Albumin vs Crystalloid Fluid for Resuscitation in Cardiac Surgery: New Evidence and Arguments in the Timeless Debate

Mihai V. Podgoreanu, Negmeldeen Mamoun

JAMA. 2022;328(3):246-248. doi:10.1001/jama.2022.10113

Adequate intravenous (IV) fluid administration is essential during and after cardiac surgery to restore circulating blood volume and improve end-organ tissue perfusion. Clinical decisions about which fluid type to use, when to use it, and in what patient populations continue to be made in the absence of consensus recommendations or practice guidelines. This uncertainty has fueled the long-standing “great fluid” debate, which evolved from a colloid-crystalloid debate after recognition of potential harm associated with synthetic colloid use among critically ill patients and among patients undergoing cardiac surgery, making albumin the colloid of choice.¹

Clinical equipoise surrounding using albumin or balanced crystalloids in cardiac surgery persists, perpetuating wide practice variation in fluid replacement strategies. Putative protective effects of albumin on endothelial glycocalyx and microvascular integrity, reduced platelet consumption, and prevention of acute kidney injury are mainly derived from preclinical or small clinical studies or extrapolated from different critically ill patient populations but have not been substantiated by high-quality evidence of its greater clinical benefit or safety profile compared with balanced crystalloid solutions in patients undergoing cardiac surgical procedures.

In this issue of JAMA, Pesonen and colleagues² report findings from the ALBICS (Albumin in Cardiac Surgery) trial and add a persuasive argument to the albumin-crystalloid debate. In this single-center, randomized, double-blind, pragmatic, superiority trial involving 1386 patients undergoing cardiac surgery with cardiopulmonary bypass, patients were randomized in a 1:1 ratio to receive either 4% albumin solution (n = 693) or Ringer acetate (n = 693) for both cardiopulmonary bypass priming fluid and perioperative IV volume replacement (intraoperative and up to 24 hours postoperatively).

The authors reported no significant difference in the 90-day incidence of major adverse events (MAEs; ≥1 of the following: death, myocardial injury, acute heart failure, resternotomy, stroke, arrhythmia, bleeding, infection, or acute kidney injury) between the albumin and Ringer groups (257 of 693 patients [37.1%] vs 234 of 693 patients [33.8%]; P = .22) and total serious adverse events (SAEs) (40.8% vs 45%, P = .13), respectively.

Exploratory analyses of individual components of the composite primary outcome revealed a lower incidence of myocardial injury (3.9% vs 8.9%; relative risk [RR], 0.44; 95% CI, 0.28-0.68; P < .001) but conversely higher incidence of bleeding (7.5% vs 4.3%; RR, 1.73; 95% CI, 1.12-2.68; P = .01), resternotomy (10.7% vs 5.8%; RR, 1.85; 95% CI, 1.28-2.68; P = .001), and infection (13% vs 8.9%; RR, 1.45; 95% CI, 1.07-1.97: P = .02) in the albumin group. Notably, increased bleeding in the albumin group was corroborated in secondary outcome analyses by higher rates of chest tube drainage (albumin group −Ringer group difference of means, 178 mL; 95% CI, 138-219; P < .001), transfusions of red blood cells (albumin group −Ringer group difference of means, 107 mL; 95% CI, 60-155; P < .001), and platelets (albumin group −Ringer group difference of means, 71 mL; 95% CI, 41-100; P < .001). Albumin was more effective for intravascular volume expansion, as evidenced by the lower total fluid balance during the intervention period (albumin group vs Ringer group difference of means, −1277 mL; 95% CI, −1433 to −1120; P < .001), even when factoring in the higher transfusion requirements.

Several aspects of the study could affect the interpretation of the findings and reduce generalizability. First, the 4% albumin solution and Ringer acetate solution used in the ALBICS trial differ from the 5% albumin and Ringer lactate commonly used in the US. Second, clinical practice surveys in the US and Europe indicate that balanced crystalloid solutions are the first choice for fluid management in cardiac surgery.³^,4 Findings from the ALBICS trial, in which albumin or crystalloid were used exclusively as cardiopulmonary bypass priming fluid and for perioperative volume replacement, will not add clinical insight on the optimal time and criteria to switch from crystalloids to colloids during cardiothoracic resuscitation or the patient subgroups that could benefit the most from such switch. The findings also do not allow definitive conclusions about the optimal cardiopulmonary bypass prime fluid, for which previous studies suggested benefit with albumin.⁵

Third, exclusion of high-risk patients (any significant preoperative organ dysfunction, hemodynamic instability), as reflected in a median EuroSCORE of 1.7, limits the generalizability of findings to a subgroup who might benefit the most from albumin. Fourth, current literature does not support the effect of albumin on some components of the composite primary outcome, such as stroke or arrhythmia. The influence on other components such as acute kidney injury is biologically plausible, but the study was underpowered to detect this outcome.

Albumin is commonly used for patients undergoing cardiac surgery in the US.³ The physiological basis for this practice includes an array of biologically plausible benefits inferred from a multitude of oncotic and nononcotic functional properties of albumin, including as a “molecular core”⁶ or as suggested from preclinical and pilot clinical studies,⁷ increased vascular integrity through microvascular endothelial protective effects (stabilization of glycocalyx structure),⁸ reductions of platelet and leukocyte adhesion, and amelioration of platelet activation. However, the clinical evidence is sparse and is based on retrospective studies in cardiac surgery cohorts that reported reduced in-hospital mortality and 30-day readmissions associated with albumin⁹ or on extrapolations from randomized clinical trials in heterogeneous cohorts of critically ill patients, including those affected by trauma or sepsis, sometimes with opposing findings but with albumin seemingly benefiting specific subgroups.¹⁰

In placing the findings of the study by Pesonen et al in context with other relevant research, it is worth pointing out that cardiac surgery is a singular example of a so-called “quadruple hit,” including controlled trauma, hemorrhage or hemodilution, exposure to nonpulsatile extracorporeal circulation, and ischemia-reperfusion injury. These events trigger a complex response in the host that only partially overlaps with those seen in patients who have experienced major trauma or who have sepsis. It has been postulated that several complications associated with cardiac surgery are potentially modifiable by choice of fluid strategy, including excessive bleeding, fluid overload, acute kidney injury, and systemic inflammatory response syndrome, among others.

The ALBICS trial is the first large interventional trial to clearly show the lack of greater benefit of albumin compared with a balanced crystalloid in cardiac surgery resuscitation in terms of effectiveness and safety. The physiological benefit of albumin attenuating crystalloid hypervolemia was reconfirmed in the ALBICS trial, but albumin was not associated with greater effectiveness for any proven clinical end points, including the incidence of organ dysfunction. Although the secondary analyses were inadequately powered and thus are exploratory (as the authors acknowledge), the findings from these analyses of individual components of the primary outcome and secondary end points suggest a potential for harm of using albumin in cardiac surgery due to the association of albumin with increased bleeding, resternotomy, transfusion requirements, and infection.

Ongoing enthusiasm for the beneficial effects of albumin in reducing postoperative bleeding, reoperation, and transfusion requirements in cardiac surgery has been fueled by comparisons with synthetic colloids (mainly hydroxyethyl starch).¹¹ Clinical findings were corroborated by hemostatic parameters (including thromboelastometry), which were significantly abnormal after administration of synthetic colloids but were unchanged with albumin,¹²^,13 leading to the premature conclusion that albumin does not impair hemostasis in cardiac surgery. However, when compared with crystalloids in a single-center retrospective analysis involving 2594 high-risk patients undergoing cardiac surgical procedures, albumin administration was associated with increased bleeding, reoperation, transfusion requirements, intensive care unit (ICU) and hospital lengths of stay, and health care expenditures.¹⁴ This is consistent with the increased bleeding, reoperation, and transfusion requirements (of red blood cells and platelets) observed in the albumin group in the ALBICS trial. The mechanistic basis for this finding remains elusive. It is particularly challenging to reconcile with the putative glycocalyx stabilization properties of albumin, which should reduce acquired platelet dysfunction through adhesion, activation, and consumption. However, the authors do not report perioperative changes in platelet count, hemostatic parameters, or any biomarkers of glycocalyx degradation.

Albumin also displays a host of immunomodulatory and anti-inflammatory effects through binding of bacterial products, modulation of antigen-presenting cell function, antibiotic transport, modulation of cytokine production, and reducing hypoxia-inducible factor-1α gene expression, all derived from in vitro studies and animal experiments.¹⁵ One small clinical study (n = 35 patients) found that albumin infusions may attenuate immune suppression and reduce the risk of infection in patients with acutely decompensated cirrhosis or end-stage liver disease by reducing circulating prostaglandin E₂ levels.¹⁶ It is therefore difficult to reconcile these theoretical benefits of albumin against the increased incidence of infection in ALBICS. The authors discuss the association between bleeding, resternotomy, and infection, supported by post hoc analyses, as a possible clinical link and reduced free concentrations of antimicrobial drugs in the albumin group through increased drug binding as a pharmacokinetic link. The latter is speculative, absent reports of perioperative albumin plasma concentrations between the study groups.

A potential mechanistic link underpinning the failed clinical translation of the theoretical benefits of albumin for both bleeding and infection outcomes may be related to known differences between endogenous and exogenous albumin. Pharmaceutical-grade albumin is highly sensitive to processing-related posttranslational modifications, resulting in proportions of oxidized albumin as high as 57% and widely variable between pharmacological preparations.¹⁷ The consequences of infusing these oxidized forms of human serum albumin to acutely ill patients are under investigation.

There is no doubt the ALBICS trial will not settle the albumin-crystalloid debate. This study raises additional important research questions for potential indications of albumin utilization in cardiothoracic resuscitation. Clinically, these revolve around timing and duration of administration in the perioperative continuum; use in cardiopulmonary bypass priming fluids vs perioperative resuscitation; criteria for switching from crystalloid to albumin resuscitation; optimal concentration; subpopulations that might benefit; effectiveness in high-risk cardiac surgical patients, including those with kidney dysfunction or requiring mechanical circulatory support; role in correcting preoperative or postoperative hypoalbuminemia; and quality control of commercial albumin products. Scientifically, the role of albumin in the repertoire of glycocalyx stabilizers needs to be clarified in adequately designed cardiac surgical translational and clinical studies.

Determining the optimal tonicity of resuscitative fluids for distinct populations of acutely ill patients, either for albumin or crystalloids, remains an area of active investigation. The ongoing Albumin Replacement in Septic Shock (ARISS) trial¹⁸ seeks to identify the effect of 20% albumin administered with prespecified temporal and serum concentration targets on survival in patients with septic shock. For patients undergoing cardiac surgery, the ongoing Albumin Infusion and Acute Kidney Injury Following Cardiac Surgery (ALBICS) trial¹⁹ is investigating the nephroprotective effects of 20% albumin infused postoperatively after high-risk cardiac surgery on acute kidney injury. Furthermore, existing evidence implicates both preoperative and postoperative hypoalbuminemia as independent risk factors for poor outcomes in cardiac surgery, including long-term survival.²⁰^,21 Although exogenous albumin substitution to correct hypoalbuminemia in critically ill patients is controversial, targeted supplementation stratified by preoperative or postoperative hypoalbuminemia deserves further investigation.

Economic analyses are challenging given fluctuating albumin costs, which are often confidential and subject to negotiations between hospitals and manufacturers. Nevertheless, a somewhat dated analysis of the cost differential between albumin and saline-based fluid resuscitation in the Saline versus Albumin Fluid Evaluation (SAFE) study²² found albumin to be substantially more expensive. As part of the Choosing Wisely initiative, a list of top-5, low-value perioperative services was developed, including avoidance of routine colloid administration for resuscitation in the absence of appropriate indications.²³ According to a 2016 report, reducing albumin utilization in the ICU has resulted in significant cost savings without affecting patient outcomes.²⁴

In an era in which fluids are recognized as drugs with indications, contraindications, and adverse effects and in a time of spiraling health care costs, the lack of effectiveness or safety benefits of hypotonic 4% albumin compared with Ringer acetate when used exclusively for cardiopulmonary bypass prime and perioperative volume replacement in elective low-risk cardiac surgery reported in the ALBICS trial adds compelling evidence against the use of albumin in this setting. Because albumin is progressively becoming a niche drug, refining the specific subpopulations of acutely ill patients who might benefit from its administration represents an important nuance of an ongoing fluid debate. However, the results from the ALBICS trial indicate that further debate is not required for 1 patient subpopulation—routine use of albumin should be avoided for patients undergoing cardiac surgery with cardiopulmonary bypass.