According to the Revised Atlanta Classification (a standard that defines complications and severity of AP), severity is categorized into three levels: mild (absence of complications), moderately severe (presence of local complications, transient-lasting up to 48 hours-organ failure or exacerbation of previous co-morbidity), and severe (presence of persistent-lasting more than 48 hours-organ failure) [5]. Based on a prospective multicenter study carried out by our group at a national level, pancreatitis is mild in 65% of cases, with an excellent prognosis. In 28% it is moderately severe, with notable morbidity but low mortality, and in 7% of cases it is severe with a 50% mortality rate [3].

Pancreatitis is an inflammatory disease with an acute onset. An intense inflammation inadequately controlled by the immune system can lead to local complications (peripancreatic fluid collections, necrosis of the pancreatic gland and/or the fatty tissue surrounding it) and organ failure (cardiovascular, renal and/or respiratory) [5,6]. In the context of a common acute disease that can cause both local and systemic complications, it would be ideal to have a treatment capable of controlling the initial inflammatory process, and altering its natural course. However, we currently lack available drugs that achieve this. Presently, the management of AP in its initial phase relies on supportive treatment, which primarily includes fluid therapy, pain relief, monitoring for early signs of organ failure, and, in some patients, nutritional support [7]. Notably, fluid therapy has been emphasized in the early phase of pancreatitis for nearly thirty years [8]. The pancreas secretes inactive digestive enzymes (zymogens) that are activated in the intestine to initiate the digestive process. An intrapancreatic enzymatic activation can initiate acinar cell damage that triggers a complex inflammatory cascade, in which different proinflammatory mediators recruit immune system cells to the pancreas [9]. The release of intracellular molecules and elements (Damage Associated Molecular Patterns, DAMPs), such as histones, by acinar cell necrosis also contributes to the stimulation of the immune system [9]. A controlled inflammatory response results in mild AP, without complications and with an uneventful disease course. However, extensive phenomena of cellular necrosis and local inflammation are associated with local complications. The massive release of DAMPs results in a significant proinflammatory reaction of the immune system which may be associated with systemic manifestations (systemic inflammatory response syndrome) [9]. If this intense inflammation is not adequately controlled, organ failure (renal, respiratory, cardiovascular/ distributive shock) or a combination of these may be triggered. Organ failure is the most feared complication, because it is associated with increased mortality, especially multi-organ failure or failure lasting more than 48 hours (both associated with a 50% mortality rate) [3].

In an observational study conducted by our group and Brigham and Women’s Hospital in Boston (USA), we found that each patient with AP has different fluid requirements in the initial days of the disease. These requirements can fluctuate between a neutral balance (no extra requirements) and the need for several liters of fluid resuscitation each day due to a significant positive fluid balance caused by the retention of large amounts of administered fluids in the body (fluid sequestration) [10]. The severity of the disease, along with the development of local complications and organ failure, were major determinants of fluid sequestration. Thus, in general, cases of mild AP do not have increased fluid requirements, but moderately severe to severe AP carries a high risk of hypovolemia. Hypovolemia is a condition characterized by a decreased volume of blood circulating in the body, which can lead to inadequate tissue perfusion and organ dysfunction: renal failure and shock. In addition, if an excessive volume of fluids is administered, we can cause fluid overload, which can lead to respiratory failure due to acute pulmonary edema and cardiovascular failure. As we mentioned before, organ failure is the most feared complication of AP due to its strong association with mortality. A lack or excess of fluid volume can harm the patient. There would be an ideal balance in which the fluid administration strategy would be efficient in treating hypovolemia, but without tending towards the excessive overload that is associated with cardiac and pulmonary complications. Unfortunately, we do not have precise means of calculating the fluid deficit that patients have. Therefore, on the one hand, we must look for efficient fluid administration strategies, and on the other hand, new markers of fluid needs that allow for personalized medicine.

The endothelium is a layer of endothelial cells that lines the internal surface of blood vessels, acting as a barrier between blood and tissue [11]. This semi-permeable barrier exchanges plasma, nutrients, and metabolites between the organs and the blood [11]. The glycocalyx is a protective carbohydrate-rich layer covering the endothelium’s luminal surface. It is composed mainly of membrane-bound proteoglycans (such as syndecans and glypicans), glycosaminoglycans (such as heparan sulfate, chondroitin sulfate and hyaluronan) and glycoproteins (cell adhesion molecules and components of the coagulation and fibrinolysis systems) [11]. The glycocalyx plays several key roles in vascular homeostasis: it regulates the response of the endothelium to changes in blood flow, it acts as a barrier to prevent inappropriate activation of coagulation, it participates in the interaction between endothelial cells and circulating mediators and limits the passage of fluids and proteins from the blood to the tissues [11-14]. Under physiological conditions, the endothelial glycocalyx undergoes continuous turnover. However, numerous pathological conditions such as acute diseases, inflammation, shock, aggressive fluid resuscitation and hypoperfusion have been linked to its deterioration. The process is marked by the release of its components into the bloodstream, ultimately leading to endothelial dysfunction [14]. Consequently, this damage may contribute to the development of capillary leak syndrome [15] and activation of coagulation [11]. Capillary leak syndrome is a pathological condition observed in acute inflammatory diseases like AP, characterized by increased vascular permeability, leading to fluid and protein extravasation into the interstitial space, resulting in hypovolemia, edema, and potential organ dysfunction. Microcirculatory changes in the pancreas may induce necrosis of the gland [16], so we can hypothesize that endothelial dysfunction may be involved in local complications in AP [15]. Importantly, different components of the glycocalyx, such as shed proteoglycan ectodomains, hyaluronan fragments and free heparan sulfate chains, function as DAMPs, which when released into the circulation, exacerbate endothelial dysfunction, trigger inflammatory cascades, and contribute to microvascular injury thereby compromising the effectiveness of interventions such as intravenous fluid resuscitation [17] For all these reasons, the endothelium and the glycocalyx appear to be key elements in the intravenous fluid requirements of patients with AP. Their integrity could improve the prognosis, and markers associated with their dysfunction could help us detect those patients who require a greater volume of fluids or who are at risk of pancreatic necrosis.