Short-term improvement in hemodynamics

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The short-term, immediate hemodynamic improvement is a primary concern for anesthetists encountering anesthetic-induced hypotension compounded by sepsis-related hypotension. As such, it was a persistent, recurring topic through much of the literature included in this evaluation. Although some studies mentioned sufficient hemodynamics indirectly through all-cause mortality, several overtly discussed the immediate effects of intravenous albumin administration.

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In perhaps the most widely known related work, the ALBIOS trial, Caironi et al. found albumin administration exhibits hemodynamic advantages when compared to crystalloid administration in patients with severe sepsis or septic shock.10 The randomly assigned 1818 patients with severe sepsis received either crystalloid alone or 20% albumin with crystalloid.10 The study showed that a significantly greater proportion of patients in the albumin group than in the crystalloid group reached targeted mean arterial pressure within 6 hours after administration.10 Additionally, during the first seven days after albumin administration, the mean arterial pressure (MAP) was higher in the albumin group, and the heart rate and net fluid balance were lower in the albumin group.10 The suspension of inotropic or vasopressor agents was also sooner, indicating a decreased use of vasopressors compared to the crystalloid group.10 It is noteworthy that a sizable portion (>43%) of the 1810 patients assigned to an experimental group were surgical patients before admission to the intensive care unit (ICU) (127 elective, 654 emergency).10

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The Wiedermann & Joannidis review highlighted a subgroup of patients with septic shock. The patients treated with albumin demonstrated a favorable negative fluid balance at an earlier stage of recovery, and hemodynamic stabilization was achieved more frequently in the first 24 hours.11 The timeframe requiring vasopressor therapy was shortened.11 The authors also refer to a separate study in which fluid balance (itself a partial reflection of hemodynamics) was linked to survival in patients with Acute Kidney Injury (our synthesis topic impact on organ dysfunction included later).11

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Martin & Bassett in their comprehensive work, revealed that in patients with septic shock, there was no difference in stroke volume index (SVI) between the albumin and crystalloid groups at the end of fluid infusion.12 Despite this, the cardiac index was considerably higher in the albumin group than in the crystalloid group (p < 0.001) within the first 24 hours and 24–48-hour periods after administration.12 The study concluded that in addition to cardiac index improvements, important hemodynamic resuscitation endpoints such as central venous pressure (CVP) and MAP were higher in patients who received albumin.12 As these measurements comprise an essential hemodynamic assessment bundle utilized by anesthetists nationwide, this knowledge is paramount.

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The FRISC trial was completed at a single center and enrolled 308 patients with cirrhosis and sepsis-induced hypotension.13 The patients were then randomized to receive either 5% albumin or 0.9% normal saline.13 The study's primary endpoint was the reversal of hypotension determined by a MAP ≥ 65 mmHg at 3 hours.13 Secondary endpoints monitored were heart rate, lactate, and urine output – all important hemodynamic attributes.13 Philips et al. concluded the reversal of hypotension was higher in the group that received 5% albumin at the end of 1 and 3 hours when compared to 0.9% normal saline (NS).13 Heart rate reduction was more significant in the albumin group than in the 0.9% NS group.13 Finally, serum lactate reduction (another essential assessment tool for assessing tissue perfusion) was better in the albumin group than in the NS group.13 A limitation to the inclusion of this study is the cirrhotic nature of the patients in the study, who not only suffered from septic shock but potentially also hypoalbuminemia.13

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In summary, the studies which focused on the short-term improvements in hemodynamics (measured through various assessments but primarily involving resolution of hypotension) revealed that early administration of colloids, such as 5% albumin was superior to crystalloid administration in patients with septic shock. Although short-term improvements in hemodynamics are critical in treating patients with septic shock, the definitive description of longer-term implications was lacking in these and other included studies. The initial search yielded many works addressing short-term improvements, but few addressed endpoints such as mortality and end-organ function. The following sections address these topics.

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All-cause mortality

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            With long-term complications being a broad and multifaceted topic, we sought to find a central theme in the literature review that addressed our concerns regarding sepsis pathophysiology and albumin administration for treating perioperative hypotension. The most longitudinally researched topic found in multiple works of our evidence search was all-cause mortality. While hemodynamic endpoints are often measured during the perioperative period and subsequent admission, all-cause mortality is most frequently examined farther from anesthetic management. The subgroups of all-cause mortality most investigated were mortality at 28 days and 90 days. Our literature review demonstrated mixed results regarding mortality, ranging from improved all-cause mortality to no statistically significant difference noted.

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The ALBIOS trial compared albumin to crystalloids and found no statistical difference in mortality at 28 or 90 days.10 The albumin group’s target was a serum albumin concentration of 30g per liter or greater until transferred from the ICU or 28 days after randomization.10 The study’s primary outcome was death at 28 days from any cause.10 The secondary outcomes were death at 90 days for any reason, organ dysfunction and degree of dysfunction, and the length of ICU and hospital stay.10 As previously observed, the patients receiving albumin had a higher mean arterial pressure (MAP) when compared to the crystalloid group. Despite this, follow-up over 90 days did not show a survival advantage in the albumin addition group.10 Of the 1,121 patients with septic shock, post hoc analyses showed mortality was lower at 28 days in the crystalloid group. However, at 90 days, the inverse was true (mortality was lower in the albumin group).10 Limitations in design lead the authors to conclude the statistically insignificant differences warrant no assertion of guidelines but instead a further investigation of clinical effects.10

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Liu et al. performed a single-center, retrospective study of adult patients admitted to a mixed medical and surgical ICU with sepsis or septic shock.14 Two groups were compared, albumin vs. non-albumin, with a 1:2 propensity score used to assess for shock-free time in the ICU as the primary outcome.14 Of the 2,732 patients diagnosed with sepsis, 286 were in the albumin group, while 549 were placed in the non-albumin group.14 Overall, no clinically significant difference in 28-day mortality, length of stay, or shock-free time was noted between the albumin and non-albumin groups.14 It is noteworthy that after further categorization in a septic shock cohort, sensitivity analysis again revealed no differences in shock time, shock-free time, or other significant albumin benefits such as mortality improvement.14

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Patel et al. performed a systematic review and meta-analysis over randomized trials of human albumin for adults with sepsis to assess the efficacy and safety of human albumin for fluid resuscitation and volume expansion.15 The authors' primary outcome measurement was all-cause mortality at the final follow-up (primarily at 90 days).15 Two independent reviewers reviewed the articles and extracted the data, including bias, methods, patients, interventions, comparisons, and outcomes.15 A total of 4,190 adult patients in the ICU with the diagnoses of sepsis, severe sepsis, or septic shock were pooled from 18 articles reporting 16 RCTs.15 After reviewing the data from the trials and excluding those at high risk of bias, the cumulative results delineated the use of albumin as part of the regimen for volume expansion and fluid resuscitation again having no significant impact on reducing all-cause mortality.15 The study states that albumin appears safe for use, but the analysis does not yet point toward recommendations for its use regarding sepsis.15 No benefit with albumin was observed after reanalysis (grouping the severe sepsis and septic shock categories).15 Again, further research is indicated by the authors, who cite that albumin supporters’ reassurance of long-term safety comes only from serious adverse event reporting and epidemiology data, which cannot entirely exclude deaths.15

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Zhou et al. investigated the timing of albumin administration and the 28-day mortality of patients with sepsis.16 The investigators placed the participants in a crystalloid or early combination group that included crystalloids and albumin administration within the first 24 hours of admission.16 Unlike the secondary hemodynamic outcomes listed, the study’s primary outcome was 28-day mortality.16 The authors found that the combination group had increased survival at day 28.16 Although the 28-day mortality was lower in the combination group, the length of ICU stay was consequently longer.16 This study ultimately concluded that the timing of albumin administration might play an essential role in the survival of septic patients, again underpinning the importance of understanding sepsis pathophysiology and the timing of the weakened glycocalyx.16 The authors also recommended further randomized trials to verify findings.16

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Rochwerg et al. reviewed multiple randomized trials that evaluated the difference between resuscitation fluids in adults with sepsis or septic shock and death.17 The reviewers took 14 studies with a combined 18,916 patients and performed a meta-analysis.17 This meta-analysis demonstrated that at the 4-node level, there was a lower mortality associated with albumin than with crystalloids.17 At the 6-node level, albumin had lower mortality than normal saline.17 The reviewers concluded that there was a decrease in mortality when septic patients were resuscitated with albumin compared to other fluids used for resuscitation.17 This was the only study of the literature review to assert a statistical significance regarding the mortality advantages of albumin. The limitation noted within this study is the low number of studies yielding low confidence levels on the key analyses.17

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Perhaps the most substantial and comprehensive work, the current Cochrane review from 2018 by Lewis et al., included mortality at 30 days and 90 days in their albumin or FFP vs. crystalloid analysis.18 The authors found all-cause mortality had little or no difference at 30 days (addressing 11 studies, one of which is also delineated here – the ALBIOS trial).18 The same outcome was described within 90 days (also addressing the same 11 studies).18 As appears to be the pattern, the authors end their conclusions with the hope that three ongoing studies and seven awaiting classification will improve the certainty of the evidence.18 It is noteworthy that the Cochrane review does address other complications beyond mortality, including several adverse events (allergic reactions, itching, rashes), and again noted little or no difference between groups; however, this outcome is limited by the number of studies (1), and lack of perioperative setting inclusion.18

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Unlike the prior section, in which the short-term hemodynamic benefits are clear and supported almost unanimously, the same confidence is not seen with all-cause mortality at either interval. Since mortality is a central theme to almost every comparison article and is the direct determinant of longevity, anesthetists working in short-term implications must understand the more extended, bigger picture. While immediate improvement of hemodynamics may present a temporizing improvement in overall perioperative stability, the astute anesthetist is aware that the effect on mortality is unclear. An additional long-term measurement of anesthetic success is listed next.

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Potential Renal Implications

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The topic of organ dysfunction development also appeared routinely in the evidence, albeit somewhat differently from the clearly outlined topics mentioned previously. Many differing variables of organ function were measured, some as direct as Acute Kidney Injury (AKI), yet others as ambiguous as the frequency of Renal Replacement Therapy (RRT) implementation. The differing variables placed part of the burden of interpretation on the shoulders of the reader to ascertain the results' implications in this topic. For this reason, there is comparatively less reliability in the recommendations regarding organ dysfunction illuminated in this section; however, there are several clear and important points to delineate.

Wiedermann and Joannidis, in their narrative review, concluded that in the subgroup of patients with septic shock, albumin has nephroprotective possibilities through an array of actions.11 These actions included limiting risk factors for developing an acute kidney injury (AKI) such as hypoalbuminemia, preventions of fluid overload, and prevention of the detrimental effects of heme related to tumor necrosis factor and reactive oxygen species.11 The examined studies showed that patients with hypoalbuminemia who received albumin had improved organ function.11

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Wiedermann’s separate review of RCTs found evidence that hyperoncotic albumin supported renal safety compared to an increase in adverse renal events in artificial hyperoncotic colloids.19  In the review, Wiedermann also found that using albumin and furosemide positively affected the duration of mechanical ventilation and maintenance of organ function compared to furosemide and placebo.19 These effects were thought to be from albumin decreasing fluid overload, reducing hypoalbuminemia, and the scavenging effects of reactive oxygen species.19

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Tseng et al. reviewed 20 trials with 4512 participants regarding surgical patients and fluid resuscitation volumes.20 The authors found that in patients with sepsis, isotonic albumin was associated with reduced incidents of AKI.20 Hyperoncotic albumin, however, was not associated with a decrease in the incidence of AKI.20 The authors posit that hyperoncotic albumin leads to higher osmotic pressures, which may contribute to worsened kidney damage compared with isooncotic albumin.20 Balance crystalloids were cited as requiring fewer red blood cell transfusions than hyperoncotic albumin administration.20 Interestingly, it was also found that balanced crystalloid also reduced the incidents of AKI statistically slightly better than isotonic albumin.20 However, isotonic albumin effectively restored intravascular volume in septic patients with increased vascular permeability fluid loss.20  The authors, who find mixed results, acknowledge that overall, with sepsis patients receiving balanced crystalloids and isooncotic albumin, there is a reduced risk of acute kidney injury compared to starches and hyperoncotic albumin.20 However, no significant differences are seen in surgical patients without sepsis.20 The authors carefully note that balanced crystalloids required the largest volume for fluid resuscitation among all fluid types.20

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In a 2021 retrospective study, Ge et al. addressed the association between albumin administration and acute kidney injury.21 The authors totaled 12,884 patients from a database who fit the description of sepsis and utilized 2,861 in septic shock with acute kidney injury who were either administered an albumin infusion (891) or did not receive albumin infusion (1970).21 After propensity score matching, the authors concluded that no significant correlation was found (SOFA) between albumin administration and renal function recovery.21 In a subgroup analysis, however, the authors suggested that albumin administration compared with crystalloids "might" be better in older populations of septic shock patients with acute kidney injury.21 The authors theorized that older populations' reduced vascular response and compliance might be associated with reduced albumin volumes to maintain vascular tone.21

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In the ALBIOS trial, Caironi et al. investigated several secondary outcomes, including the incidence of new organ failures.10 It is noted that higher sequential organ failure assessment (SOFA) scores were noted with albumin in the coagulation and liver categories.10 The converse was noted in the cardiovascular category, in which the crystalloid group appears inferior.10 The authors offer reflections on differences in intravascular expansion, possibly explaining the SOFA score discrepancies, but ultimately conclude that the incidence of new organ failure in the two groups was similar.10

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As with the previous section, multiple works in the evidence agree and disagree on various organ dysfunction endpoints. However, most of the studies agree that there is more need for research on using albumin in septic patients and its advantages or disadvantages on organ dysfunction. As the anesthetist is the critical decisionmaker regarding perioperative hemodynamics, this final point is critical to remember.