Intravenous human albumin has been used broadly and extensively for many years as nonwhole blood (purified blood component) plasma replacement fluid to correct intravascular hypovolemia and hypoalbuminemia in perioperative and critical care settings, despite the fact that the current evidence supports albumin administration only in limited clinical scenarios.1–6 In fact, the practice of albumin administration for critically ill or acutely hypovolemic patients, as evidenced by the literature, appears to be more custom or institutionally driven rather than evidence-based.3,7
Some of the current indications for albumin administration include spontaneous bacterial peritonitis, hepatorenal syndrome, large-volume paracentesis, and plasmapheresis, though albumin is also frequently administered in other clinical settings without strong evidence for benefits.8,9 However, the potential and perceived benefits of albumin administration need to be cautiously weighed against its potential harm, which includes pulmonary edema and coagulopathy. Specifically, and relevant in a neurosurgical context, is the recent evidence suggesting that the combination of albumin and mannitol impairs in vitro whole blood coagulation and platelet function.10,11 One should also consider the cost-effectiveness of albumin administration when its benefit is unclear, given the 100-fold price difference between an equal volume of albumin and crystalloid as determined in one cost-analysis.3
The purpose of this narrative review is to describe the physiological rationale (or lack thereof) for the use of albumin in various clinical scenarios, to describe the mechanisms by which albumin exerts its effects, and to examine the clinical evidence that exists to-date for and against the use of albumin in various neurological states and in those patients presenting for various neurosurgical interventions.
PHYSIOLOGICAL PROPERTIES OF ALBUMIN
Albumin accounts for 50% of total body protein, with a total mass of 4 to 5 g/kg in an average healthy adult.12,13 It has a molecular weight of 66,500 Da and distributes relatively evenly between intravascular and extravascular spaces.2 The average biological half-life of albumin is 15 to 19 days.13–15 Albumin is produced in the liver at a rate of 10 to 12 g/d in a healthy adult and is eliminated by intracellular lysosome proteases via uptake into endocytic vesicles at a similar rate.2,4,16,17 As albumin makes up 75% of total plasma oncotic pressure (ie, ∼22 to 28 mm Hg), it contributes only trivially to the total normal plasma osmotic pressure of 5545 mm Hg.12,18–20 Despite the plasma oncotic pressure exerted by albumin constituting only 0.5% of total plasma osmotic pressure, albumin plays a critical role in the maintenance of fluid dynamics in the peripheral circulation. This is because the intravascular compartment is surrounded by a semipermeable membrane that permits free movement of water and electrolytes (but not albumin), making the subendothelial glycocalyx space a low-protein environment relative to the intravascular compartment.
The peripheral vasculature at the microscopic level is composed of a nonfenestrated capillary, made up of a continuous basement membrane and a single layer of endothelial cells with “clefts” between the cellular junctions. On the endoluminal side of the capillary is the endothelial glycocalyx layer that covers these “clefts.” The endothelial glycocalyx layer allows fluid and electrolytes, but not larger proteins, to traverse, making the subendothelial glycocalyx space (which is considered intravascular space) relatively “protein-poor.” Protein does, however, enter the interstitial space via endocytosis and exocytosis. This phenomenon renders the albumin content in the interstitial and intravascular space relatively equal, while the subendothelial glycocalyx space contains little albumin. Thus, the transcapillary membrane pressure gradient is primarily determined by the hydrostatic pressure and plasma oncotic pressure—which in turn is determined mostly by serum albumin—as per the Starling principle.21
Conversely, with an intact blood-brain barrier (BBB) where only water—but not electrolytes and albumin—can move freely between the 2 compartments due to endothelial tight junctions, the transcapillary membrane pressure gradient is determined only by the serum osmolality.12,22 Hence, with an intact BBB, changes in albumin concentration and the associated changes in plasma oncotic pressure would theoretically have little effect on brain bulk so long as serum osmolality remains unchanged. This histologic property of the BBB is the rationale for the clinical observation that the brain is “protected” from cerebral edema even when large volumes of isotonic crystalloids are administered.22,23 However, when the BBB is disrupted, as is the case with cerebral tumors, trauma, and ischemic insults or hemorrhagic transformations, movement of most large proteins, ions, and the transcapillary flux of solutes tends to occur in a simple concentration-dependent fashion into the brain extracellular fluid space and subsequently into the neuronal intracellular space. Without the benefit of an intact BBB, and with the loss of endothelial tight-junction integrity, there is a real and clinically observed potential for sometimes severe cerebral edema, owing to the free water which must subsequently follow an increase in intracellular osmotically active particle concentration (Fig. 1).
In addition to its role in maintaining plasma oncotic pressure, albumin has important transport properties for numerous endogenous substances and drugs. It also plays a critical role in maintaining the integrity of the endothelial glycocalyx and protecting the microvasculature via its anti-inflammatory, antiapoptotic, and antioxidant effects.25 Albumin also appears to have neuroprotective effects according to several preclinical studies.26–29 Nonetheless, the administration of intravenous human albumin to the critically ill patient—despite multiple purported secondary effects—does not always translate into observable improvements in clinically relevant outcomes.
COMMERCIAL PREPARATIONS OF ALBUMIN
The commercial preparations of albumin vary depending on manufacturers and countries of origin. However, all are derived from human plasma and subjected to multiple steps of viral inactivation and pasteurization at 60°C for 10 to 12 hours.13,30 “Processed” albumin is then diluted with free water and 0.9% saline for injection to create the desired concentration. The albumin solution is then adjusted to physiological pH with the addition of neutralizing and stabilizing agents, and the resultant pH can vary greatly from 6.4 to 7.4.13,15,30 No preservatives are added in the process.
In North America, the most readily available concentrations are 5% and 25% albumin, while other concentrations are commercially available in other parts of the world. 5% albumin solution contains ∼145 mEq/L of sodium, although this can vary from 130 to 160 mEq/L, even among solutions produced by the same manufacturer, depending on the volume of diluting solutions and additives used.15,30 Chloride concentration also varies significantly between each commercial albumin preparation.31 For the most part, most 5% human albumin solutions are approximately iso-oncotic and isotonic to human plasma (Table 1).15,30,32
TABLE 1 -
Physiological Properties of Commercial Preparations of Intravenous Human Albumin Compared With Human Plasma and Commonly Used Crystalloid Solutions
|Norma saline 0.9%
*Calculated based on 3.2 mg/mL of Na+ as reported in product monograph.
Cl− indicates chloride; Na+, sodium; NR, not reported.
CLINICAL INDICATIONS AND USAGE
Acute Ischemic Stroke (AIS)
Stroke is the second leading cause of death worldwide, accounting for ∼10% of total deaths in both low-income and high-income countries.33 AIS accounts for ∼87% of all strokes.33,34 Several preclinical studies involving iatrogenic cerebral ischemia in rodent models have demonstrated neuroprotective effects of 25% albumin administration with the improved cerebral microcirculatory flow, decreased cerebral edema, reduced infarct size, and improved neurological scores.26–28 Furthermore, retrospective human studies have demonstrated that low albumin levels on admission were associated with a higher incidence of hemorrhagic transformation in patients with AIS who received intravenous thrombolysis.35 In light of the available evidence, prospective efforts were made to determine if albumin administration would offer neuroprotective effects for AIS patients in the clinical setting.
The Albumin in Acute Ischemic Stroke (ALIAS) Part 1 trial was designed as a double-blinded, multicenter, randomized controlled trial, where patients with AIS were randomized to receive either 2 g/kg of 25% albumin or an equal total volume of 0.9% saline over 120 minutes, within 5 hours of stroke.36 Patients otherwise received conventional care, including thrombolytic therapy if indicated. The study, however, was suspended prematurely after an interim safety analysis revealed an increased incidence of pulmonary edema and higher 30-day mortality in the albumin group. The study design was subsequently modified for the ALIAS Part 2 trial to incorporate additional exclusion criteria and new safety measures.37 The pooled analysis of the data from the ALIAS Part 1 and Part 2 trials—with a combined sample size of 1275 patients—showed no difference in 90-day modified Rankin Score between AIS patients who received 25% albumin and those who received 0.9% saline.38 Although there were no differences in mortality or the incidence of symptomatic intracranial hemorrhage between groups, there was an increased risk of congestive heart failure within 48 hours in the albumin group (relative risk=7.7, 95% confidence interval [CI]: 3.87-15.57). On the basis of this clinical evidence, many practitioners have deemed the administration of 25% albumin in the setting of AIS to be unwarranted, if not potentially harmful. Indeed, the European Society of Intensive Care Medicine (ESICM)—based on current evidence—recommends strongly “against the use of high-dose (20% to 25%) albumin in acute ischemic stroke patients” in its most recent consensus and clinical practice recommendations.39 Furthermore, the ESICM recommends the use of crystalloid as the preferred maintenance fluid of choice and recommends against the use of low-dose (4%) or high-dose (20% to 25%) albumin in neurointensive care patients—including those with AIS—as resuscitation fluid in the setting of hypotension.
Aneurysmal Subarachnoid Hemorrhage (aSAH)
aSAH is associated with significant morbidity and mortality, with the majority of patients developing vasospasm and delayed cerebral ischemia following the initial aneurysm rupture.40–42 On the basis of preclinical evidence supporting the neuroprotective effects of albumin in experimental ischemic stroke models, some investigators have explored the potential effect of albumin in preventing secondary injury following aSAH.26–28
Animal studies have demonstrated the potential beneficial effects of albumin administration in experimental subarachnoid hemorrhage,26–29 and a human retrospective study identified albumin administration following aSAH as an independent predictor for the improved neurological outcome at 3 months.43 In addition, the incidence of new neurological deficits, cerebral infarcts, and mortality were also noted to be higher among aSAH patients with lower plasma albumin levels as compared with a cohort with higher plasma albumin levels.44
The Albumin in Subarachnoid Hemorrhage (ALISAH) Trial was an open-label, dose-escalating, nonblinded, multicenter pilot study designed to determine the feasibility and safety of albumin administration in aSAH patients.45 In this study, 47 aSAH patients were allocated in a dose-escalating design to receive either 0.625, 1.25, 1.875, or 2.5 g/kg/d of 25% albumin for 7 days. The study was terminated after recruiting 47 patients; 20 patients to each of tiers 1 and 2 dosages and 7 patients to the tier 3 dosage. Recruitment was terminated as there were 2 serious adverse events (ie, pulmonary edema) reported among patients receiving the tier 3 dosage that were thought to be related to albumin administration. Patients receiving 1.25 g/kg/d for 7 days demonstrated better neurological outcomes—as defined by modified Rankin Score and the Glasgow Outcome Scale—as compared with patients receiving the lower dose of albumin and with historical controls from the Intraoperative Hypothermia for Aneurysm Surgery (IHAST) study.46 Follow-up analysis of the ALISAH patients also demonstrated that there was a propensity (not statistically significant) toward better neurological outcomes—as defined by the incidence of delayed cerebral ischemia, vasospasm detected by transcranial Doppler, and cerebral infarctions seen on computed tomography scan—in patients receiving the higher dose of albumin as compared with those receiving the lower dose.47
Of note, the findings from the ALISAH Trial should be interpreted with caution as this was a dose-escalating study with a primary objective of testing for the feasibility and safety of albumin administration, and to determine the maximum tolerated dosage of exogenous albumin. Given its limited sample size, the study was not powered to examine the potential beneficial effects of albumin in aSAH, nor was this its stated primary outcome. Thus, a large randomized, placebo-controlled trial would be necessary to determine the neuroprotective effects of albumin in the setting of aSAH.
Intracerebral Hemorrhage (ICH)
Spontaneous, nontraumatic ICH is associated with significant mortality, with a reported incidence as high as 59% at 1 year.48,49 Given the potential neuroprotective effects of albumin in preclinical studies, along with retrospective data demonstrating the association between low albumin level on admission and worse neurological outcome in patients with ICH, study efforts have been directed toward examining albumin as a potential therapy to prevent secondary brain injury in ICH.26–28,50 The Albumin for ICH Intervention (ACHIEVE, NCT00990509—not completed) study—a randomized, placebo-controlled trial—was intended to examine the potential neuroprotective benefits of albumin in the setting of ICH. However, the study was terminated in 2014 due to low recruitment following the move of the principal investigator to another institution.51 Thus, to date, it is unclear if albumin administration would be beneficial in patients with spontaneous, nontraumatic ICH.
While the merits of albumin administration for rapid and effective volume replacement in the setting of acute blood loss during major spine surgery has been established, thereby minimizing the amount of free water accumulation that can be observed with crystalloid resuscitation, issues related to the role of colloids in averting potential visual disturbances in spine surgery have been more pressing in modern anesthetic practice and the recent literature.52 Postoperative visual loss (POVL) is among the most devastating complications associated with prone-position spine surgery. Though POVL was reported as early as the 1950s, this complication only began to gain widespread attention, both within the perioperative community and lay medical press, in the 1990s.53,54 As the result of a perceived increase in POVL, presumably due in part to the staggering increase in the overall number of spine surgeries performed, the American Society of Anesthesiologists (ASA) established the ASA POVL Registry in 1999 with the intention of building a database to facilitate analysis of risk factors associated with POVL.
The most common cause of POVL after spine surgery is ischemic optic neuropathy, with posterior ischemic optic neuropathy being more common than anterior ischemic optic neuropathy in the perioperative setting.55,56 The estimated incidence of ischemic optic neuropathy after spine surgery was initially reported to be ∼0.1%, although the incidence has decreased to 0.01% in more recent years.57–59 The complex pathophysiology of ischemic optic neuropathy is postulated to be related to the combination of intraoperative hypotension, decreased hematocrit associated with blood loss, an excess of positive fluid balance, and position-dependent venous congestion with resultant increased intraocular pressure and concomitant decreased ocular perfusion pressure, ultimately resulting in impaired perfusion of the optic nerve.54,60,61
In a multicenter, case-controlled study by the POVL Study Group, 80 patients with ischemic optic neuropathy after spine surgery from the ASA POVL Registry were matched with 315 control patients without ischemic optic neuropathy.62 Multivariate regression analysis identified several risk factors associated with the development of ischemic optic neuropathy following spine surgery. However, one protective factor was identified, namely the use of colloids, which has an odds ratio of 0.67 per 5% of colloid used for total nonblood volume replacement (95% CI: 0.52-0.82, P<0.001). It has been theorized that colloid administration may reduce edema formation associated with crystalloid administration, as a lower volume of colloid may be administered to achieve the same hemodynamic endpoints as compared with crystalloid.62,63 This study, though observational and retrospective in design, represents the best clinical evidence to date supporting the use of albumin for preventing POVL in spine surgery, as conducting a randomized controlled trial would not be feasible given the extremely low incidence of ischemic optic neuropathy. Of note, a case series has shown that ischemic optic neuropathy may still occur in spine surgeries despite the intraoperative administration of a significant volume of colloid.56
Farag et al64 conducted a randomized controlled trial comparing the administration of 5% albumin to Ringer lactate on intraocular pressure during posterior spine surgery.64 It was hypothesized that goal-directed albumin administration would result in less volume shift from the intravascular space to interstitial tissues and thus lower intraocular pressure as compared with goal-directed crystalloid administration. In this randomized study of 60 patients, the intraocular pressure at the end of anesthesia was significantly lower in the albumin group when compared with the Ringer lactate group (36 vs. 40 mm Hg, difference=−5.02, 95% CI: −9.56 to −0.47, P=0.03). While the evidence is far from conclusive, the findings of this study provide support to the previously proposed notion that albumin administration may be protective from POVL in spine surgeries by virtue of avoiding the administration of excessive volume of free fluid and a concomitant increased intraocular pressure that may compromise optic nerve perfusion.
As stated by the ASA Practice Advisory for Perioperative Visual Loss Associated with Spine Surgery 2019, taskforce-appointed experts and the participating stakeholders generally agree with the recommendation that either crystalloids or colloids, alone or in combination, may be used to maintain adequate replacement of intravascular volume in spine surgery.65
Traumatic Brain Injury (TBI)
Approximately 69 million individuals sustain a TBI each year worldwide.66 TBI is an umbrella term representing a spectrum of disease that is heterogenous in its etiology, pathology, and outcome, making it difficult to study the potential neuroprotective effect of any single intervention.67,68
The Saline versus Albumin Fluid Administration (SAFE) trial was the first study to shed light on the use of albumin in TBI patients. The SAFE trial—a multicenter, randomized, double-blinded trial involving 6997 critically ill patients who were randomized to receive either 4% albumin or 0.9% saline for 28 days from the time of intensive care unit (ICU) admission—showed that there was no significant difference in mortality, rates of organ failure, duration of hospital stay, duration of ICU stay, duration of mechanical ventilation, and duration of renal replacement therapy between the 2 groups.63 The SAFE-TBI study—a post hoc, follow-up analysis of patients from the SAFE trial who had TBI—identified 515 eligible patients, of which 420 were included in the final analysis of the primary outcome.69 The 2-year mortality was significantly higher among the TBI patients receiving 4% albumin as compared with those receiving 0.9% saline (33.2% vs. 20.4%, relative risk=1.63, 95% CI: 1.17-2.26, P=0.003), with the majority of death occurring within the first 28 days (26.4% vs. 15.7%, relative risk=1.68, 95% CI: 1.16-2.43, P=0.005). It is important to note that the difference in mortality was observed only in severe TBI patients (Glasgow Coma Score 3 to 8) and not among those with Glasgow Coma Score 9 to 12. TBI patients who received 4% albumin also had higher intracranial pressure in the first week following the injury as compared with TBI patients who received 0.9% saline (19.2±1.07 vs. 15.4±1.06 mm Hg, P=0.01), suggesting that the increased intracranial pressure from cerebral edema may have been contributory to increased mortality in the albumin group.70
The findings from the TBI-SAFE study should be interpreted with caution, taking into account the limitation of a post hoc subgroup analysis, recognizing that TBI is an umbrella term representing a spectrum of a heterogenous pathology, and considering that the increased mortality associated with 4% albumin administration was observed only among those patients with severe TBI.69,70 Furthermore, it should also be noted that the 4% human albumin (Albumex 4; CSL Behring, Melbourne, Vic., Australia) used in the SAFE study—conducted in 16 academic centers in Australia and New Zealand—has different properties than the 5% human albumin formulations that are commonly used in North America.13 According to the CSL Behring product monograph, the nominal osmolality of its 4% human albumin preparation is 260 mOsm/L—substantially lower than the plasma osmolality seen in a healthy adult (Table 1). Therefore, TBI patients who were randomized to receive 4% albumin in the SAFE-TBI subgroup did, in fact, receive a relatively hypotonic solution from the time of randomization until death, discharge from the ICU, or 28 days postrandomization. Conversely, though the results have not been consistently demonstrated, animal studies involving experimental brain injuries have shown that the administration of multiple doses of mannitol—another potent osmotically active agent—could aggravate brain edema in the setting of BBB disruption, where the accumulation of mannitol in the parenchymal tissue resulted in osmotic shifting of free water into the brain.71–75 On the basis of these observations, the question is raised regarding the mechanism underlying the increased intracranial pressure and increased mortality observed in patients receiving 4% albumin in the SAFE-TBI subgroup. The potential mechanisms might include (1) leakage of albumin through a disrupted BBB in a similar fashion to that observed with mannitol, resulting in increased intraparenchymal oncotic pressure and ultimately increased cerebral edema, (2) the relative hypotonicity of the 4% albumin solution resulting in cerebral edema from osmotic shift, or (3) an intrinsic property of albumin that aggravates cerebral edema.22 A recent experimental study involving healthy adult ewes showed that the administration of hypotonic 4% albumin resulted in a significant increase in intracranial pressure, while the administration of isotonic 4% albumin and 0.9% saline did not significantly change intracranial pressure.76 Although the safety, or lack thereof, of albumin administration in TBI patients, cannot be presumed based on this study, the question of the pathophysiology behind the increased intracranial pressure and increased mortality observed, both in such animal models and with regard to the patients in the SAFE-TBI study, might be most suitably framed in relation to the tonicity of the fluid administered.
Intracranial Tumor Resection
To date, there is no preclinical or clinical evidence to support or advise against the use of albumin for intracranial tumor resection, where BBB disruption occurs either by virtue of surgical resection of brain tumor and normal tissue or with preexisting oncological BBB disruption as manifested by the occurrence of vasogenic edema.77 One concern regarding the use of albumin in these patients that has been postulated is the potential accumulation of albumin in parenchymal tissue in the setting of BBB disruption, causing intracerebral fluid shift and cerebral edema due to increases in intracellular oncotic pressure. As mentioned previously, some animal studies have shown that multiple doses of mannitol likely aggravate cerebral edema due to the accumulation of the substance in the brain parenchyma, though this is not consistently demonstrated in other animal studies.71–75 Ostensibly, albumin could have the same effect, by a similar pathophysiological mechanism. Conversely, in a rat model with TBI and disruption of the BBB, at 3 hours postinjury, 90 mL/kg crystalloid administration, but not 50 mL/kg of crystalloid or 20 mL/kg of albumin administration, resulted in cerebral edema, lending support to the notion that perhaps the total administered volume of solution is more critical than the actual composition of the solution in contributing to cerebral edema.78 This might support the use of albumin in non-TBI craniotomy for tumor resection, from a purely physiological rationale, as it could potentially reduce the total fluid volume that is being administered to maintain euvolemia. This same study, however, found that at 24 hours, the albumin cohort accumulated less overall edema than the 2 crystalloid groups, giving some support to the notion that the higher oncotic pressure associated with albumin helps to reduce brain edema in the setting of TBI in the long run. Clearly, future clinical studies with a randomized, case-controlled design and clinically meaningful endpoints are necessary to address and answer the clinical question of the safety and efficacy of albumin administration in the intracranial tumor resection population.
Currently, high-quality human evidence to support or reject the administration of albumin across the spectrum of neurological diseases and in the perioperative period of neurosurgical procedures is lacking. The few existing large-scale studies regarding the use of albumin in these clinical settings have shown that albumin administration may, in some cases, result in harm to patients with AIS and TBI. Even in complex, multilevel posterior spine surgery, where albumin administration is possibly indicated, this recommendation is derived from a retrospective, observational, case-controlled study.62 The clinician is urged to exercise caution in interpreting these data, which are often preclinical, as the proposed neuroprotective effects of albumin in animal models have not translated consistently to human clinical studies. In contrast, one should also recognize that each of these neurosurgical diseases represents a heterogenous group of processes and patients and that it cannot be ruled out that a subset of patients with one of these neurosurgical diseases would in fact benefit from albumin administration. At this moment, in the absence of definitive data to either support or dissuade from the use of albumin in most neurosurgical scenarios, practitioners should consider the potential risks and benefits of albumin administration, based on its purported physiological effects and the scarce literature available, on a case-by-case basis when justifying its use.
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