In general, our research is the first clinical investigation concentrating on the role of albumin infusion in the hospital outcomes of patients diagnosed with acute pancreatitis since 2008. Through a retrospective cohort of 950 contemporary acute pancreatitis patients from the MIMIC-IV database, our research showed that the infusion of human serum albumin (HSA) was not associated with hospital or ICU mortality in acute pancreatitis patients with ICU admission and significantly prolonged their hospitalization and ICU duration. This result was independent of whether the patient had a positive bacterial culture result. In subsequent subgroup analyses, albumin infusion still did not affect the patients' prognosis with significant hypoalbuminemia (< 2.5 g/dL), while even tended to have an adverse effect on group of patients with near-normal (3.0-3.5 g/dL) initial serum albumin levels. A cohort from the eICU database partially supported these results above after being PSM matched (104 patients).
Acute pancreatitis is characterized by local, systemic inflammatory and immune responses, leading to organ failure even death in severe cases. Subsequent fluid extravasation in the third space is one of the critical reasons for the severity of the disease[1, 6, 27]. In current guidelines, adequate fluid resuscitation was considered an essential step of the initial treatment in severe acute pancreatitis patients. As indicated, the goal-directed therapy advised a resuscitation rate of 5-10 mL/kg/h to avoid the potentially detrimental influence that improper fluid replacement might cause. While as for the type of fluid, study evidence with high confidence is still scarce. Only several RCTs with small sample size concluded that Ringer's lactate solution had an unconfirmed benefit in reducing the chance of SIRS (systemic inflammatory response syndrome) and C-relative protein concentrations compared with normal salina[7–10, 29].
Though the value of colloids was not confirmed in the therapy of acute pancreatitis, it has been demonstrated that HSA required less fluid than crystalloid solutions to provide effective fluid resuscitation. On the other hand, some studies had also shown that hypoalbuminemia negatively influenced acute pancreatitis patients' prognosis significantly[14, 30]. For the reasons above, the doctors were accustomed to apply the albumin infusion to increase colloidal osmotic pressure and improve hypoalbuminemia in clinical practice. However, the actual association between albumin infusion and acute pancreatitis patients' prognosis has not been confirmed by clinical studies so far.
To confirm the influence of HSA infusion on acute pancreatitis, we designed the research. Our primary study cohort was extracted from MIMIC-IV (v1.0), published on March 16, 2021. MIMIC-IV was a newly-updated version of MIMIC-III, which had been improved on numerous aspects. In MIMIC-IV, the patients' data from 2008 to 2019 could better reflect the current diagnosis and treatment of diseases and provide better suggestions for the current clinical practice. Our research also used data of acute pancreatitis patients from the eICU database. The eICU Collaborative Research Database (v2.0) contained clinical data of patients with ICU admission from 208 hospitals in 2014 and 2015. In our study process, we applied the MIMIC-IV cohort as our primary analysis group, while the eICU cohort after PSM matching was applied as an external verification.
In our study, patients in the albumin infusion group showed a more severe disease state than the other group, which could be indicated by discrepant parameters such as higher SOFA, SAPS II scores, lower serum albumin level, and lower mean arterial pressure. This phenomenon was consistent with the clinical decision strategy often made by doctors previously analyzed. The Alb group showed a poorer prognosis in K-M survival analyses, and this survival difference disappeared after balancing covariates between treatment groups by PSM or IPTW methods. Furthermore, after including covariates from multiple clinical aspects of each patient, multivariate Cox regressions still showed no correlation between albumin infusion and patients' in-hospital prognosis before and after matching. In addition, through multivariate linear regressions, we found that intravenous albumin infusion was associated with a longer hospital length of stay and ICU duration. It seemed that albumin infusion could not benefit the prognosis of acute pancreatitis patients. This is consistent with previous studies[31–38]. Since the meta-analysis study of increased mortality rates in patients who received albumin solutions was first reported in 1998, more and more well-controlled RCTs have concentrated on the actual benefit of human serum albumin in specific patients groups. One of the most influential prospective studies, published in 2014, was a multi-centre trial of 1,818 patients with severe sepsis, which concluded that the addition of albumin did not improve the 28- or 90-day mortality compared with crystalloids alone. Another trial, including 193 cirrhotic patients with infection other than SBP (spontaneous bacterial peritonitis) in 2015, also negated the benefit of albumin infusion in overall patient survival and improvement of renal failure. The plausibility of our results was strongly supported by many prospective studies that had concluded similar opinions with other specific patients groups in recent years[33–38]. We also performed an external validation with a cohort of 104 well-matched acute pancreatitis patients from the eICU database to strengthen our conclusion. Similar to the results of the MIMIC-IV cohort, albumin infusion continued to have no beneficial effect on primary and secondary outcomes in patients with acute pancreatitis through K-M survival analysis and multivariate Cox regressions.
To further support our results, we also conducted well-developed subgroup and sensitivity analyses. Patient's initial serum albumin level was likely to influence the study results from clinical practice, and we performed subgroup analyses for patients with different first measured serum albumin level after ICU admission. According to our results, even among acute pancreatitis patients with obvious hypoalbuminemia (< 2.5 g/dL), albumin infusion still had no statistically significant advantage on patients' outcomes before and after matching. This finding was consistent with a large meta-analysis study published in recent years that there was no evidence albumin infusion improved prognosis in critically ill patients with baseline hypoalbuminemia. Moreover, compared with other subgroups, albumin infusion had a negative effect on the prognosis of patients whose initial serum albumin level was 3.0-3.5 g/dL. This phenomenon might be explained by the body's self-compensation mechanism, which suggested that albumin infusion might be even more discouraged in acute pancreatitis patients where albumin levels are near normal. It has been proved that early bacteraemia and secondary pancreatic or peripancreatic necrosis might result in sepsis with a poor prognosis in acute pancreatitis patients. Thus, we performed a subgroup analysis of patients with positive blood or peritoneal fluid bacterial cultures, and the results were robust with the primary analysis. As mentioned above, the role of albumin infusion in sepsis patients has been extensively studied in recent years. The current consensus was that the benefit of albumin in improving the prognosis of patients with sepsis relative to crystalloid remained unclear, which was consistent with our results. Our study also considered the possible impact of the total albumin infusion dose on the results as the sensitive analysis. According to the results, albumin infusion was not a beneficial factor, regardless of the total dose.
The initial management of acute pancreatitis included not only adequate fluid resuscitation but also effective nutritional support. Current guidelines mainly recommended enteral feeding because of its beneficial role in nourishing the intestinal barrier, preventing bacterial translocation and reducing the probability of SIRS when compared with conventional parenteral nutrition[1, 6, 40, 41]. On the other hand, serum albumin level was also an important indicator to evaluate the nutritional status of patients. In combination with our findings, it was not difficult to conclude, due to the irrelevance of intravenous albumin infusion to patient prognosis, our study might emphasize the importance and necessity of enteral nutritional support for patients with acute pancreatitis from another perspective.
There were still several limitations in our research. First, the estimation bias was unavoidable as a retrospective study due to complex confounding factors in actual clinical treatment that could not be considered, though we had already significantly reduced the bias by several ways of adjustment and well-developed subgroup analysis. Large-scale, well-controlled RCTs are still desperately required to reach a more convincing conclusion. Secondly, due to the limitations of the MIMIC-IV and eICU database, the clinical indicators reflecting the possible benefits of drug administration were still insufficient, resulting in the possibility to neglect the potential beneficial effects of albumin infusion for patients with acute pancreatitis. For example, previous studies had reported significant hemodynamic advantages of albumin infusion in patients with sepsis, although improvement in patients outcomes was also not observed. In addition, the MIMIC-IV database was still unable to obtain data on patients' out-of-hospital survival status due to inadequate follow-up time, which might result in our study ignoring the possible positive influence of albumin infusion on patients' long-term survival.