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The administration of human albumin as a clinical treatment for critically ill patients has been much debated in the past 20 years.1 Despite the undeniable importance of this molecule in human physiology, the publication in 1998 of a large meta-analysis by the Cochrane Injuries Group Albumin Reviewers2 highlighted a possible increased risk of death, even in categories of patients historically considered as ‘therapeutic targets’ of this treatment. Unfortunately, subsequent research on this topic did not yield full clarification, and scarcely led to evidence-based recommendations, with the exception of very few.3,4 There are two likely reasons for such uncertainty: first, the excessive emphasis on meta-analyses as a tool to achieve high-quality evidence, in association with the lack of well-designed randomised, controlled trials (RCTs); and second, the great heterogeneity characterising critically ill patients.5 Therefore, to fully understand whether human albumin may be beneficial in ICU, the appropriate strategy could be to determine specific categories of patient who may benefit from this treatment, based upon a robust physiological rationale and solid clinical evidence, and individualise its application. In parallel, because the efficacy of albumin may rely on still-unveiled relevant secondary functions, further research is warranted to pinpoint specific effects which might be clinically relevant, as it has been shown in the last few years. This approach is crucial, in terms of efficacy (favourable balance between beneficial and detrimental effects), as well as in terms of costs (favourable balance between benefits and costs). It is therefore worthwhile summarising the physiological rationale and the available clinical evidence supporting the potential benefit or harm of using human albumin in critically ill patients.
In humans, albumin is a protein presenting many crucial functions.1 In healthy conditions, the liver, under the stimulation of the neuroendocrine system and the intravascular oncotic pressure, employs about 50% of its energy expenditure for the synthesis and the secretion of 10–12g/day of albumin. Moreover, although mainly located within the intravascular compartment, albumin may pass at various degrees into the interstitial space, through a partially receptor-mediated process termed ‘trans-capillary escape rate’. Indeed, albumin is generally distributed in the entire extra-cellular space.
As a primary function, human albumin is responsible for about 80% of the intravascular oncotic pressure, thereby assuming a key role in processes regulating micro-circulatory fluid dynamics.6 In addition, specific characteristics of its molecular structure provide human albumin with important ancillary properties, with undoubtedly clinically relevant effects. Among others, the presence of cysteine residues, especially of in position 34, leading to the exposition of a thiol group (-SH radical), provides human albumin the ability of binding free oxygen radicals and nitric oxide, and therefore the ability to act as an antioxidant and anti-inflammatory agent.7,8 The presence of the specific domains I and II makes human albumin extremely important for the transportation of several molecules, both endogenous (such as electrolytes, hormones, fatty acids) and exogenous (such as antibiotics and other drugs). Moreover, the presence of 16 histidine imidazole residues confers the ability of acting as a buffer molecule within the context of acid–base equilibrium. Lately, recent evidence has suggested the potential role of albumin as a stabilising agent both for the immune system,9 and for the endothelial functions.10 On the whole, there is a strong physiological rationale to consider human albumin as a crucial molecule, both as a natural colloid, and also as a ‘drug’, with potential clinically relevant pharmacological properties.1
Human albumin has a crucial role in regulating the homeostasis of the intravascular blood compartment. Consequently, it is reasonable to consider this molecule as relevant for the haemodynamic management of critically ill patients, especially when dealing with fluid therapy. Being a natural colloid, albumin-containing solutions are generally considered more effective for intravascular volume replacement as compared with crystalloids, and similarly less prone to accumulation within the interstitial space.5 Although the classical view by Ernest Starling on the compartments’ model has recently been questioned,11 the biological rationale for considering volume replacement with colloids more effective than with crystalloids still stands. This argument becomes even more relevant when facing the recent evidence on increased risk of acute renal injury, bleeding and ultimately death, which accompanies the administration of hydroxyethyl starches, one of the most employed categories of synthetic colloids.12,13
Despite a clear rationale, no robust clinical advantages seem to justify its costs in a general un-characterised population of critically ill patients, as recently concluded by the updated edition of the Cochrane meta-analysis on the use of crystalloid and colloid solutions.14 Nevertheless, these findings do not reject the hypothesis that the oncotic properties of human albumin may have beneficial effects in specific categories of critically ill patients, or specific phase of their treatment, especially regarding the fluid therapy applied. In a post hoc analysis performed on patients with severe sepsis included in the SAFE trial, the use of 4% albumin solution was associated with an increased central venous pressure and a reduced heart rate over the first seven days as compared with crystalloids, suggesting a greater intravascular blood volume.15 Similar findings were also observed in the ALBIOS trial, which randomised patients with severe sepsis or septic shock to receive 20% albumin in addition to crystalloids or only crystalloids for fluid replacement during the first 28 days of treatment.16 Patients receiving albumin and crystalloids did show a higher mean arterial pressure and a lower daily net positive fluid balance over the first seven days of treatment, as compared with those receiving just crystalloids.
Very likely, this is the reason why, in the absence of a detrimental effect, the Surviving Sepsis Campaign guidelines for the management of severe sepsis and septic shock have included the suggestion (graded as grade 2C) of using albumin during the first phase of fluid resuscitation, especially when large amounts of crystalloids are required.17 In a meta-analysis including more than 27,000 critically ill patients and investigating the possible effects of different type of colloids (including albumin) on haemodynamics, as compared to the use of crystalloids, the use of albumin appeared to be associated with a higher mean arterial and central venous pressure, and more adequate cardiac index.18
Historically, the current evidence investigating the clinical benefits of the secondary functions of human albumin has been relatively scarce until the last decade. Certainly, the molecular specificity and complexity of some of these properties make this task difficult. Nonetheless, indirect evidence, paralleled by preliminary findings (both experimental and clinical), may provide new insights. Moreover, in the last years, specific aspects on the possible albumin ancillary properties have been investigated quite properly, leading to novel findings related to specific aspects.
On the antioxidant properties of human albumin, two different studies, one in patients with severe sepsis19 and the other in patients with acute lung injury,20 have reported increased plasma thiol levels after albumin supplementation. Moreover, such supplementation appeared to improve thiol-dependent antioxidant properties of plasma obtained from these categories of patients, suggesting a direct effect of albumin replacement on the overall plasma antioxidant capability. In addition, in a single-centre study including critically ill patients with hypoalbuminaemia, albumin supplementation for a maximal period of 28 days appeared to be associated with a reduction of the severity and the number of organ failures, indirectly suggesting a clinical benefit related to albumin secondary properties.21
More recently, O’Brien et al, in a multi-model investigation, elucidated the possible role of albumin, during cirrhosis, on the immunosuppressive effects of cyclooxygenase-derived eicosanoid prostaglandin E2 (PGE2).9 In this context, albumin administration appeared to actively reduce circulating PGE2 levels, thereby significantly improving the plasma-induced impairment of macrophage pro-inflammatory actions. Thus, albumin-containing solutions were effective in attenuating PGE2-mediated immunosuppression, and the consequent risk of secondary infections, especially in patients with acutely-decompensated cirrhosis.
Further studies have recently provided also new insights on the potential efficacy of albumin administration as a beneficial ‘tool’ to counteract infections. Del Giudice and colleagues elucidated, in a series of in vitro experiments, the effects of the exposition to hypoclorite species on the molecular structure of human albumin.21 Albumin appeared to be a molecule highly resistant to hypochlorite oxidation. At the same time, the link of hypochlorite to albumin as chloramines, appeared to be an effective way by which albumin might transfer local bactericidal activity systemically. In addition, Giacobbe et al nicely observed that hypo-albuminaemia is a strong predictor of risk for acute kidney injury during treatment with the antibiotic colistin, providing therefore the first evidence of a possible specific binding-site for colistin on albumin.23
After the publication of several meta-analyses of the possible role of albumin administration, the first large RCT (SAFE study) evaluating the safety of human albumin in critically ill patients was concluded in 2004.24 The trial enrolled approximately 7000 critically ill patients, in need of volume replacement, randomised to receive either 4% albumin or normal saline for intravascular fluid resuscitation. Mortality rate after 28 days appeared to be identical between the two groups (relative risk of death 0.99; 95% CI 0.91–1.09; p=0.87). Moreover, no differences were observed among the secondary outcomes of the study. On the whole, the study concluded that, in critically ill patients, the use of either 4% albumin or normal saline for fluid resuscitation results in similar outcomes, as originally hypothesised by the investigators, and in contrast to previous findings.
In addition to the main findings of the trial, a post hoc analysis on pre-defined subgroups identified two specific categories of patient in which a potentially different effect of the treatment applied was observed. In patients with severe sepsis, the administration of albumin was associated with a tendency towards a reduction in mortality rate (relative risk of death 0.87; 95% CI 0.74–1.02, p=0.09), whereas in patients with trauma the administration of albumin was observed to be associated with an increased risk of death (relative risk of death 1.36; 95% CI 0.99–1.86, p=0.06), especially in those with associated brain injury.24 In both subgroups, the findings did not achieve a statistical significance, but strongly suggested two important differences in the treatment effect of albumin to be further investigated.
Following the conclusion of the SAFE study, and the observation of possible harm of albumin administration in patients with traumatic brain injury, the same investigators performed a post hoc follow-up study on patients with traumatic brain injury at the time of randomisation.25 After a detailed characterisation of the brain injury at baseline, 460 patients, randomised in the SAFE study to receive either 4% albumin or crystalloids for intravascular fluid resuscitation, were followed for 24 months. Survival analysis confirmed a significant increased risk of death associated with the use of human albumin as compared to crystalloids (relative risk of death 1.63; 95% CI 1.17–2.26; p=0.003), which appeared greater in patients with severe brain injury at the time of randomisation. After a subsequent analysis, an increased intracranial pressure during the first week of treatment with albumin appeared to be the most likely mechanism associated with the increased mortality observed.26 Although these findings have been criticised,27 at the moment, patients with a traumatic brain injury are the first category of critically ill patients in which a specific and strong indication regarding human albumin administration has been achieved, including ultimately a ban on its use.
After the post hoc analysis on the pre-defined subgroup of patients with severe sepsis enrolled in the SAFE study, many investigators have focused their attention on the potential benefit of human albumin in severe sepsis or septic shock.28 The Albumin Italian Outcome Sepsis (ALBIOS) trial, the first trial focused on this category of patients, has been completed and the results published.16 This was an Italian multicentre, open-label RCT that enrolled 1818 patients with severe sepsis or septic shock from 100 Italian ICUs. Patients were randomised to receive either 20% albumin and crystalloids or crystalloids alone during the first phase of volume replacement, and targeting, during the next 28 days, albumin administration to a serum albumin concentration ≥30g/l.
The primary outcome was death from any cause at 28 days and secondary outcomes were death from any cause at 90 days, number of patients with organ dysfunction, the degree of dysfunction, and length of stay in the ICU and the hospital. During the first seven days, patients in the albumin group, as compared with those in the crystalloid group, showed a higher mean arterial pressure (p=0.03) and lower net fluid balance (p<0.001). The total daily amount of administered fluid did not differ significantly between the two groups (p=0.10).
At 28 days, 285 of 895 patients (31.8%) in the albumin group and 288 of 900 (32.0%) in the crystalloid group had died (relative risk in the albumin group, 1.00; 95% CI 0.87–1.14; p=0.94).
At 90 days, 41.1% of the albumin group and 43.6% of the crystalloid group had died (relative risk, 0.94; 95% CI, 0.85–1.05; p=0.29). No significant differences in other secondary outcomes were observed between the two groups. Nonetheless, in a post hoc, though not pre-defined, analysis, patients with septic shock receiving albumin administration showed a significant 6.3% absolute reduction in 90-day mortality compared with those receiving only crystalloids. It was therefore concluded that in patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days, and that the clinical benefit observed in those with septic shock warrants further confirmation.
More recently, based upon previous findings, the efficacy of 4% albumin administration during the early phase of sepsis was investigated, as compared to lactated Ringer administration, in patients with cancer.29 After the enrolment of 360 patients, no difference was observed in survival between the two groups at seven days (26% vs. 22%, p=0.5; primary outcome), as well as at 28 days, nor in the other secondary outcomes observed.
Further RCTs will allow us to better dissect the effects of albumin, in terms of patient characteristics (severe sepsis versus septic shock), adequate timing of treatment (early versus late), adequate trigger for albumin administration (volume versus albumin replacement), and adequate concentration of albumin solutions (20% versus 4–5%). At the moment, for patients with septic shock, two large RCTs are ongoing: one in Italy (the ALBIOSS-BALANCED – Albumin Italian Outcome Septic Shock – trial; NCT03654001) and one in Germany (the Albumin Replacement Therapy in Septic Shock – ARISS – trial; NCT03869385). Their results, which are likely to be available in few years from now, are eagerly anticipated.
There is a strong biological and physiological rationale on which it is reasonable to hypothesise a potential beneficial effect of human albumin administration in the critically ill. At the same time, the available clinical evidence is still limited. A key limiting factor is the large heterogeneity characterising the population of the critically ill. Therefore, a crucial next step will be to characterise the effects of albumin administration in specific categories of patient. Ongoing research will certainly provide future and interesting insights, which hopefully will further clarify specific and more adequate indications for the use of albumin in critically ill patients.