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Animal studies have long demonstrated the vulnerability of pancreatic parenchyma to ischemic insults [28,29]. This understanding is the basis for all societies’ universal recommendations for early aggressive fluid resuscitation to prevent microcirculatory compromise [13,30–32]. As such, efforts have been made to find surrogate parameters that represent intravascular volume deficit early in the disease course. The best‐known markers are blood urea nitrogen (BUN) and hemoconcentration (hematocrit). In a landmark observational study using large administrative data, Wu and colleagues showed that BUN elevation and its rise in the first 24 hours of admission was associated with increased mortality and this finding has been validated in multiple subsequent prospective studies using patient‐level data [5,33]. Similarly, hemoconcentration and lack of hemodilution has been associated with pancreatic necrosis in several studies [34].

Table 4.1 Existing scoring systems for prediction of severe pancreatitis.

Source: adapted from Mounzer et al. [6].

Namea	Score component	Comment	AUC for severe pancreatitis
Ranson’s	Admission: age (>55 years), WBC (>16 × 109/l), glucose (>200 mg/dl), LDH (>350 IU/ml), AST (>250 IU/ml) 48 hours: hematocrit (decrease >10%), BUN (increase >5 mg/dl), calcium (<8 mg/dl), PaO 2 (<60 mmHg), base deficit (>4 mEq/l), fluid sequestration (>6 l)	Needs 48 hours of clinical data Requires blood gas and careful fluid balance data: not routinely available in every patient	0.69–0.72 [6,8]
Glasgow	Age (>55 years), WBC (>15 × 109/l), glucose (>180 mg/dl), BUN (>45 mg/dl), PaO 2 (<60 mmHg), calcium (<8 mg/dl), albumin (<3.2 g/dl), LDH (>600 IU/l)	Validated and commonly used in trials including predicted severe acute pancreatitis [20,21] Not all components routinely available or checked PaO 2 (<60 mmHg), LDH (>600 IU/l)	0.73–0.84 [6,10,22]
APACHE‐II	Age, temperature, MAP, heart rate, respiratory rate, A–aPaO 2 or PaO 2, arterial pH or HCO3, sodium, potassium, creatinine, hematocrit, WBC, GCS score, chronic health problemsb	Cumbersome to calculate with lack of clear superiority over other models	0.77–0.80 [6,8,9]
SIRS	Temperature (<36 or >38°C), heart rate (>90 bpm), respiratory rate (>20/min or PaCO 2 <32 mmHg), WBC (<4 × 109/l, >12 × 109/l or >10% bands)	Extremely easy to calculate and all components widely available Reflects only one pathophysiological mechanism of severity (i.e. host inflammatory response)	0.70–0.88 [6,10,23]
Panc 3	Hematocrit (>44%), BMI (>30 kg/m2), pleural effusion	Simple score but it requires a chest X‐ray; inferior accuracy and sensitivity	0.64–0.76 [6,11]
POP	Age, MAP, PaO 2/FiO 2, arterial pH, BUN, calcium	Derived from intensive care unit patients with acute pancreatitis May not be applicable to patients on the regular nursing floor Requires an arterial gas reading	0.67–0.83 [6,24]
BISAP	BUN (>25 mg/dl), impaired mental status (GCS score <15), SIRS (≥2), age (>60 years), pleural effusion	Easy to calculate Requires chest X‐ray Most extensively validated among all scores Poor sensitivity, thus low negative predictive value	0.72–0.90 [6,8,10]
JSS	Base excess (≤3 mEq/l), PaO 2 (≤60 mmHg or respiratory failure), BUN (≥40 mg/dl) or creatinine (≥2 mg/dl), LDH (≥2× upper limit of normal), platelets (≤100 × 109/l), calcium (≤7.5 mg/dl), CRP (≥15 mg/dl), SIRS (≥3), age (≥70 years)	More cumbersome to calculate than BISAP score without offering clear performance advantage Requires an arterial blood gas sample	0.76–0.83 [6,9]
HAPS	Abdominal tenderness, hematocrit (>43% for men or >39.6% for women), creatinine (>2 mg/dl)	Extremely simple More applicable for patients in the emergency room Designed to identify patients with “nonsevere” pancreatitis	0.62–0.85 [6,25]
PASS	Organ failure (100 points) SIRS (25 points for each criterion) Abdominal pain (5 points) Morphine equivalent dose (5 points/mg) Tolerating solid diet (yes = 0, no = 1 – 40 points)	Designed to be measured and followed over time Easy to calculate and measure Needs validation studies	0.7 [26,27]

^a SIRS, systemic inflammatory response syndrome; Panc, pancreatitis; POP, Pancreatitis Outcome Prediction; BISAP, Bedside Index for Severity of Acute Pancreatitis; JSS, Japanese Severity Score; HAPS, Harmless Acute Pancreatitis Score; PASS, Pancreatitis Activity Scoring System.

^b Chronic health conditions: cirrhosis with portal hypertension, New York Heart Association class IV heart failure, chronic respiratory failure, dialysis‐dependent renal failure, or immunocompromised state.

AST, aspartate aminotransferase; AUC, area under the response curve; BMI, body mass index; BUN, blood urea nitrogen; CRP, C‐reactive protein; GCS, Glasgow Coma Scale; LDH, lactate dehydrogenase; MAP, mean arterial pressure; WBC, white blood cell count.

While these parameters are readily available predictors of severity, they have limitations. BUN level is also a function of a patient’s muscle mass and it decreases with age. Additionally, it is elevated at baseline in patients with chronic kidney disease. Hematocrit is affected by anemia and age, so it is not a reliable marker in such populations. Nevertheless, their simplicity and strong association with necrosis and mortality led to studies examining the impact of lowering BUN and hemodilution on AP outcomes, with mixed results [35–37].

Interestingly, existing fluid resuscitation studies failed to convincingly show that lowering BUN and hematocrit improved outcomes [38]. This could suggest that hemoconcentration and BUN elevation may simply indicate the severity of disease that has already occurred rather than being early markers, and they unfortunately do not represent a targetable end point for volume resuscitation. Additionally, intravascular volume deficit is ultimate result of complex pathophysiological events such as capillary leakage, systemic inflammation, and vascular shunting. This highlights the need for a more sensitive and specific biomarker that can detect intravascular volume deficit at the earliest stage. While novel noninvasive tools have been developed to dynamically measure volume deficit in other clinical settings, none have been extrapolated for use in AP patients [39,40].

Fluid sequestration and intra‐abdominal hypertension are other important phenomena relative to AP severity. Patients often have systemic capillary leak syndrome leading to severe “third‐spacing” of fluids. Age under 40 years, alcohol etiology, hemoconcentration, and presence of SIRS are risk factors for fluid sequestration and predicted severity of AP [41,42]. Aggressive fluid resuscitation in this population will eventually lead to intra‐abdominal hypertension and compartment syndrome, which portends a poor prognosis [43]. As such, intra‐abdominal pressure as measured via a urinary catheter has been examined as a predictor of severity with promising results [44]. At a biomarker level, angiopoietin‐2, a regulator of capillary permeability, has been shown to predict severe pancreatitis [45,46].