A meta-analysis of Lactate Ringer's solution versus Normal Saline in the treatment of acute pancreatitis

Abstract

Fluid resuscitation is an important way in the treatment of acute pancreatitis (AP). This meta-analysis aimed to compare the safety and efficacy of Lactate Ringer's solution (LR) and Normal Saline (NS) in the treatment of patients with acute pancreatitis. Searched in PubMed, Web of Science Core Collection (Clarivate), Embase, Cochrane Library, CNKI, China Wanfang, and China VIP database. All randomized controlled clinical trials (RCTs) were identified. Six studies with 431 patients were included. Compared with NS, LR can significantly reduce the incidence of SIRS at 24 h, reduce the length of hospitalization, moderate–severe AP, ICU admission and local complications, especially pancreatic necrosis. It is safe and effective to choose LR for fluid resuscitation in AP, but due to the small number of included studies, multi-center and large-sample RCTs are still needed for further verification.

PROSPERO registration number: CRD42022322788.

Resumen

La reanimación con fluidos es una forma importante en el tratamiento de la pancreatitis aguda (PA). Este metaanálisis tuvo como objetivo comparar la seguridad y eficacia de la solución de Ringer de lactato (LR) y la solución salina normal (NS) en el tratamiento de pacientes con pancreatitis aguda. Se realizaron búsquedas en PubMed, Web of Science Core Collection (Clarivate), Embase, Cochrane Library, CNKI, China Wanfang y China VIP database. Se identificaron todos los ensayos clínicos controlados aleatorios (ECA); se incluyeron seis estudios con 431 pacientes. En comparación con la NS, la LR puede reducir significativamente la incidencia de SIRS a las 24 horas, reducir la duración de la hospitalización, la PA moderada-grave, el ingreso en la UCI y las complicaciones locales, especialmente la necrosis pancreática. Es seguro y eficaz elegir LR para la reanimación con fluidos en la AP, pero debido al pequeño número de estudios incluidos, todavía se necesitan ECA multicéntricos y de muestra grande para una verificación adicional.

Introduction

Acute pancreatitis (AP) is a common clinical acute abdomen, mainly manifested as acute onset of severe abdominal pain. It is one of the leading causes of hospitalizations for gastrointestinal diseases worldwide.¹ It is characterized by severe morbidity and high mortality, leading to the admission of many patients to intensive care units (ICU). The global incidence of AP is reported to be increasing at a rate of 3.07%,² which fully demonstrates that AP is posing a huge threat to people's lives and health. According to the revised Atlanta classification method in 2012,³ mild acute pancreatitis (MAP) has a low case fatality rate and usually resolves spontaneously within a week. Moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) are often accompanied by systemic inflammatory response syndrome (SIRS), persistent organ failure, and high mortality. Therefore, early implementation of intervention measures for AP becomes particularly important.

Studies have found that AP patients receiving aggressive fluid resuscitation at an early stage have more improvements in clinical symptoms and can reduce persistent SIRS within 36 h.^4,5 Recent studies^6,7 suggest that early aggressive fluid resuscitation may lead to fluid overload, increasing the risk of adverse outcomes, which contradicts previous results. Moderate fluid resuscitation may be a better regimen for patients with AP. Both American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis⁸ and Guidelines for diagnosis and treatment of acute pancreatitis in China (2021)⁹ clearly state that fluid resuscitation is the cornerstone of treatment for AP patients.⁵ However, there are still some controversies about the type of fluid, rehydration speed, rehydration volume, and rehydration time of fluid resuscitation.^10–12 The two most commonly used fluids are Normal Saline (NS) and Lactated Ringer's solution (LR). In the past, NS was the preferred liquid type for AP fluid resuscitation,¹³ but it will lead to hyperchloremic metabolic acidosis, and aggravate the condition of AP patients.^14,15 LR may be a preferable option because of its potential to possess anti-inflammatory properties.^16,17 However, just as aggressive fluid resuscitation and moderate fluid resuscitation are associated with different clinical outcomes, several studies comparing the efficacy of NS and LR have also yielded conflicting results.^16–18 So far, the type of fluid chosen for fluid resuscitation is based solely on expert opinion. Although there have been some meta-analyses^19–23 to compare the role of NS and LR in the treatment of AP patients, the results of these studies are also inconsistent, and no clear conclusions have been drawn.

Given the discrepancies among previous studies, recently published meta-analyses did not draw clear conclusions, and there were conflicting results among several meta-analyses. Therefore, it is necessary to conduct a systematic review and meta-analysis of existing studies to evaluate the benefits and harms of NS and LR fluid resuscitation schemes, and to further clarify the impact of the two fluid resuscitation schemes on prognostic-related measures such as SIRS incidence after admission, the length of hospitalization, and moderate–severe AP incidence in AP patients.

Methods

Research question and outcomes

We used Patients, Intervention, Control, Outcomes, Design (PICOD) methodology to define our research question. The patient population of interest was the patients with AP. The primary intervention was LR fluid resuscitation, and the control group was NS fluid resuscitation. The primary outcome was the incidence of SIRS at 24 h, 48 h and 72 h, and the secondary outcomes were the length of hospitalization, the incidence of moderate–severe AP, mortality, and by comparing adverse events such as local complications and organ failure to assess the primary and secondary outcomes of AP patients in both groups. Only randomized controlled clinical trials (RCTs) were included in this meta-analysis.

Search strategy

This meta-analysis follows the Systematic Review and Meta-Analysis (PRISMA) guidelines.²⁴ We conducted a comprehensive search of the following databases: PubMed, Web of Science Core Collection (Clarivate), Embase, Cochrane Library, CNKI, China Wanfang, and China VIP database. The retrieval time was from the creation of each database to September 16, 2022. Export the retrieved citation information, use EndNote X9 bibliography management software to process the retrieved results, and delete duplicate data. Keywords used in the search strategy include “acute pancreatitis” AND “Lactated Ringers Solution” OR “Lactated Ringer's” OR “Ringers Lactate” AND “Normal Saline” OR “0.9% NaCl” OR “0.9% Saline” AND “random allocation” OR “randomized clinical trial” OR “Randomized Controlled Trial”.

Study definitions

Patients with AP should meet the Atlanta Diagnostic Criteria,³ that is, patients who meet 2 of the following 3 criteria can be defined as AP patients: acute onset of epigastric pain, serum lipase activity or amylase activity at least three times greater than the upper limit of normal, and imaging examinations consistent with the characteristic manifestations of AP. The diagnosis of SIRS meets 2 of the following 4 criteria: (1) temperature > 38 °C or <36 °C, (2) heart rate > 90 per minute, (3) respiratory rate > 20 per minute or PaCO₂ < 32 mmHg, (4) white blood cell count < 4000 cells/mm³ or >12,000 cells/mm³ or >10% bands. MSAP was defined as the presence of transient organ failure (<48 h) and/or local or systemic complications without persistent organ failure. SAP was defined as persistent organ failure (>48 h). Organ failure was defined by the modified Marshall scoring system.²⁵ Local complications include pancreatic necrosis, acute peripancreatic fluid collection, pseudocyst, and walled-off necrosis.

Study selection and data collection

Two authors screened the studies. Firstly, preliminary screening was performed based on the title and abstract of the literature, and the full text of the literature that basically met the inclusion criteria was further reviewed before deciding whether to include it. Two authors extracted data from the studies included in the analysis, including authors, year of publication, study country, sample size, and study time. In addition, patients’ gender, age, total volume of fluid, length of hospitalization, the incidence of SIRS at 24 h, 48 h and 72 h, ICU admission rate, moderate–severe AP incidence, local complications, organ failure, and mortality were also collected and tabulated on Microsoft Word. When the two authors disagreed, a third author stepped in to reach a consensus to resolve the differences. The studies included in this meta-analysis should meet the following criteria: (1) AP patients aged 18 years and older; (2) Comparison of the efficacy of LR and NS in the treatment of AP; (3) RCTs. Other literature types including case reports, reviews, systematic reviews, and conference abstracts were excluded (see Fig. 1a for the literature selection process).

Figure 1.

Literature selection process and risk assessment. (a) Flow chart of included studies. (b) Summary of the cochrane risk of bias assessment. The “green +” means “low risk of bias”; the “yellow ?” means “unclear risk of bias”; the “red -” means “high risk of bias”.

Risk of bias and quality of evidence assessment

The risk of extracted data was assessed using the Cochrane risk of bias tool,²⁶ including random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other bias. Funnel plots were visualized for the included studies to assess the presence of publication bias. The quality of evidence for all outcomes was assessed using the Jadad scale,²⁷ which included randomization, double blinding and withdrawals and dropouts.

Data analysis

Statistical analysis using Review Manager 5.3 software. For dichotomous variables, calculate relative risk (RR), 95% CI, and P-values to assess statistical difference; for continuous variables, weighted mean difference (WMD), 95% CI, and P-values were calculated to assess statistical difference. P < 0.05 was considered statistically significant. The heterogeneity test used the I² defined by the Cochrane Handbook²⁸ to assess the heterogeneity among studies. I² > 50% was considered to be heterogeneous, using a random effects model, and sensitivity analysis was performed to clarify the source of heterogeneity by article-by-article exclusion; I² < 50% was considered non-heterogeneous, and a fixed-effects model was used.

Results

Retrieval results

According to the established search strategy, a total of 2341 possible documents were retrieved. Endnote X9 software was used to screen the titles, authors, and abstracts of the literature for duplication, and 246 duplicate articles were excluded. Read the titles and abstracts of the remaining 2095 articles, and conduct a full-text review of the articles that basically meet the inclusion criteria. Finally, 6 RCTs were included.^{16–18,29–31} Details of the study options are in Fig. 1a.

A total of 431 patients were included, with 215 patients receiving LR, and 216 patients receiving NS. Features of studies are shown in Table 1. All 6 studies reported length of hospitalization, and 4 studies reported the incidence of SIRS at 24 h, local complications (including data on pancreatic necrosis), and mortality (Table 2). At least 3 of the 6 studies reported other interesting results, such as the need for nutritional support, the need for invasive treatment, pH and HCO3 at 48 h after admission. However, their data volumes were too small for further analysis. Each study was assessed for publication bias (Fig. 1b) and the quality of the evidence was assessed using the Jadad scale.

Table 1.

Features of studies.

Study	Country	Study duration	Jadad scale score	Sample size		Age (years)		Sex, male (%)		SIRS before resuscitation (%)		Total volume of fluid (L)
				NS	LR	NS	LR	NS	LR	NS	LR	NS	LR
Lee, 2020	USA	2018.09–2019.08	5	60	61	43.5 ± 14.2	42.3 ± 14.0	33 (55.0)	30 (49.2)	NR	NR	5.8 (4.8–6.8)	6.0 (5.2–6.9)
Choosakul, 2018	Thailand	2015.11–2016.12	5	24	23	48.3 ± 13.6	54.8 ± 20.4	17 (70.8)	12 (52.2)	10 (41.7)	8 (34.8)	5.4 ± 0.8	4.9 ± 1.3
de-Madaria, 2018	Spain	2013.02–2015.03	5	21	19	61.4 ± 15.5	63.8 ± 19.1	11 (52.4)	8 (42.1)	14 (66.7)	9 (47.4)	6.9 (6.4–8.6)	5.9 (4.9–7.0)
Karki, 2022	Nepal	2018.10–2019.06	3	25	26	41.3 ± 14.2		1 (4.0)	25 (96.2)	14 (64.0)	12 (46.2)	NR	NR
Kayhan, 2021	Turkey	2019.01–2019.09	2	65	67	56.3 ± 17.2	54.6 ± 17.9	21 (32.3)	23 (34.3)	NR	NR	NR	NR
Wu, 2011	USA	2009.05–2010.02	3	21	19	54 (40, 60)	50 (40, 73)	14 (66.7)	8 (42.1)	4 (19.0)	6 (31.6)	NR	NR

Note: NS: Normal Saline; LR: Lactated Ringer's; NR: not reported.

Table 2.

Outcomes of studies.

Study	Length of hospitalization (days)		Moderate –severe pancreatitis (%)		Local complications (%)		Pancreatic necrosis (%)		SIRS at 24 h (%)
	NS	LR	NS	LR	NS	LR	NS	LR	NS	LR
Lee, 2020	5.02 ± 3.34	3.82 ± 2.96	15 (25.0)	9 (14.8)	9 (15.0)	4 (6.6)	NR	NR	19 (32.2)	21 (37.5)
Choosakul, 2018	6.22 ± 3.94	6.36 ± 3.95	NR	NR	9 (37.5)	6 (26.1)	2 (8.3)	0 (0.0)	9 (37.5)	2 (8.7)
de-Madaria, 2018	10.08 ± 8.75	9.29 ± 5.77	10 (47.6)	7 (36.8)	NR	NR	10 (47.6)	4 (21.1)	4 (19.0)	4 (21.1)
Karki, 2022	6.20 ± 2.50	5.15 ± 0.09	11 (42.3)	6 (23.1)	7 (28.0)	6 (23.1)	3 (12.0)	2 (7.7)	11 (44.0)	4 (15.4)
Kayhan, 2021	3.35 ± 2.27	3.00 ± 1.52	25 (38.5)	17 (25.4)	22 (33.8)	14 (20.9)	NR	NR	NR	NR
Wu, 2011	6.22 ± 2.39	4.64 ± 2.40	NR	NR	NR	NR	1 (4.8)	0 (0.0)	NR	NR

Outcomes of studies
Study	SIRS at 48 h (%)		SIRS at 72 h (%)		Mortality (%)		Organ failure (%)		ICU admission
	NS	LR	NS	LR	NS	LR	NS	LR	NS	LR
Lee, 2020	18 (38.3)	18 (41.9)	14 (32.6)	11 (32.4)	NR	NR	9 (15.0)	7 (11.5)	15 (25.0)	6 (9.8)
Choosakul, 2018	2 (8.3)	2 (8.7)	NR	NR	1 (4.2)	0 (0.0)	NR	NR	NR	NR
de-Madaria, 2018	9 (42.9)	3 (15.8)	7 (33.3)	3 (15.8)	1 (4.8)	0 (0.0)	1 (4.8)	0 (0.0)	1 (4.8)	0 (0.0)
Karki, 2022	NR	NR	3 (12.0)	0 (0.0)	1 (4.0)	0 (0.0)	NR	NR	NR	NR
Kayhan, 2021	NR	NR	NR	NR	NR	NR	13 (20.0)	6 (9.0)	NR	NR
Wu, 2011	NR	NR	NR	NR	NR	NR	NR	NR	3 (14.3)	1 (5.3)

Note: NS: Normal Saline; LR: Lactated Ringer's; NR: not reported.

Incidence of SIRS at 24 h, 48 h, and 72 h

Four studies^17,18,29,31 reported the incidence of SIRS at 24 h in both groups. The results showed that 31/129 (24.0%) patients in the LR group and 43/130 (33.1%) patients in the NS group developed SIRS 24 h after the two fluid resuscitation regimens, and the difference was not statistically significant (RR = 0.63, 95%CI: 0.28–1.43, P = 0.27; Fig. 2a). However, I² = 63% for the test of heterogeneity among these 4 studies, suggesting heterogeneity among several studies. The source of heterogeneity was analyzed by article-by-article exclusion method, and it was found that when the study by Lee et al.¹⁸ was removed, I² = 36%. Further analysis of the remaining three studies^17,29,31 found that at 24 h of fluid resuscitation, SIRS occurred in 10/68 (14.7%) patients in the LR group and 24/70 (34.3%) patients in the NS group, the difference was statistically significant (RR = 0.43, 95%CI: 0.22–0.82, P = 0.01; Fig. 2b).

Figure 2.

Forest plot of LR versus NS for SIRS. (a) SIRS at 24 h. (b) SIRS at 24 h after the heterogeneity study was removed. (c) SIRS at 48 h. (d) SIRS at 72 h.

Three studies^17,18,29 reported the incidence of SIRS at 48 h in both groups. The results showed that 23/103 (22.3%) patients in the LR group and 29/105 (27.6%) patients in the NS group developed SIRS, and the difference was not statistically significant (RR = 0.87, 95%CI: 0.55–1.35, P = 0.53; Fig. 2c).

Three studies^17,18,31 reported the incidence of SIRS at 72 h in both groups. The results showed that at 72 h, SIRS occurred in 14/106 (13.2%) and 24/106 (22.6%) patients in the LR and NS groups, respectively, and the difference was not statistically significant (RR = 0.71, 95%CI: 0.41, 1.22, P = 0.21; Fig. 2d).

Length of hospitalization

All 6 studies^{16–18,29–31} reported the length of hospitalization, but not all of the data were normally distributed. Five of these studies^{16–18,29,30} reported the median and interquartile range of length of hospitalization. In order to meet the format requirements of Review Manager data analysis, we refer to the methods of Luo et al.³² and Wan et al.³³ to estimate the sample mean and standard deviation according to the sample size, median, and interquartile range of the study, making the data comparable. The results showed that compared with patients in the NS group, the length of hospitalization of the patients in the LR group was shortened, and the difference was statistically significant (Mean Difference (MD) = −0.74, 95%CI: −1.20 to −0.28, P = 0.001; Fig. 3). No evidence of publication bias was found in the funnel plot of length of hospitalization.

Figure 3.

Forest plot of LR versus NS for length of hospitalization.

ICU admission

Three studies^16–18 reported ICU admission in both groups. The results showed that 7/99 (7.1%) patients in the LR group and 19/102 (18.6%) patients in the NS group required ICU admission, and the difference was statistically significant (RR = 0.39, 95%CI: 0.18–0.85, P = 0.02; Fig. 4a), indicating that patients receiving LR needed less ICU admission compared with patients receiving NS.

Figure 4.

Forest plot of LR versus NS. (a) ICU admission. (b) Local complications. (c) Pancreatic necrosis. (d) Incidence of organ failure. (e) Incidence of moderate–severe AP. (f) Mortality.

Local complications

Four studies^18,29–31 reported the incidence of local complications in both groups. The results showed that local complications occurred in 30/177 (16.9%) and 47/174 (27.0%) patients in the LR and NS groups, respectively, and the difference between the two groups was statistically significant (RR = 0.63, 95%CI: 0.42–0.94, P = 0.02; Fig. 4b), indicating that the incidence of local complications was lower in the LR group than in the NS group.

However, not all local complications were reported in the above 4 studies. Two of the above studies^29,31 reported on the pancreatic necrosis situation, and 2 additional studies^16,17 also reported this result. The results of these 4 studies showed that 6/87 (6.9%) patients in the LR group and 16/91 (17.6%) patients in the NS group developed pancreatic necrosis, and the difference between the two groups was statistically significant (RR = 0.44, 95%CI: 0.20–0.97, P = 0.04; Fig. 4c).

Organ failure and moderate–severe AP

Three studies^17,18,30 reported the occurrence of organ failure. The results showed that organ failure occurred in 13/147 (8.8%) patients in the LR group and 23/146 (15.8%) patients in the NS group. Although the incidence of organ failure was lower in the LR group than in the NS group, the difference between the two groups was not statistically significant (RR = 0.56, 95%CI: 0.30–1.06, P = 0.07; Fig. 4d).

Moderate–severe AP was defined by the presence of transient or persistent organ failure according to the Atlanta diagnostic criteria.³ Four of the six studies^17,18,30,31 reported the occurrence of moderate–severe AP. 39/173 (22.5%) and 61/171 (35.7%) patients in the LR group and the NS group developed moderate–severe AP, respectively, and the difference between the two groups was statistically significant (RR = 0.64, 95%CI: 0.45–0.89, P = 0.008; Fig. 4e).

Mortality

Four studies^16,17,29,31 reported the occurrence of mortality in the two groups. However, in the study by Wu et al.,¹⁶ no patients died, so the RR value of this study cannot be estimated. The results showed that 0/87 (0.0%) and 3/91 (3.3%) patients died in the LR and NS groups, respectively. Although the LR group had a tendency to reduce the occurrence of mortality, the difference between the two groups was not statistically significant (RR = 0.34, 95%CI: 0.06–2.12, P = 0.25; Fig. 4f).

Discussion

As an acute abdomen of the digestive system, the main pathogenesis of AP is that pancreatic enzymes damage pancreatic acinar tissue and lead to dysfunction of other organs and systems.³⁴ It has been reported that the incidence of AP is increasing year by year in several countries.^35–37 Some researchers predict that the incidence of AP will continue to increase year by year in the future.³⁸ Insufficiency of effective circulating blood volume due to vomiting, decreased oral intake, sweating, and peripancreatic inflammation may lead to multiorgan failure,³⁹ which is the most important reason for early fluid resuscitation in AP patients. Regarding the type of fluid resuscitation, crystalloid preparations should be the first choice,⁸ because the use of hydroxyethyl starch in patients with severe sepsis increases renal failure and mortality.⁴⁰ There is currently no research confirming that adding hydroxyethyl starch during fluid resuscitation in AP patients may be beneficial.⁸ However, the preferred choice of NS or LR in crystalloid preparations is still controversial. In the past, NS was the preferred liquid type for AP fluid resuscitation,¹³ but it contains higher chloride ion concentration than LR, which will lead to hyperchloremic metabolic acidosis, and it will cause pathological zymogen activation and aggravate the condition of AP patients.^14,15 LR with a more balanced pH becomes a better option because lactic acid can be metabolized in the liver to generate bicarbonate, which can act as a buffer to prevent acidosis.¹⁶ Some guidelines^41,42 recommend the use of LR, because the lactic acid contained in LR may reduce the release of inflammatory cytokines through various pathways, and inhibit macrophage inflammation and NF-κB activation,^17,43,44 thereby alleviating the inflammatory response and reducing the occurrence of SIRS. In this meta-analysis, there was no difference in the incidence of SIRS at 48 h and 72 h between the two groups. However, there was heterogeneity among the 4 studies included in the incidence of SIRS at 24 h, and after sensitivity analysis, it was found that the heterogeneity originated from the study by Lee et al.¹⁸ In this study, some patients with mild symptoms were discharged within 24 h of fluid resuscitation, so the data for these patients were not collected, which may account for the heterogeneity. Interestingly, heterogeneity persisted after we adjusted for the number of patients and the total number of patients at the three nodes according to the results reported in this study. We speculate that the heterogeneity may be due to the fact that the number of participants in this study differed greatly from other studies, or that the investigators reported that most patients received different fluids than random allocation before enrollment, but the reason is not clear. Finally, after removing this study, the analysis of the remaining three studies found that LR can reduce the incidence of SIRS at 24 h, and the result is statistically significant, indicating that LR can reduce the incidence of early SIRS in AP patients. This result is consistent with the results of two previous meta-analyses.^19,45

As mentioned above, the application of massive NS resuscitation can lead to increased chloride ion concentration and lower blood bicarbonate concentration, thereby triggering hyperchloremic metabolic acidosis.^46,47 Acidosis can enhance the inflammation and necrosis of AP, and cause acute kidney injury.⁴⁸ Studies have confirmed that in a rat model of pancreatitis, acidosis may activate trypsinogen, thereby aggravating pancreatic tissue damage.¹⁴ The lactic acid contained in LR can be metabolized into bicarbonate in the liver, thereby reducing pH decline, reducing the activation of zymogens caused by acidosis, reducing local exudation, and reducing the release of inflammatory cytokines,^16,43,45 and then reducing pancreatic damage. As reported in the literature, we found that LR can reduce the occurrence of local complications in AP patients, which also includes the condition of pancreatic necrosis. This result is different from several previous meta-analyses.^19,21,45 We speculate that the possible reason is that the amount of previous data is small, and most of them are included in retrospective studies, and retrospective studies, as observational studies, are more likely to be affected by confounding bias, which will have a negative impact on the results. This is why this meta-analysis only includes RCTs, so that more reliable results can be obtained to guide clinical practice.

Studies have found that exogenous calcium supplementation can effectively avoid hypocalcemia, thereby reducing lipotoxic necrosis that occurs in acute pancreatitis, and reducing the incidence of organ failure; The calcium contained in LR can also reduce acinar necrosis around fat and reduce the degree of SIRS and organ failure.⁴⁹ So LR is superior to NS not only because it can avoid the pH decline and reduce the release of inflammatory cytokines, but from another perspective, the calcium ions contained in LR can reduce the occurrence of hypocalcemia, thereby reducing the incidence of pancreatic necrosis and organ failure. It is well known that serum calcium ion concentration can be used to estimate disease severity in AP patients.⁵⁰ According to the Atlanta diagnostic criteria,³ the occurrence of organ failure is also used to assess the severity of AP. In this meta-analysis, although the incidence of organ failure was lower in the LR group than in the NS group, this difference was not statistically significant. The difference between the two groups of patients developing moderate–severe AP was statistically significant, indicating that LR can reduce the progression of MAP to MSAP and SAP.

Based on the above results, LR can reduce the incidence of SIRS at 24 h, local complications, and the occurrence of moderate–severe AP, which will theoretically, shorten the length of hospitalization and reduce ICU admission rate. Our results showed that patients who received LR fluid resuscitation had a shorter length of hospitalization than those who received NS, and this difference was also statistically significant. A recent meta-analysis⁵¹ showed that an aggressive hydration regimen can effectively shorten the length of hospitalization in patients with MAP, and this study supports our results. The previous meta-analyses^20,22 also concluded that LR has a tendency to shorten the length of hospital stay, but these results are not statistically significant. We speculate that it may be due to the small data volume, and it is difficult to avoid bias. Furthermore, consistent with previous meta-analyses,^19–23 our results showed that LR can significantly reduce the need for ICU admission in patients with AP, although only 3 studies were included in this result, this was statistically significant.

However, although LR can shorten the length of hospitalization and reduce the ICU admission rate of AP patients, it does not mean that LR can reduce the mortality of AP patients. Because differences in length of hospitalization and ICU admission requirements can vary by criteria for each center and clinician experience. We also obtained the corresponding results that there was no difference in mortality between the two groups, probably due to the small amount of data, or that the two fluids did not have an effect on mortality, but this still needs further research to confirm.

Compared with the previous meta-analyses,^{19–23,45,52} our updated meta-analysis mainly has the following advantages: (1) We included only RCTs, which allow for more reliable results; (2) We evaluated the incidence of SIRS at different times after resuscitation with the two fluids and compared the effects of the two fluids in reducing local complications, organ failure, the occurrence of moderate–severe AP, ICU admission requirement, and length of hospitalization. Therefore, we believe that the results of this meta-analysis will be more reliable than previous meta-analyses.

There are also some deficiencies in this meta-analysis: (1) The number of studies included was limited, which could produce false positive or false negative results; (2) 4 studies^16,17,29,31 had small sample sizes, which may also have produced erroneous results; (3) Some studies have low Jadad scale scores, and the quality of the evidence may not be high. (4) A recent RCT⁶ conducted across multiple centers and with a large sample size concluded that there are significant differences in outcomes between aggressive and moderate fluid resuscitation. The study found that early aggressive fluid resuscitation may lead to fluid overload, increasing the risk of adverse outcomes. Only 3 out of the 6 studies in this meta-analysis reported their total fluid volume. Thus, it remains to be investigated whether the conclusion that LR is better than NS is due to different fluid resuscitation protocols. Our results should therefore be treated with caution.

In conclusion, compared with NS, LR may be a better choice for early fluid resuscitation in AP patients because it significantly reduces the length of hospitalization, the incidence of SIRS at 24 h, ICU admission requirement, and the incidence of local complications and moderate–severe AP. However, some of the studies included in this meta-analysis were not double-blind, the quality of the evidence may not be high, and the results may be biased. Therefore, multicenter, large-sample, prospective randomized controlled clinical trials are still needed to further confirm our findings and determine the role of LR in reducing the incidence of SIRS, mortality, etc.

Authors’ contributions

Zhengwang Wang wrote the manuscript, collected and tabulated the research data; Keru Shi analyzed the data and made figures; Shaojian Mo screened the studies, collected and tabulated the research data; Ziang Liu screened the studies; Yanzhang Tian and Jie Yao reviewed the manuscript.

Funding

This article was supported by Shanxi Province Education Department (Grant No. 2022Y389), Shanxi Provincial Department of Human Resources and Social Security (No. 20210002) and Shanxi Provincial Department of Science and Technology (No. 202104041101024).

Conflict of interest

The authors declare that they have no conflict of interest. All authors had access to the study data and had reviewed and approved the final manuscript.