Acute pancreatitis is a common condition encountered within emergency general surgery presentations, frequently accounting for acute admissions [1]. Although a large proportion (up to 80%) of patients are classified as having disease, which is mild or moderate in severity, whereby there is an absence of local or systemic complications and symptoms typically settle with conservative measures, in up to 20% of patients, the condition is classified as severe and life threatening [2,3]. Given the potential to rapidly progress to fulminant illness with multiple organ dysfunction, various measures have been implemented in an effort to improve morbidity and mortality in this patient population [4]. This includes efforts to predict disease severity utilizing scoring systems, such as the Glasgow score, whose criteria are displayed in Supplementary Table 1 [5], revised Atlanta Criteria, and APACHE II score, in addition to rationalizing the use of antibiotics, providing aggressive nutritional support, and optimising the timing of intervention for management of necrosis and collections [6].

There is a wealth of evidence to suggest that the management within the first 48–72 hours of an episode of acute pancreatitis heavily influences the disease course, length of stay, and overall morbidity and mortality [7]. It is during this early disease period that optimal resuscitation is essential. However, despite this knowledge, there is little guidance from national associations and poor-quality evidence in the research literature regarding optimal intravenous fluid administration [8].

On review of published recommendations regarding intravenous fluid administration in acute pancreatitis, it was found that the recommendations were vague and unclear. The American Gastroenterology Association published recommendations on the basis of seven randomized controlled trials (RCTs) examining this subject, yet they failed to find high quality evidence, concluding a “conditional recommendation” with regards to judicious goal directed usage [9]. Working party guidelines published in Gut BMJ highlighted more specific guidelines, recommending that fluids should be given intravenously (crystalloid or colloid as required) to maintain urine output > 0.5 mL/kg. However, they also advised frequent measurement of central venous pressure to guide the replacement rate, a form of monitoring that typically requires a higher level of care [10].

Lastly, NICE have published guidelines with respect to the management of pancreatitis; however, when it comes to advice regarding fluid administration, they simply refer to the general principles and protocols for intravenous fluid therapy, rather than specific guidelines related to pancreatitis [11].

The term “goal directed therapy” is often relied upon when referencing optimal fluid administration, whereby intravenous fluids are titrated against various clinical and biochemical targets (heart rate, blood pressure, urine output, urea, and haematocrit) that reflect perfusion. Historically, this mantra has been the cornerstone of sepsis management, with good evidence that it reduces mortality. Given the similarities in physiological upset caused by the systemic inflamatory response syndrome in acute pancreatitis, it would be assumed that the principles of sepsis management apply in a similar way; however, none of the research studies have been able to replicate the same beneficial outcomes in acute pancreatitis as seen in sepsis.

With intravenous fluids ultimately being the cornerstone of management in these patients to replace third space losses, prevent hypovolaemia, and avoid organ hypoperfusion and associated failure, clearer guidance is needed.

Therefore, this study aims to establish current clinical practice within the North East of England regarding the rate of intravenous fluid administration in patients with acute pancreatitis and to assess its effect on patient outcomes. These findings may also help guide best practice and assist in future trial design.

Data were collected prospectively from all adult patients with acute pancreatitis at nine sites with general surgical units across the North-East of England. Each site collected data over a 60-day period with 30 days of follow-up. Data collection was conducted between November 2020 and February 2021. Adult patients (aged 18 years or over) presenting with acute pancreatitis, as defined by pre-set biochemical parameters or radiological confirmation in accordance with the revised Atlanta classification, were included [7]. Patients with known hepatobiliary malignancy, chronic pancreatitis, or patients on established renal replacement therapy were excluded. Patients were categorised into severe vs. non-severe pancreatitis based on Glasgow score of ≤ 3 (non-severe) or > 3 (severe).

Using the Northern Surgical Trainees Research Association collaborative surgical network, each participating local hospital allocated a principal investigator team consisting of a consultant surgeon, higher surgical trainee, and a number of junior trainees. Data were collected using a standardised Excel spreadsheet and anonymised data were submitted centrally via a secure, password protected website. The Fluid Resuscitation in Pancreatitis (FLIP) Study was an audit of practice, and therefore, formal ethics approval was not sought. Local Caldicott approval was obtained at each participating centre.

Data were collected on intravenous fluid administration within 72 hours of initial presentation to hospital, in addition to patient demographics, disease characteristics, and clinical outcome measures. As this was a pragmatic study of current practice, patients were managed according to their local hospital intravenous fluid protocol. The primary outcome of interest was 30-day mortality with secondary end-points including admission to high dependency unit/intensive care unit, length of stay, radiological necrosis, and organ failure.

Overall, 254 participants admitted to hospital with acute pancreatitis were included, with 11.2% being readmitted during the study period. The most common aetiology was gallstones (44.4%). A total of 29 participants (14.1%) had severe pancreatitis, as determined by a Glasgow prognostic score of ≥ 3. Three patients underwent endoscopic pancreatic necrosectomy. Full demographics and outcomes of the entire cohort are given in Table 1 and 2, respectively. A separate analysis for each aetiology was not performed. Due to incomplete data collection of some secondary outcomes highlighted in Supplementary Table 2, our analysis focused on the clinically relevant outcomes.

This study showed significant variations in prescribing IV fluids for patients with acute pancreatitis as well as an associated higher mortality in patients with a Glasgow score of ≥ 3 who receive less IV fluid in the first 72 h of their admission.

Significant variation in the volume of intravenous fluids being delivered over the first 72 hours of admission was likely to be due to the lack of clear published guidance at a regional and national level during the study period. Fluid was consistently given in significantly larger volumes in the first 24 hours of admission, with significantly less fluid being given in the following 48 hours. This was assumed to be due to the fact that patients are typically prescribed a “pancreatitis bundle” of analgesia and fluids on admission, with IV fluids given in the initial period and then they are commonly stopped as oral intake is encouraged and patients work towards discharge if they are clinically well and do not require any intervention. Nonetheless, the variation in practice highlights the absence of knowledge regarding how to safely individualise patient care.

Despite the emphasis on the importance of fluid resuscitation in acute pancreatitis, caveats have been added in the form of warnings against overly aggressive administration. Two RCTs revealed that either hourly rates exceeding 10 mL/kg or haematocrit < 35% within 48 h increased morbidity [12,13], with the American Gastroenterological Association also advising that overly aggressive fluid therapy can be harmful with resultant respiratory compromise or abdominal compartment syndrome [9]. However, in this study, it was found that large volumes of fluid given to those with mild pancreatitis had no effect on mortality. This finding is supported by a similar study whose cohort was predominantly risk-stratified as having mild disease [14]. However, it is of greater interest that despite there being no overall association between volume of intravenous fluid and mortality in those with severe pancreatitis (Glasgow score ≥ 3), giving more aggressive fluid resuscitation is associated with decreased mortality.

Adding to the argument against aggressive resuscitation, the recently published WATERFALL Trial randomly assigned patients with acute pancreatitis to receive either goal-directed aggressive or moderate fluid resuscitation [15]. This trial found that aggressive fluid resuscitation increased the risk of volume overload, causing harm without any improvement in the primary outcome, which was development of severe pancreatitis during admission. It was concluded that aggressive fluid resuscitation was linked to worse outcomes in critically ill patients. However, this trial excluded patients who were classified as having moderately-severe to severe disease at admission. The FLIP Study adds a new body of evidence, which suggests that the impact of fluid resuscitation strategies differs significantly between those with severe pancreatitis and those with milder disease. Therefore, the findings of the WATERFALL study are likely not generalisable to patients with severe pancreatitis. Further prospective trials are needed to guide fluid resuscitation in those with severe pancreatitis in order to propose a guideline on intravenous fluid administration.

In patients with severe pancreatitis, significantly more fluid was being prescribed in comparison to those with mild/moderate disease and it was typically prescribed in the first 24 h. Those who died had been given significantly less fluid in the first 72 hours of admission. As such, the results suggest that the Glasgow score has an added benefit of identifying those patients who require more IV fluids and more rigorous goal-directed fluid management in the first 72 h of admission. Of note, these results contradict the findings from previously mentioned RCTs [12,13] and a recent meta-analysis published in the World Journal of Gastroenterology [16]. This meta-analysis concluded that early aggressive intravenous fluid therapy (defined as 3–5 mL/kg/h in 24 hours) did not improve mortality, and it reported the potential for increased acute kidney injury and pulmonary oedema. However, these trials failed to risk stratify their patients into severe and non-severe pancreatitis, which may have accounted for their failure to identify improved mortality found in this study, and they concluded that studies are required to investigate subsets of acute pancreatitis, which could benefit from aggressive intravenous therapy.

It is widely accepted practice to risk stratify patients with acute pancreatitis to identify those at risk of developing complications. The basis of this practice is that the triaging of patients within 48–72 hours of presentation allows them to be directed to appropriate levels of care to decrease morbidity and mortality. Although risk stratification is advocated by published guidelines, no single prediction tool has been proven to be the gold standard in practice [17,18]. With a spectrum of severity prediction tools in use in clinical practice, it was found in this cohort that use of the Glasgow-Imrie score was the most prevalent, likely due to the relative simplicity of use. Although the Glasgow score has been criticised as being a poor predictor of pancreatitis severity [19], the fact that it is widely known by junior surgical trainees, who arguably have the maximum influence on the initial volume of intravenous fluid being prescribed, adds to its value in comparison to no severity score being considered. Higher Glasgow scores triggered the clinicians to increase the aggressiveness of their treatment, resulting in significantly higher volumes of intravenous fluids being prescribed. In those with severe disease, more aggressive fluid prescription within 24 hours of admission was associated with improved mortality.

Going forward, this study provides further support towards the need for performing a RCT, specifically looking at the severe pancreatitis patient population, to provide the evidence required to establish if the significant decrease in mortality with increased fluid prescription in patients with severe pancreatitis is causative, and furthermore, establish a recommended fluid regime protocol. Although the study design will be challenging due to the acute nature of disease presentation, the WATERFALL TRIAL has proven that such trials are possible. Alternatively, a cluster trial design, which randomised individual units to specific fluid regimes in appropriate patients, with regimes differing according to volumes given and with volumes administered based on either weight or goal-directed approaches, could be used to ultimately determine the most efficacious and safe approach in this commonly encountered disease and guide best practice.

Supplementary data related to this article can be found at https://doi.org/10.14701/ahbps.23.044.