Introduction

Some evidence suggests that fluid resuscitation with lactated Ringer’s solution (LR) may have an anti-inflammatory effect on acute pancreatitis (AP) ^{1 2}when compared to normal saline (NS). A meta-analysis of randomized studies described that using LR was associated with less severity, less need for admission to the intensive care unit, and less frequent local complications ³, but existing single-center randomized controlled trials show conflicting results.

Aims & Methods

The WATERLAND trial is a multicenter, open-label, randomized, controlled, superiority trial. Patients were randomly assigned in a 1:1 ratio to receive LR versus NS-based fluid resuscitation (following the WATERFALL moderate volume strategy ⁴) for at least 48 hours. The primary outcome was moderately severe or severe AP (MSAP). The secondary objectives were to determine the effect of LR versus NS fluid resuscitation on several efficacy and safety outcomes. A total sample of 720 patients was calculated to achieve 90% power to detect a difference between the group proportions of 10%, assuming that the frequency of MSAP in the LR group is 17%, and 27% in the NS group ³. A loss to follow-up of 10% of patients was expected, so the total sample size was 396 patients in each treatment arm (792 patients overall).

Results

A total of 792 patients from 43 centers across 18 countries from the 5 continents were included (399 were randomized to LR and 393 to NS). The frequency of MSAP in the LR group vs. the NS group was 23.3% vs. 25.2%, p=0.536 (Table 1). LR was robustly associated with significantly reduced inflammation, showing both a lower frequency of systemic inflammatory response syndrome at 24 and 48h, and lower serum C-reactive protein levels at 48h (Table 1). NS was associated with a significantly higher frequency of acidosis and hyperchloremic acidosis at 24 and 48h (Table 1). No differences were observed in other efficacy or safety outcomes, including local complications, necrosis, infection of necrosis, need for invasive treatment, need for nutritional support, intensive care unit admission, organ failure, hospital stay, fluid overload, hypercalcemia, hyperkalemia, mortality or PAN-PROMISE AP symptom score.

Table 1. Arm of treatment and selected outcomes.

Conclusion

Lactated Ringer's solution consistently has an anti-inflammatory effect in patients with acute pancreatitis and is associated with a lower incidence of acidosis and hyperchloremic acidosis. Nevertheless, these benefits do not lead to improvements in key clinical outcomes, including symptom intensity, disease severity, local or systemic complications, length of hospital stay, or mortality. The WATERLAND trial stands as the largest and most globally representative randomized clinical trial conducted in acute pancreatitis to date.

References

1. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol. 2011 Aug;9(8):710-717.e1. doi: 10.1016/j.cgh.2011.04.026.
2. de-Madaria E, Herrera-Marante I, González-Camacho V, et al. Fluid resuscitation with lactated Ringer's solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial. United European Gastroenterol J. 2018 Feb;6(1):63-72. doi: 10.1177/2050640617707864.
3. Zhou S, Buitrago C, Foong A, et al. Comprehensive meta-analysis of randomized controlled trials of Lactated Ringer's versus Normal Saline for acute pancreatitis. Pancreatology. 2021 Dec;21(8):1405-1410. doi: 10.1016/j.pan.2021.07.003.
4. de-Madaria E, Buxbaum JL, Maisonneuve P, et al (ERICA Consortium). Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med. 2022 Sep 15;387(11):989-1000. doi: 10.1056/NEJMoa2202884.

Introduction

Endoscopic ultrasound (EUS) is the gold standard for evaluating pancreatic lesions, allowing for real-time imaging and biopsy sampling. Nevertheless, the differentiation between solid pancreatic lesions — such as pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PNETs) — as well as cystic lesions is often troublesome. Specifically, identifying intraductal papillary mucinous neoplasms (IPMNs) with varying degrees of dysplasia is crucial for guiding clinical management. However, the diagnostic accuracy of current methods remains suboptimal. This multicenter study aimed to develop and validate convolutional neural networks (CNNs) to characterize solid and cystic pancreatic lesions and stratify IPMNs into high-grade dysplasia/carcinoma (HGD/C) and low-grade dysplasia (LGD).

Aims & Methods

This multicenter study included EUS images from 12 centers in Spain, Brazil, the United Kingdom and the United States of America. Solid lesion differentiation (PDAC vs. PNET) was achieved using a CNN trained on 49034 images from 95 patients (n=69 for PDAC and n=26 for PNET), with diagnoses confirmed via EUS-guided fine-needle biopsy or surgical specimen analysis. A second CNN was trained on 79395 images from 82 patients (n=64 for mucinous cystic lesions and n=18 for non-mucinous cystic lesions). Finally, a third model used the subset of IPMNs (n=51046 frames, 30 patients) to distinguish between HGD/C (n=5 patients) and LGD (n=25 patients). Histological confirmation was used as the gold standard. Performance metrics included sensitivity, specificity, accuracy, and area under the precision-recall curve (AUC-PR). To comprehensively determine the model's performance, we evaluated multiple thresholds for the confidence score and the IoU, between 0.45 and 0.55 with a step of 0.02 ([0.45, 0.47, 0.50, 0.52, 0.55]). The datasets were split into training (70%), validation (20%), and testing (10%) subsets.

Results

For solid lesions, the model differentiated PDAC from PNETs with an accuracy of 91.8%, with sensitivities of 96.2% and 97.8%, respectively. The AUC-PR was 0.982 for PDAC and 0.977 for PNET. Regarding cystic lesions the model detected mucinous cystic lesions with a sensitivity of 97.5%, an overall accuracy of 89.7% and an AUC-PR of 0.977. When the subset of IPMNs was specifically analyzed, the model distinguished IPMNs with HGD/C from those with LGD with a sensitivity of 97.5%, specificity of 94.3%, and an overall accuracy of 89.8%. The AUC was 0.988.

Conclusion

This is the first multicenter, transatlantic AI study aiming to provide a holistic approach to both solid and cystic pancreatic lesions, focusing on those with a significantly higher malignant potential. Our models achieved high accuracy in identifying and differentiating these conditions. Furthermore, to our knowledge this is the first integrative model to include the ability to stratify IPMNs into LGD and HGD/C, which has significant clinical implications, potentially reducing unnecessary surgeries and ensuring timely intervention for high-risk patients. The inclusion of data from diverse regions reduces demographic bias and enhances model generalizability. Real-time implementation of these solutions could significantly improve decision-making in EUS and optimize patient outcomes.