Abstract

Background

Sepsis, a life-threatening organ dysfunction resulting from infection, remains a common cause of death in critically ill patients [1]. Worldwide, sepsis affects over 30 million patients with approximately 5.3 million people dying per year [2], the prevention and treatment of sepsis have become a global health priority. Recently study reports that sepsis, in the USA, affects over 1.7 million patients and accounts for more than 50% of mortality in hospitals annually [3]. Due to the published guidelines for sepsis, the advance of machines, and antibiotic therapy, the mortality of sepsis has been decreased in these years, but still stayed at a high level [4– 8].

Fluid therapy, which is a cornerstone in the treatment of sepsis and associated with outcome in emergency department patients, is commonly used to restore and maintain patients’ tissue perfusion [9– 11]. For many years, the types of fluid administration regarding “crystalloids” and “colloids” is under the heated debate [12, 13]. Many prior studies have found that patients receiving colloids, compare to crystalloids, were not associated with decreased mortality [14, 15]. Only a few subgroup analyses showed that the colloids group may potentially reduce mortality [14, 16]. Therefore, crystalloids, as they are safe, inexpensive, and widely available, remain the first line of fluid administration in patients with sepsis [17]. Nevertheless, colloids, especially albumin, for its larger molecular weight, can stay longer in the intravascular space and expand the volume efficiently [18]. Hence, the combined administration that using crystalloids plus albumin for initial resuscitation and subsequent intravascular volume replacement has been widely used for septic patients in fluid therapy and was recommended by Surviving Sepsis Campaign Guidelines [19]. However, it remains unclear when albumin should be combined after the initiation of fluid therapy.

In this study, we sought to evaluate whether albumin combined within a specific time, compared to receiving crystalloids alone, would have a beneficial effect on survival in patients with sepsis. Additionally, we further examined the association of the different timing for albumin combined with crystalloids and increased survival. Since 2004, the guideline had recommended sets of bundles, for instance, 6-h, 3-h, and recently 1-h bundles [20– 23], highlighting that the treatment of sepsis is a “time matters” campaign. Considering the realizability in the intensive care unit, “within the first 24-h” might be an optimal time for the combination of albumin and crystalloids. We, therefore, hypothesized that combining with albumin within the first 24-h after initiation of crystalloids administration, would increase the survival time in patients with sepsis.

Methods

Results

The MIMIC-IV database included 11,263 adult patients with sepsis, and finally, 7519 patients were included in this study (Fig. 1). Of this study, 6597 patients had used crystalloids alone as the fluid administration (group crystalloids alone), while 920 patients received albumin combined with crystalloids for the fluid administration within the first 24-h (group albumin combination).

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Fig. 1

Study flowchart. MIMIC Medical Information Mart for Intensive Care

In total, 6641 patients were included in our analysis (Table 1), the mean (SD) age was 66.75 (16.24) years, 48.57% were female, 64.82% were white person, and 5.99% had used the renal replacement therapy (RRT). Mortality was significantly lower in the combination group than in the crystalloids group (12.5% vs. 16.4%, P = 0.003). Similarly, respiratory rate, temperature, and urine output were significantly higher in the crystalloids group than in the combination group. Compared to the crystalloids group, patients with 3 stages of AKI, higher SAPS II score, SOFA score, and serum lactate levels were more likely to combine the albumin with crystalloids as the fluid administration within the first 24 h. A larger percentage of received mechanical ventilation (71.63% vs. 43.85% P < 0.001) and the use of the vasopressors (85.43% vs. 50.52% P < 0.001) were significantly higher among the combination group. After PSM (Additional file 1: Table S1), the SMD were all less than 0.1, indicating the baseline variables in the two groups have similar distributions.

Timing of albumin and 28-day mortality

Table ​Table22 and Fig. 2a showed that, before PSM, for the first 28 days after ICU admission, patients in the combination group were expected to live 25.10 (95% CI 24.60–25.60) days vs. 23.37 (95% CI 23.12–23.61) days in crystalloids group. Patients who received combination therapy within the first 24 h after fluid administration lived, on average, 1.73 more days (95% CI 1.17–2.29; P < 0.001) than the crystalloids group over 28 days. After PSM, the KM curve is shown in Fig. 2c, and as expected, the combination therapy was associated with increased 28-day survival time (3.23 days; 95% CI 2.38–4.08; P < 0.001). The RMST analysis indicated a beneficial effect of the combination group among 28-day follow time before and after PSM. Also, the sensitivity analysis (Additional file 1: Table S2) for the distinctive type of crystalloids and albumin revealed similar results to our main analysis (Table ​(Table2).2). Similar outcomes were found across subgroups regarding age (< 60 and ≥ 60 years), gender and septic shock (Additional file 1: Table S3).

Table 2

Primary and secondary outcomes

Outcomes	Crystalloids (n = 6597)		Combination (n = 920)		Difference (95%CI)	P
	Values	95%CI	Values	95%CI
Before PSM
RMST for 28 days (days)	23.37	23.12–23.61	25.10	24.6–25.6	1.73 (1.17–2.29)	< 0.001
RMST for 60 days (days)	46.09	45.31–46.88	50.93	49.37–52.49	4.84 (3.09–6.58)	< 0.001
LOS ICU (days)	6.65	6.47–6.83	10.37	9.65–11.09	3.72 (2.98–4.46)	< 0.001
LOS Hospital (days)	14.32	13.93–14.71	19.03	18.00–20.07	4.72 (3.61–5.82)	< 0.001
Total volume of crystalloids (L)	2.37	2.27–2.41	3.11	2.84–3.40	0.78 (0.49–1.07)	< 0.001
After PSM (1:1)
RMST for 28 days (days)	22.20	21.53–22.86	25.10	24.60–25.60	3.23 (2.38–4.08)	< 0.001
RMST for 60 days (days)	42.18	40.09–44.27	50.93	49.37–52.49	9.09 (6.49–11.69)	< 0.001
LOS ICU (days)	7.73	7.25–8.21	10.37	9.65–11.08	2.64 (1.77–3.50)	< 0.001
LOS Hospital (days)	15.21	14.89–17.44	19.04	18.00–20.07	2.88 (1.24–4.52)	< 0.001
Total volume of crystalloids (L)	2.76	2.46–3.06	3.11	2.84–3.40	0.36 (-0.05–0.77)	0.085

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RMST (days) means the restricted mean survival time in each group during the first 28 and 60 days after ICU admission. The difference in RMST (95%CI) was calculated with the difference of restricted mean survival time between the two groups (RMST_combination-RMST_crystalloids), which means the increment or reduction of survival owing to the combination therapy. LOS ICU Length of ICU stay, LOS Hospital Length of hospital stay, PSM propensity score matching

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Fig. 2

Kaplan–Meier survival curve of the two groups. Shaded regions are the difference of restricted mean survival time (RMST) for two groups among 28 (a, c), 60 (b, d) days before and after propensity score matching (1:1), means the increment of survival days due to the combination therapy among 28 and 60 days. Combination group: patients who received albumin within the first 24 h after initiation of crystalloids administration. Crystalloids group: patients who received crystalloids alone as fluid therapy

Additional analysis

In total, 1671 patients had received albumin and crystalloids during the ICU. Except for 920 patients who combined albumin at 0-24 h were included in our primary analysis, 333 (19.93%) patients were combined albumin preceded of crystalloids (< 0 h) and 418 (25.01%) patients had combined with albumin greater than 24-h after crystalloids administration (> 24 h). The comparisons of the three combination group with the crystalloids group are presented in Fig. 3. Compared to the crystalloids group, significantly increased survival among the preceded combination group was shown during the 28-day (1.10 days, 95%CI 0.38–1.83) but not found in the 60-day (1.14 days, 95%CI -1.21–3.50) follow-up. For the late combination group, there were no significant survival benefits among the first 28 and 60 days (all P > 0.05). After PSM, the RMST analysis (Additional file 1:Figure S1) indicated that patients who received albumin combined in three periods (< 0 h, 0–24 h, > 24 h) resulted in a significant improvement of survival than those who received crystalloids alone. But the increased survival days (survival benefits owing to combination therapy) among the preceded combination group (< 0 h, 1.98 days) and late combination group (> 24 h, 2.25 days) decreased compared to the early combination group (0-24 h, 3.23 days) during the 28 days. Similarly, the results of a 60-day follow-up were comparable with 28 days.

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Fig. 3

Association of increased survival and the combination group before propensity score matching. The difference in days (95%CI): The difference of restricted mean survival time (RMST) between the two groups (RMST_combination-RMST_crystalloids), means the increment or reduction of survival owing to the combination therapy. The preceded combination group (< 0 h) is defined as patients who received the albumin solution as the initiation of fluid administration and subsequently combined with crystalloids. The late combination group (> 24 h) is defined as patients who received the albumin greater than 24 h after crystalloids administration

Considering the secondary outcomes of the three different timing groups (< 0 h, 0–24 h, > 24 h) and the crystalloids group. The preceded combination group (< 0 h) had a significantly less volume of total crystalloids administration during the ICU than the crystalloids group. Also, patients’ delay in combining albumin was associated with the larger volume of crystalloids infusion (1.9L vs. 3.1L vs. 3.9L in three timing). In contrast, patients in the late combination group (0.99L; 95%CI 0.88–1.11) were associated with less volume of albumin infusion compared with the early combination group (1.37L; 95%CI 1.27–1.47) and preceded combination group (1.65L; 95%CI 1.44–1.87), respectively (Fig. ​(Fig.4).4). The LOS of ICU and hospital in the crystalloids group were significantly shorter than the three combination groups (All P < 0.05). Among the three combination group, combining in 0-24 h resulted in the shortest LOS in ICU and hospital (Fig. ​(Fig.5, All5, All P < 0.05).

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Fig. 4

Total volume of fluid administration for each group. *: significant

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Fig. 5

Length of stay in ICU and hospital for each group. *: significant

Discussion

In present study, we demonstrated the association of albumin combined within 24 h after the initiation of crystalloids administration and the increased 28-day survival time. The beneficial effect of combination therapy increased along with the prolonged follow-up time. Furthermore, the additional analysis showed that the increased survival days due to combination therapy varied by different combination timing. Compare with early (0–24 h) for albumin combined, preceded combined (< 0 h) or late combined (> 24 h) of albumin resulted in less increment in survival at three follow-up time. The benefits of survival among 28-d regarding the preceded combination group and late combination group comparing the crystalloids group revealed contradictory results before and under the PSM. Despite applying the PSM or prolonging the follow-up time, the combination therapy regarding the early albumin combined was still associated with the decreased risk of mortality and also associated with the longest increment in survival among three time of combination.

Many prior studies comparing the outcomes between the “crystalloids group” and “colloids group” in septic patients suggested that initiation administration with colloids and subsequently combined with crystalloids was associated with no difference or increased mortality. Conversely, a subgroup analysis [14] that included 1121 patients with septic shock suggested that albumin was associated with a significant survival benefit among 90 days (HR = 0.87; 95%CI 0.77–0.99). The definition of the colloids group in these studies is similar to the preceded combination group (< 0 h) mentioned in our additional analysis. Patients who accepted albumin as the initiation fluid (“ < 0 h” in Fig. 3), compared to the crystalloids group, showed a slightly decreased risk of mortality among 28 days (increment in survival: 1.10 days; 95%CI 0.38–1.83) and this beneficial association vanished among the 60 days (increment in survival: 1.14 days; 95%CI-1.21–3.50). One possible explanation is that in the few hours after the recognition of sepsis, patients were going through the profound alternations in tissue perfusion as well as the related hypovolemia and needed a timely and plentiful amount of fluid therapy [9]. Receiving albumin as the initiation of fluid therapy following crystal liquids not an advisable strategy.

Nevertheless, guidelines from SSC suggest albumin in addition to crystalloids for initial resuscitation and subsequent intravascular volume replacement in patients with sepsis and septic shock when patients require substantial amounts of crystalloids (weak recommendation, low quality of evidence) [19]. Albumin exhibits antioxidant effects and positive effects on vessel wall integrity [31]. The administration of albumin raises colloid osmotic pressure and reduces vascular permeability and adhesion of leukocytes and platelets, thus limiting edema formation [32]. Moreover, a recent pilot study demonstrated the beneficial effects on skin endothelial function after albumin administration within 24 h of septic shock [33]. The endothelial dysfunction is involved in microcirculatory blood flow impairment and associated with vasomotor tone dysregulation, activation of coagulation, and glycocalyx damage, thus, the benefit of the albumin administration within 24 h may owe to its anti-oxidant properties [33, 34]. Albumin infusion also helps maintain glomerular filtration via hemodynamic and oncotic mechanisms [35]. Albumin combined with crystalloids can balance the risk of fluid-induced adverse effects, especially in patients who need large volumes [9].

Also, Ospina-Tascon et al. [36] has reported that patients receiving 4% albumin or Ringer’s lactate solution as the fluid administration in the early phase (within 24 h) would improve microvascular perfusion but not in the late phase (more than 48 h). Additionally, a previous study evaluating the effects of repeated fluid boluses showed that only the first bolus was associated with an improvement in microvascular perfusion [37]. In the late phase of sepsis, the effect of fluid administration on tissue perfusion was limited. Similarly, Bo and colleagues [38] found that a fast rate of infusion in fluid resuscitation for septic shock patients was associated with the early shock reversal (HR = 0.78; 95% CI 0.66–0.91; P = 0.010) and survival gain in 28 days (HR = 0.71; 95%CI 0.60–0.85; P < 0.001) compare to infuse slowly. Hence, we suspected that the impact of combination therapy on survival was likewise limited. In our results, as the delay of albumin combined (> 24 h), the increment in survival they induced was decreased. Especially in 60-day follow-up, there were significantly increased survival in patients who combined albumin within 24 h after the initiation of crystalloids administration but not found in those who combined among < 0 h and > 24 h (Fig. 4). Even when applying the PSM, their increment in survival days was approximately 50% of the early combination group. It should be noted that the timeliness of albumin combined in fluid administration for sepsis is essential, a longer deferred combination indicated the less improved outcomes. In addition, we need to consider the medico-economic problem of albumin. The price of a bottle of 10 g albumin is even dozens of times the price of a bag of Ringer's lactate solution. Unnecessary use of albumin can significantly increase the patient's medical expenses. In this study, we confirmed that even within 24 h, the hospitalization cost of early albumin combined with fluid therapy is significantly increased.

To date, there is still insufficient evidence to demonstrate the better beneficial effect of albumin than crystalloids in fluid administration for sepsis. Our study does not attempt to address this debate. Indeed, the type of fluid solution influences the outcomes in septic patients but the timing is of equal importance [36]. Hence, we magnify the importance of the timing for albumin combined in fluid administration. In our design, the crystalloids were the main component, and albumin was supplemented. On this basis, we divided the timing for albumin combined into several periods and examined whether different combined time influenced outcomes. Our findings raise the assumption that albumin combined with crystalloids might be beneficial for survival in septic patients when the time they combined is appropriate (0–24 h in our results). Additional analysis in our study compared the association of increment in survival and other timing for albumin combined and, which strengthening the robustness of our conclusion. A clear understanding of fluid administration may help decision-making in the treatment of sepsis, and lower the mortality in septic patients. Our conclusion is based on a retrospective database study. More prospective multi-center studies are needed in the future to further clarify the benefits of early albumin combined with crystal fluid rehydration in the treatment of patients with sepsis. Moreover, better monitoring of vasopressor usage would be a more natural improvement, as would a prospective randomization of individuals with sepsis and/or septic shock. In addition, the effects of the timing of albumin administration on the pulmonary edema, mechanical ventilation time, and intestinal function of septic patients are also needed to be analyzed, not just the 28-d case fatality rate, 28-d survival time and ICU hospital stay. Since albumin can maintain a higher colloidal osmotic pressure as combined fluid rehydration program, that may reduce crystalloid fluid intake and tissue edema, thus help to maintain the function of cavity organs such as lung and intestine.

The strength of this study was the RMST analysis. RMST was firstly proposed in 2010 and well established in Cardiovascular and Cancer studies as an alternative measure of the intervention effect [25, 39– 41]. At present, most randomized controlled trials and observational studies in critical care evaluated the intervention effect with the increment or reduction of risk utilizing hazard ratio (HR) and its 95% CI [39]. The interpretation of HR depended on the reference from the control group. Unlike the HR, the RMST analysis could intuitionally and validly quantify the mean survival benefits of a period for the combination therapy by directly estimating the area of survival curves [42]. Furthermore, when conducting the HR analysis (e.g., Cox proportional hazards model), the proportional hazard (PH) assumption should be met [43]. However, in practice, especially in critical care medicine, it’s hardly plausible to validate. In this condition, the intervention effect might not be significantly examined for the lacking of statistical power, while RMST analysis could neglect the PH assumption and maintain the stable estimation of the interventional effect [26].

There are several limitations to our study. Firstly, the use of propensity score matching may minimize the possible confounding factors but also substantially reduced the sample size of our study populations. Although all patients in the early combination group (< 24 h) were matched, and balance properties were satisfied (all SMD less than 0.1 in Additional file 1: Table S2), the distribution of matched dataset were less comparable to the original dataset, thus the conclusion of the results should be interpreted with caution. Secondly, although we had performed the propensity score matching to control the confounding, there might exist some residual confounders that would not be measured in this study. Thirdly, records of fluid administration for patients who had received before ICU admission were not stored in the database, which may mar our results. Fourth, in additional analysis, the definition of the combination group is determined by different timing for combination and its sample size is lower by the decrease of albumin combining periods, which may be skewed as the insufficient sample size. Fifth, because the data we based on is an observational database, the results reported in our study should be regarded only as of reference and must be further verified. Additional high-quality and larger sample size randomized trials are needed to investigate the optimal combination time for fluid administration and the optimal strategy to guide fluid therapy.

Conclusion

In conclusion, our retrospective study confirms that different timing of albumin combined in fluid therapy may influence survival under the propensity score matching. Compared with other timing, albumin combined within 24 h after the initiation of crystalloids administration was associated with the longest increment of survival in septic patients. Considering its inherent flaw of propensity score method, further evidence of albumin combined should be verified by additional randomized trials.

Supplementary Information

Acknowledgements

Abbreviations

Authors' contributions

SYZ and ZHZ contributed equally to this work. SYZ and SLA designed the study and drafted the manuscript. HXW and TS extracted the data from the MIMIC-IV database. ZHZ and SLA guided the literature review. All authors read and approved the final manuscript.

Funding

Dr. An reports grants from National Science and Technology Major Project (2018YFC1312803), grants from Guangdong Province (2020JGXM025), during the conduct of the study. Dr. Zeng grants from Natural Science Foundation of China (81701955), Grants from Natural Science Foundation of Guangdong Province, China (2020A151501361).

Availability of data and materials

The datasets are available in the physionet (https://physionet.org/content/mimiciv/0.4/).

Declarations

Footnotes

References