular However, HSA to not to help with the postoperative and are more in high-risk patients with a pump or a procedure. studies to HSA more benefit in this specific Recommendation HSA is not routinely recommended as the of fluid resuscitation during and after cardiac surgery (COR III: No LOE The between crystalloids and for fluid resuscitation has been for the of crystalloids in volume no evidence has shown that resuscitation with albumin operative in patients undergoing cardiac the ALBICS trial to significant by HSA infusion as the of fluid resuscitation regarding major in patients who underwent cardiac surgery compared with In the of its albumin use in only to patients more than 3 of crystalloid infusion in the first 24 h after cardiac surgery, hypoalbuminemia albumin concentrations or patients to have fluid venous pressure artery pressure and A study from this compared patients who received albumin use with patients in albumin was used without This study showed that a significant in albumin use vs. P <0.001) after albumin resulted in similar and This study that albumin in postoperative care of cardiac surgical patients is and Therefore, the high and limited of albumin, it is not recommended as the for fluid replacement. Recommendation HSA for fluid resuscitation in patients with and bleeding is not recommended (COR III: No LOE The to cardiac surgical patients with bleeding and should on of surgical correction of and adequate fluid In patients who are with bleeding or blood products such as red blood and should be to blood on the basis of hemodynamic the rate of and In crystalloid should as the after blood products for fluid resuscitation to its and safety on To no studies have the safety and of albumin use in cardiac surgical patients by and However, albumin and a such as crystalloids, are in because of its effect on Recommendation HSA infusion is to volume and albumin loss in patients with (COR LOE in during or after cardiac surgery have been with crystalloids and blood After the bleeding has been these patients often volume resuscitation and have an intravascular oncotic from albumin In postoperative bleeding and blood the systemic and of the endothelial glycocalyx in cardiac surgical In this HSA infusion is indicated to help with volume replacement, positive fluid balance, restore microvascular integrity, and reduce systemic SECTION 2: HSA is used for pump priming, volume loss, and a in oncotic pressure. Recommendation priming with HSA for blood management might be (COR LOE Recommendation priming with HSA might be in specific cardiac surgical such as those undergoing and (COR LOE priming approximately to of fluid and This priming may to a in colloid oncotic pressure and fluid which cause and as well as postoperative are used as priming fluid to help maintain oncotic pressure. However, because of the concern regarding AKI and the bleeding risk the use of synthetic has over the plasma is also not recommended as priming fluid in the because of the risk of blood However, some use HSA as a pump priming According to two HSA is used for CPB priming by approximately of healthcare in the and approximately in European have shown that priming with HSA an in and positive fluid In and a pressure the pump may inflammatory and a systemic inflammatory response, which may cause the of endothelial HSA has been to help the endothelial glycocalyx and microvascular blood with and the of and which may cause platelet on fibrin and platelet Albumin from pump priming the of the circuit and which during bypass and helps from platelet and the of other coagulation A meta-analysis of 1346 patients from 21 studies compared platelet fluid balance, and postoperative with crystalloid priming, albumin priming significantly the in the postoperative platelet 95% CI, to the in 95% CI, to during and a less positive fluid mL, 95% mL to and less postoperative 95% CI, to the pump priming with HSA has to into an improvement in the in the general cardiac surgery In the ALBICS trial, the group with pump priming of g of HSA did not compared with the group of priming with However, HSA is widely used for high-risk such as those with a and a pump studies should the benefit of HSA priming in these patients and provide evidence for this SECTION of Recommendation HSA infusion is to preoperative hypoalbuminemia in normovolemic patients (COR LOE is as serum albumin concentrations hypoalbuminemia is common among cardiac surgical and is by and hypoalbuminemia is with and adverse and albumin concentrations have been used to help assess the operative risk in cardiac surgical patients. However, exogenous HSA supplementation can improve operative is still A meta-analysis of clinical trials on surgical patients was This showed that HSA infusion significantly the incidence of postoperative complications in patients preoperative albumin was to higher than However, limited evidence is available in cardiac surgical patients. A single-center, RCT of 220 patients who underwent off-pump coronary artery bypass with preoperative albumin concentrations showed that preoperative administration of 20% albumin solution the risk of postoperative AKI vs. vs. 25.7%, P =0.048), but there was no significant effect on or other major hypoalbuminemia often in preoperative patients with and HSA infusion, should be in such patients who are of Recommendation postoperative hypoalbuminemia by HSA infusion in normovolemic patients might be (COR LOE In cardiac surgical hypoalbuminemia, operative loss, to the and hemodilution often to postoperative hypoalbuminemia. observational study of patients who underwent cardiac surgery showed that of patients had serum albumin concentrations have shown that postoperative hypoalbuminemia is with adverse HSA is used to an albumin during the postoperative to maintain oncotic pressure, tissue and maintain microvascular and In the studies should be to determine exogenous HSA the clinical of patients who have postoperative hypoalbuminemia, but not volume HSA can be used for volume replacement, pump priming, and hypoalbuminemia in cardiac surgical patients. We the recommendations for use of human serum albumin (HSA) in adult cardiac surgery in Table However, more evidence is required to this practice, regarding the improvement of clinical This expert consensus to the regarding the use of HSA during and after cardiac surgery. Table 3 - for use of human serum albumin (HSA) in adult cardiac surgery. COR LOE Volume Replacement 1 A comprehensive multimodality approach by a multidisciplinary team is recommended to minimize hemodilution during cardiac surgery. I C-EO 2 Goal-directed fluid therapy is recommended to assess the volume status and optimize fluid resuscitation during and after cardiac surgery. I B-NR 3 is to HSA following crystalloid resuscitation in patients who volume replacement during and after cardiac surgery to excessive positive fluid IIb B-NR HSA infusion might be to maintain intravascular volume and arterial pressure when is given to fluid and after cardiac surgery. or HSA is in this IIb C-LD 5 HSA is not routinely recommended as the of fluid resuscitation during and after cardiac surgery. III: No Benefit B-R HSA for fluid resuscitation in patients with and bleeding is not III: No Benefit C-EO Recommendation HSA infusion is to volume and albumin loss in patients with IIa C-EO priming with HSA for blood management might be IIb B-NR priming with HSA might be in specific cardiac surgical such as those undergoing and IIb C-EO of HSA infusion is to preoperative hypoalbuminemia in normovolemic patients. IIb B-NR postoperative hypoalbuminemia by HSA infusion in normovolemic patients might be IIb C-EO Class of Level of We from for the of a draft of this of This consensus was by the The had no in the consensus process or in the and of the or the to