In this meta-analysis of 13 trials incorporating 3,127 patients, treatment with AFT compared with CFT indicated a significant disadvantage in terms of in-hospital mortality, renal failure and pancreatic necrosis with relatively strong evidence. Additionally, the incidence of respiratory failure seems to be higher in the AFT subgroup with average age > 50 years. In the sensitivity analysis, omitting one study at a time yielded no significant change in the above outcomes with the remaining studies.
Simultaneously, we found no significant difference in organ failure, persistent SIRS within 24 h or LOS; however, pooled estimates from the sensitivity analysis were changed after excluding the study conducted by Warndorf et al. Although this study fulfilled the inclusion criteria and the risk of bias assessment indicated that the study was high quality, there were several potential factors relevant to the statistical alteration. Two important differences displayed in this study were an FV less than 4,000 ml and unbalanced sample sizes in both study arms. In addition, the calculated standard deviation of LOS may not be normally distributed. As a result, if the factors were indeed shown, a significant difference in estimates for organ failure and persistent SIRS could be found, and AFT was potentially related to the increased incidence of organ failure and persistent SIRS in the subgroup of patients aged > 50 years. Nevertheless, the LOS data remained inconclusive, possibly due to the nonnormal distribution published by two other studies[16, 30].
In the evolution of AP, there are multiple factors, including vomiting, fluid loss in the third space, and reduced oral intake, that could induce hypovolemia. Following the progression of hypovolemia, pancreatic microcirculation could be disturbed, with the result being the release of multiple inflammatory cytokines and pancreatic ischemia and multisystem organ failure. Therefore, improved splanchnic hypovolemia and inhibition of the early inflammatory cascade are the fundamental goals of AFT. In particular, the study published by Buxbaum et al. showed obvious clinical improvement and a decreased incidence of persistent SIRS in the AFT group. However, these findings should be viewed with caution due to the limited or unbalanced sample sizes and the mild severity of AP.
Broader implementation of aggressive fluid treatment should be more cautious according to this meta-analysis. The recommendations for AFT from previous guidelines[5, 6] were mainly based on observational trials, expert opinions and experimental findings. A number of studies[12, 13, 16, 19] reported important outcomes in line with the recommendations in recent years. However, AFT is commonly accompanied by visceral edema and excessive chloride, which may contribute to intra-abdominal hypertension and impaired renal function, and both of these results can affect each other simultaneously[34, 35]. In addition, rapidly increasing intravenous volume did not change oxygen delivery and oxygen consumption, even though cardiac output was remarkably improved. This type of pathological event might be caused by the hemodilution-induced decrease in hematocrit, which was noted as a risk factor the development of organ failure and pancreatic necrosis. Therefore, clinical advocation for CFT has received general attention because of the non-neglectful improvements in pulmonary/renal failure, pancreatic necrosis, and mortality[15, 17, 18, 29, 31, 38, 39]. Adverse events, which decreased as described above, are potentially related to prior underlying pathology, and the study reported by Warndorf et al might be the best proof of this. Overall, given the estimated homogeneity and significant of the results, our findings strengthen the hypothesis that CFT is not inferior to AFT.
Since the first meta-analysis on aggressive fluid resuscitation for AP by Gad et al., additional evidence to support the benefit of fluid therapy has not been reported, even though the report indicated potential inferiority of AFT without exact statistical significance. Although we agree with the standpoints from the study, some deficiencies remain that are worthy of attention. First, a lower fluid rate threshold of 3–5 ml/kg/h in the first 24 h was defined as aggressive fluid resuscitation, which was inconsistent and not specific to prior guidelines that declared aggressive FR as being higher than 10 ml/kg/h or FV as being higher than 4000 ml within 24 h. More than two-thirds of the included studies were observational studies, which means that is impossible to refine an immutable FV to an exact FR per hour per kilogram. Second, the included studies enrolled two potentially overlapping trials published by Buxbaum et al.[13, 40] and Mao et al.[15, 17] without definite reason. Exaggerative outcomes were possibly generated due to this deficiency. Third, for the meta-analysis of SIRS, data were extracted without differentiation of the stage prior to and posttreatment. The study tried to analyze the influence of fluid therapy; however, data[14, 31] extracted from the stage prior to treatment should not be regarded as the therapeutic effect. Consequently, our group was motivated to further investigate the benefit of fluid therapy.
The following limitations of our meta-analysis should be taken into account. The main limitation is that more than half of the included trials were observational studies, and the remaining 5 RCTs were conducted with small sample sizes. Although in-hospital mortality is unlikely to be influenced by a lack of blinding due to the complex dynamic evaluation, this evidence, which was rated as having a high risk of bias, should be interpreted with caution due to the small-study effect. The subgroup analysis yielded some significant outcomes compared to the original analysis, indicating unstable endpoints because of a specific study. In addition, most of the present studies did not separate the severity of AP to investigate the benefit of AFT versus CFT. Some previous studies[43–45] suggested that the type of fluid also played an important role in the prognosis of pancreatitis; however, our research could not completely distinguish the types of liquids used and perform a subgroup analysis. Future systematic analyses should evaluate the severity of AP and fluid type when sufficient data are available.
Overall, this meta-analysis is the first report of the disadvantage of AFT and found a timely, conclusive outcome as data have accumulated and become available for inspection by meta-analytical theory. A broad strategy was used to identify eligible studies to increase the sensitivity of the study. Detailed sensitivity and subgroup analysis were performed to minimize the heterogeneity of every outcome. Therefore, up-to-date information was provided in our research.