Introduction
Acute pancreatitis (AP) is one of the most common causes of gastroenterology-related hospitalization and is associated with substantial morbidity and poor outcomes.[ 1–4 ] AP is graded as mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP) based on the presence of organ failure and local or systemic complications according to the Revised Atlanta Classification.[ 5 ] There is currently no effective drug therapy available for AP; supportive treatment is the cornerstone in AP management, especially early fluid resuscitation within 12–24 h after disease onset, considering that fluid deficits are one of the main causes of pancreatic necrosis, systemic inflammatory response syndrome (SIRS), or even organ failure.[ 6,7 ]
However, although various guidelines recommended that patients with AP receive aggressive fluid resuscitation (AFR) rather than controlled fluid resuscitation (CFR), the optimal fluid resuscitation rates described in previous studies including several randomized controlled trials (RCTs) in the past decade have been inconsistent.[ 8–11 ] High-quality studies were rare until the recent publication of the WATERFALL trial (the Early Weight-Based Aggressive vs. Non-aggressive Goal-Directed Fluid Resuscitation in the Early Phase of Acute Pancreatitis : an Open-Label Multicenter Randomized Controlled Trial), which provided new evidence for this topic and suggested that early AFR resulted in a higher incidence of fluid overload without improvement in clinical outcomes.[ 12 ]
Therefore, we aimed to conduct a systematic review and meta-analysis of RCTs to compare the efficacy and safety of AFR vs. CFR in people with AP, thus providing current evidence in this field.
Methods
This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.[ 13 ] The study protocol was prospectively registered on PROSPERO (https://www.crd.york.ac.uk/PROSPERO/
Literature search strategy The literature search was performed in the following electronic databases from inception to September 30, 2022, with the keywords including "pancreatitis," "fluid therapy," "fluid resuscitation," and "randomized controlled trial" for relevant RCTs: Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library. CENTRAL and MEDLINE search strategy see supplementary file 1 and 2 [https://links.lww.com/CM9/B548
Inclusion and exclusion criteria The inclusion criteria were as follows: (a) RCTs published in any language; (b) adult participants aged 18 years or older; (c) diagnosis of AP according to the revised Atlanta classification[ 5 ] ; (d) AP without organ failure on admission before fluid treatment, as the primary aim of our study was to test whether early fluid resuscitation (before AP with organ failure) can prevent AP progression by reducing the risk of SAP, organ failure and local complications; and (e) fluid resuscitation rates were defined based on the hydration strategies of previous studies and clinical guidelines in AP.[ 9,14–17 ] The intervention measure for AFR (the aggressive group) was defined as fluid administration at a rate of 20 mL∙kg-1 ∙h-1 bolus followed by an infusion at 3 mL∙kg-1 ∙h-1 or rapid hemodilution with hematocrit (HCT) <35%, while CFR (the controlled group) was defined as fluid administration at a rate of 1.5 mL∙kg-1 ∙h-1 with or without a bolus of 10 mL/kg according to the volume evaluation or slow hemodilution with HCT ≥35%.
The exclusion criteria were as follows: (a) patients who suffered from organ failure at disease onset before fluid treatment; (b) studies of fluid therapy for prevention of post-endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis; (c) studies of non-RCTs such as observational cohort studies, case-control studies, case series, and case reports; (d) studies that did not clearly define the rate of fluid administration; (e) studies without sufficient data or duplicate publications; (f) studies published without full text.
Types of outcome measures Primary outcomes
Efficacy outcome: The development of SAP was characterized by persistent organ failure ( >48 h) with or without local complications based on previous studies.[ 5,12 ]
Safety outcomes: (a) Fluid overload; (b) Hypovolemia.
a. Fluid overload was defined as the presence of heart failure symptoms, signs, or hemodynamic-imaging evidence with acute respiratory distress syndrome (ARDS) excluded.
b. Hypovolemia was defined by the presence of low blood pressure, renal injury, elevated blood urea nitrogen, HCT, signs and/or symptoms of dehydration.
The detailed criteria for fluid overload and hypovolemia were based on previous studies.[ 18,19 ]
Secondary outcomes
(1) In-hospital mortality; (2) ICU admission; (3) length of hospital stay; (4) development of persistent (>48 h) SIRS[ 20 ] ; (5) development of respiratory failure; (6) development of renal failure; (7) development of local complications; (8) development of sepsis.[ 21 ]
Selection of studies and data extraction Two reviewers (ZY and YZ) independently screened the titles and abstracts of relevant studies and included potentially eligible articles. Subsequently, the full texts of the included articles were reviewed based on inclusion and exclusion criteria. Then, two reviewers (TH and WH) extracted all relevant data from the included studies. Disagreements among reviewers were resolved by discussion.
Statistical analysis Measures of treatment effect
We performed a meta-analysis and used RevMan (version 5.4.1, Cochrane Training, London, United Kingdom) for the statistical analysis. A random-effects model was used to poor data from the eligible trials, and the DerSimonian and Laird method was used to estimate the between-study variance. For continuous data, we extracted the mean value and standard deviation (SD) of the changes in each arm of the trial, along with the total number in each group. We used mean differences (MDs) with 95% confidence intervals (CIs) to calculate effect sizes. If the data were reported as the median, the minimum and maximum values, and/or the first and third quartiles, we transformed the data to means value and SD to pool results in a consistent format.22,23] For dichotomous data, we calculated effect sizes as risk ratios (RRs) with 95% CIs.
Assessment of risk of bias and certainty of evidence
Two review authors (TH and WH) independently assessed the risk of bias for each study and recorded it in the "Risk of bias" tables. The risk of bias of RCTs was assessed using the Cochrane Collaboration Risk of Bias tool in the RevMan version 5.4.1 (Cochrane Training, London, United Kingdom).[ 24 ] The risk of bias for each study was determined via discussion among the reviewers.
We applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess the certainty of the evidence for the main outcomes, including the primary outcomes and several secondary outcomes as in-hospital mortality, ICU admission, and development of persistent SIRS.
Assessment of heterogeneity and subgroup analysis
We utilized the I 2 statistic to measure heterogeneity among the RCTs. We considered an I 2 ≥60% to indicate moderate to substantial levels of heterogeneity. If I 2 >80% (substantial heterogeneity), we did not plan to perform the meta-analysis but instead present the results using forest plots without pooled estimates.[ 24 ] We planned to explore the potential sources of heterogeneity by performing subgroup analyses. Based on the time interval (TI) between disease onset and fluid treatment, the subgroups were classified as AP with TI no more than 24 h at baseline (AP with TI ≤24 h) vs. AP with TI more than 24 h at baseline (AP with TI >24 h).
Assessment of reporting biases
We planned to assess reporting bias qualitatively based on the characteristics of the included studies rather than using funnel plots, as there were fewer than 10 included RCTs.
Trial sequential analysis (TSA) TSA was used to control the risk of random errors and assess the conclusions in the meta-analysis. Based on previous clinical experience and RCTs in this field, we used an anticipated risk reduction of 30.0% with a power of 80% to calculate the required sample size. Boundaries in the figure included conventional boundary, trial sequential monitoring boundary and futility boundary. We assessed the clinical significance of primary outcomes according to the position relationship among the cumulative Z curve and these boundaries.[ 25 ]
Results
Search results and study characteristics As shown in Figure 1 , we identified 1501 records from four databases, of which 301 duplicated studies were excluded. Another 1195 articles were also excluded because they did not meet the selection criteria. Five RCTs were included in this meta-analysis.[ 12,14,26–28 ] Table 1 shows the details of the included studies. A total of 481 participants were enrolled in this meta-analysis, with 233 participants in the AFR and the remaining 248 participants in CFR.
Figure 1: PRISMA flowchart represents the flow of information through the different phases of the systematic review and meta-analysis. AP: Acute pancreatitis ; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCTs: Randomized controlled trials.
Table 1 -
Characteristics of the included studies in the systematic review of fluid resuscitation methods in AP.
First author
(publication year)
Patients, n (AFR/CFR)
age, years,
mean ± SD (AFR vs . CFR)
M/F, n
(AFR vs . CFR)
AFR
CFR
Fluid type
Ap with TI
≤24 h
Ap with TI >24 h
Wu 2011[28 ]
19/21
51.0 vs . 51.0*
12/7 vs . 10/11
A bolus of 20 mL/kg→3 mL∙kg–1 ∙h–1
1.5 mL∙kg–1 ∙h–1
LR+NS
Y
N
Buxbaum 2017[14 ]
27/33
44.4±13.7 vs . 45.3±12.3
21/6 vs . 24/9
A bolus of 20 mL/kg→3 mL∙kg–1 ∙h–1
A bolus of 10 mL/kg→1.5 mL∙kg–1 ∙h–1
LR
Y
N
Cuéllar-Monterrubio 2020[27 ]
43/45
36.7 ±15.9 vs . 38.6±15.1
13/30 vs . 18/27
A bolus of 20 mL/kg→3 mL∙kg–1 ∙h–1
1.5 mL∙kg–1 ∙h–1
Ha
N
Y
Angsubhakorn 2021[26 ]
22/22
46.4 ± 15.0 vs . 45.0 ± 15.0
18/4 vs . 16/6
A bolus of 20 mL/kg→3 mL∙kg–1 ∙h–1
A bolus of 10 mL/kg→1.5 mL∙kg–1 ∙h–1
LR
Y
N
de-Madaria 2022[12 ]
122/127
56.0±18.0 vs . 57.0±17.0
54/68 vs . 68/59
A bolus of 20 mL/kg→3 mL∙kg–1 ∙h–1
1.5 mL∙kg–1 ∙h–1 with/without a bolus of 10 mL/kg
LR
Y
N
*Median value. Abbreviations: AP: acute pancreatitis ; AFR: aggressive fluid resuscitation group; CFR: controlled fluid resuscitation ; M/F: male/female; TI: time interval;NM: not mentioned; Y: yes; N: no; HCT: hematocrit; LR: Lactate Ringer's solution; NS: normal saline; Ha: Hartmann's solution; Mixed: NS and/or LR as well as plasma, hydroxyethyl starch.
Risk of bias and summary of main findings The risk of bias in eligible studies were shown in Figure 2 . All RCTs had some concerns of bias. Due to the nature of fluid therapy and investigation, blinding of participants and study investigators seemed impossible. Therefore, the risk of performance bias was high in all five RCTs although three RCTs did not describe blinding.[ 14,26,27 ]
Figure 2: Methodological quality of included studies according to the Cochrane Collaborations' tool for assessing the risk of bias. (A) Risk of bias summary; (B) Risk of bias graph.
We assessed the quality of evidence for the main outcomes mentioned above using the GRADE methodology which was shown in Table 2 .
Table 2 -
Summary of main findings (Population: patients with AP; Intervention: AFR; Comparison: CFR).
Outcomes
Anticipated absolute effects* (95%CI)
Relative effect(95%CI)
No. of patients(studies)
Quality of the evidence (GRADE)
Risk with AFR
Risk with CFR
Development of SAP
99 per 1000
53 per 1000 (50 to 195)
RR 1.87 (0.95 to 3.68)
437 (4 randomized controlled trials)
⊕⊕⊕○Moderate†
Fluid overload
0 per 1000
44 per 1000 (0 to 0)
Not estimable
353 (3 randomized controlled trials)
⊕⊕○○Low†‡
Hypovolemia
95 per 1000
97 per 1000 (31 to 289)
RR 0.98 (0.32 to 2.97)
437 (4 randomized controlled trials)
⊕⊕⊕○Moderate†
In-hospital mortality
0 per 1000
4 per 1000 (0 to 0)
Not estimable
437 (4 randomized controlled trials)
⊕⊕○○Low†‡
ICU admission
68 per 1000
14 per 1000 (18 to 263)
RR 5.05 (1.31 to 19.75)
289 (2 randomized controlled trials)
⊕⊕○○Low†§
Development of persistent SIRS
98 per 1000
106 per 1000 (50 to 193)
RR 0.93 (0.47 to 1.83)
441 (4 randomized controlled trials)
⊕⊕⊕○Moderate†
*The basis for the assumed risk is the average control group proportion across all comparison; † downgraded one level for small sample size; ‡ downgraded one level for inconsistency; § downgraded one level for wide confidence interval. CI: confidence interval; RR: relative risk. ⊕and ○: Four ⊕ and zero ○ represent high quality of evidence while one ⊕ and three ○ represent very low quality, low quality and moderate quality are among them. High quality: further research is very unlikely to change our confidence in the estimate of effect; Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate, low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality: we are very uncertain about the estimate; AP: acute pancreatitis ; SAP: severe AP; AFR: aggressive fluid resuscitation ; CFR: controlled fluid resuscitation ; SIRS: systemic inflammatory response syndrome; GRADE: working group grades of evidence.
Effect of Interventions on Outcomes
Primary outcomes The development of SAP
Four RCTs assessed the development of SAP. Meta-analysis revealed that there was no significant difference between AFR and CFR (RR: 1.87, 95% CI: 0.95–3.68; P = 0.07; I 2 = 2%; n = 437; RCTs = 4; moderate quality of evidence) [Figure 3A ].
Figure 3: Forest plots illustrating primary outcomes: (A) Development of SAP; (B) hypovolemia. AFR: Aggressive fluid resuscitation ; CFR: Controlled fluid resuscitation ; CI: Confidence interval; SAP: Severe AP.
Safety outcomes: fluid overloadThere was one RCT with 249 participants that reported fluid overload events.[ 12 ] The results showed that AFR was related to a significantly higher rate of fluid overload than CFR (RR: 3.25, 95% CI: 1.53–6.93; P <0.01; I 2 not applicable; n = 249; RCTs = 1). Another two RCTs (n = 60 and n = 44) recorded no events of fluid overload in either AFR or CFR[ 14,26 ] while the other RCTs did not assess this safety outcome.[ 27,28 ] The quality of evidence was low.
Safety outcomes: hypovolemiaFour RCTs assessed safety outcomes as hypovolemia. Meta-analysis revealed that there was no significant difference between AFR and CFR in the incidence of hypovolemia (RR: 0.98, 95% CI: 0.32–2.97; P = 0.97; I 2 = 61%; n = 437; RCTs = 4; moderate quality of evidence) [Figure 3B ].
TSA for primary outcomes
For the development of SAP and hypovolemia, TSA revealed that the required information sizes were 2581 and 7753, respectively. Neither of the cumulative Z curves for these two primary outcomes crossed the conventional boundary and the futility boundary, suggesting that more studies were required for conclusive results [Supplementary Figure 1,https://links.lww.com/CM9/B548
Secondary outcomes In-hospital mortality
Only one RCT reported in-hospital mortality, and it found that there was no significant difference between AFR and CFR (RR: 4.16, 95% CI: 0.47–36.73; P = 0.20; I 2 not applicable; n = 249; RCTs = 1) with a wide CI.[ 12 ] Another two RCTs reported no in-hospital mortality during treatment,[ 14,27,28 ] and one RCT did not report this outcome.[ 26 ] The quality of evidence was low.
ICU admission
Two RCTs assessed ICU admission. Meta-analysis revealed that AFR led to a higher incidence of ICU admission than CFR with a wide CI (RR: 5.05, 95% CI: 1.31–19.45; P = 0.02; I 2 = 0%; n = 289; RCTs = 2; low quality of evidence) [Figure 4A ].
Figure 4: Forest plots illustrating secondary outcomes: (A) ICU admission; (B) length of hospital stay; (C) development of SIRS. AFR: Aggressive fluid resuscitation ; CFR: Controlled fluid resuscitation ; CI: Confidence interval; SD: Standard deviation; SIRS: Systemic inflammatory response syndrome.
Length of hospital stay
Four RCTs assessed the length of hospital stay. Meta-analysis revealed that AFR led to a significantly longer length of hospital stay than CFR (MD 0.88, 95% CI: 0.25–1.50; P = 0.006; I 2 = 0%; n = 421; RCTs = 4) [Figure 4B ].
Development of persistent SIRS
Four RCTs assessed the development of persistent SIRS after fluid therapy. Meta-analysis revealed that there was no significant difference in this outcome between AFR and CFR (RR: 0.93, 95% CI: 0.47–1.83; P = 0.83; I 2 = 20%; n = 441; RCTs = 4; moderate quality of evidence) [Figure 4C ].
Other secondary outcomes
Meta-analysis revealed that there was no significant difference between AFR and CFR in the development of persistent organ failure (RR: 1.97, 95% CI: 0.51–7.61; P = 0.83; I 2 = 63%; n = 377; RCTs = 3) [Supplementary Figure 2A,https://links.lww.com/CM9/B548 P = 0.14; I 2 = 0%; n = 377; RCTs = 3) [Supplementary Figure 2A,https://links.lww.com/CM9/B548 P = 0.32; I 2 = 0%; n = 377; RCTs = 3) [Supplementary Figure 2B,https://links.lww.com/CM9/B548 P = 0.33; I 2 = 0%; n = 377; RCTs = 3) [Supplementary Figure 2C,https://links.lww.com/CM9/B548 P = 0.26; I 2 not applicable; n = 249; RCTs = 1) with a wide CI.
Subgroup analysis Further subgroup analyses were performed for the safety outcomes as hypovolemia due to heterogeneity.
There was no significant difference between AFR and CFR for hypovolemia in the subgroup of AP with TI ≤24 h (RR: 1.19, 95% CI: 0.25–5.66; P = 0.83; I 2 = 73%; n = 349; RCTs = 3). One RCT was included in the subgroup of AP with TI >24 h and there was also no significant difference in the incidence of hypovolemia between AFR and CFR (RR: 0.63, 95% CI: 0.16–2.47; P = 0.51; I 2 not applicable; n = 88; RCT = 1) [Supplementary Figure 3,https://links.lww.com/CM9/B548
Discussion
This systematic review and meta-analysis included all RCTs that examined the efficacy and safety of aggressive vs. controlled resuscitation in AP. The results showed that there was no significant difference in the development of SAP and hypovolemia between aggressive and controlled resuscitation, while aggressive resuscitation may lead to a higher incidence of fluid overload than controlled resuscitation. In addition, aggressive resuscitation had an adverse effect on secondary outcomes such as ICU admission and length of hospital stay. The quality of evidence for the main outcomes was low to moderate due to the paucity of included studies and heterogeneity. TSA suggested that more studies were required for precise conclusions.
Compared with previous meta-analyses published in 2020 and 2021, our review first included all relevant RCTs especially with the recent WATERFALL study, suggesting that CFR was superior to AFR with respect to both safety and efficacy outcomes; and the current results were basically consistent with the findings of previous meta-analyses on the efficacy of fluid resuscitation.[ 29,30 ] However, our findings were inconsistent with those of a recent meta-analysis of RCTs published in September 2022, which suggested that an aggressive hydration protocol may be more effective than a standard hydration protocol in patients with MAP.[ 31 ] We speculated that different targeted patients might influence the results as our review focused on AP without organ failure at disease onset before fluid treatment rather than patients with MAP who showed a self-limitation process. Moreover, different retrieval databases may also influence the results as several included RCTs in that meta-analysis were searched from the database as China National Knowledge Infrastructure (CNKI) and published in local journals in the Chinese language, which seemed to have inappropriate methodology according to previous studies.[ 32 ] Certainly, large-sample studies were needed to confirm the results, as the current study had a limited sample size of present studies. In addition, the results of our review responded to the need for caution with respect to early aggressive resuscitation proposed by the American Gastroenterological Association (AGA) guidelines,[ 9 ] which was recommended by various guidelines.[ 8,10,11 ]
Moreover, our review was mostly consistent with the findings of the recent WATERFALL trial (n = 249) about the same topic published in September 2022.[ 12 ] Our review assessed fluid overload and hypovolemia rather than fluid overload alone as safety outcomes due to the presence of fluid deficits and vascular permeability in AP.[ 6 ]
In addition, the results of our review were also supported by previous studies that suggested that aggressive resuscitation was related to worse outcomes, such as increased intra-abdominal pressure, acute lung injury, acute renal failure, and mortality in AP, especially under critically ill condition due to accumulation of excess fluid in the body.[ 33–35 ]
Nevertheless, the present study had several limitations. First, the main limitation was the small number of included studies and patients. Thus, future large-sample studies were required to confirm the results, as indicated by the TSA. Second, we did not include patients with AP and with organ failure on admission before fluid treatment which was associated with substantial mortality because we aimed to test the efficacy of fluid therapy to reduce the risk of organ failure and local complications. Future studies were needed to examine these specific subpopulations. Third, precise indicators for hypovolemia should be assessed considering interference from the disease itself. For example, acute kidney injury was suggested as an indicator of hypovolemia in the WATERFALL trial and was reported to be related to acute kidney injury in previous studies.[ 19,36 ] Central venous pressure (CVP) seemed to be a considerable indicator of hypovolemia in AP, especially SAP.[ 37–39 ] Finally, we did not discuss other factors of fluid resuscitation, such as different routes and types of fluids due to a lack of data.[ 40 ]
In conclusion, for AP patients without organ failure on admission before fluid treatment, our meta-analysis suggests CFR may be superior to AFR with respect to both efficacy and safety outcomes (low to moderate quality of evidence). Large-sample, prospective, multicenter studies are needed to determine a more tailored rate of fluid resuscitation in AP, especially for specific subpopulations.
Acknowledgments
The authors would like to thank Dr. Tao Wang and Dr. Yabing Wang for their invaluable advice in the preparation of this manuscript.
Funding This research received financial support from the National Natural Science Foundation of China (Nos. 32170788, 82070665, 82200722), the National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-B-023), and the National key clinical specialty construction project (No. ZK108000).
Conflicts of interest None.
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