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Early Fluid Resuscitation in Acute Pancreatitis: A Lot More Than Just Fluids

cute pancreatitis (AP) is a common and potentially lethal acute inammatory process involving the pancreas and extrapancreatic organs that causes considerable morbidity and mortality. AP is a major health care issue in the United States with an increasing frequency of hospitalizations and costs.1 Approximately 20% of patients with AP develop a severe course and suffer from systemic inammatory response (SIR) and/or pancreatic necrosis (PNec). Several pharmacologic agents including protease inhibitors (ie, gabexate mesylate), a platelet-activating factor inhibitor (lexipafant), and agents directed at reducing pancreatic secretions (ie, somatostatin) have been evaluated as a means of altering the disease course, with none showing proven benet in clinical trials.2 Thus, there are currently no pharmacologic therapies available for clinical use in AP. The lack of effective pharmacologic treatment reects our limited understanding of the early pathogenetic mechanisms involved in the development of SIR and our moderate-to-poor ability at predicting disease severity at the time of admission. The standard management of AP early in the course of the disease, dened as the rst 72 hours, is primarily supportive (ie, uid resuscitation, pain control, correction of electrolyte disturbances, and intensive care support when cardiovascular and/or respiratory failure develops). The only exception is in patients with gallstone pancreatitis complicated by choledocholithiasis with biliary obstruction and/or cholangitis, in whom urgent endoscopic retrograde cholangiopancreatography (ERCP) is of proven benet. The cornerstone of supportive care in AP, however, lies in early uid resuscitation. Why is adequate uid resuscitation so important early in the course of AP? Animal studies have shown that pancreatic microcirculation plays a central role in modulating the severity of AP.3 In response to pancreatic injury and intrapancreatic enzyme activation, several proinammatory cytokines and vasoactive factors are locally recruited. Such mediators lead to increased capillary permeability, causing a vascular leak phenomenon, subsequent intravascular volume depletion, and underperfusion of the pancreas and other vital organs. This process is complicated further by the formation of microthrombi. Impaired pancreatic microcirculation augments pancreatic tissue ischemia and the degree of PNec, in addition to exacerbating SIR and remote organ dysfunction. There is agreement among experts that early aggressive uid resuscitation may correct hypovolemia caused by third spacing, enhance pancreatic perfusion, and preserve pancreatic microcirculation in the early phase of AP. This is reected in recent clinical practice guidelines issued by the major gastrointestinal scientic societies.4,5 The American College of Gastroenterology guidelines and the American Gastroenterology Association technical review, published in 2006 and 2007, respectively, recommended early vigorous uid resuscitation targeted toward correcting hemoconcentration and maintaining adequate urine output in such patients. The available literature in human beings is scarce, with only a limited number of small, mainly single-center studies having assessed the impact of uid resuscitation in the clinical course of AP. In 2002, a retrospective study by Brown et al,6 involving 39 patients with AP and hemoconcentration on admission (hematocrit, 44%), reported

that aggressive uid resuscitation for 24 hours (average, 4.2 L of crystalloid uids) did not prevent the development of PNec. Importantly, this study showed that patients with persistence of hemoconcentration at 24 hours, despite aggressive uid resuscitation, progressed to PNec. In 2006, a retrospective study from Sweden by Eckerwall et al,7 involving 99 patients with severe AP based on Atlanta classication, reported that administration of more than 4 L of crystalloid uids during the rst 24 hours of admission was associated with an increased rate of respiratory complications and intensive care unit admissions. There was no difference in mortality based on the extent of uid resuscitation (overall mortality, 17%). A recent retrospective study from our center involving 129 patients with AP, who underwent contrast-enhanced computed tomography, also assessed the amount of uid hydration given within the rst critical 48 hours. A similar volume of crystalloid uids was found to have been administered to patients who developed PNec when compared with those without PNec (average, 4.3 L the rst 24 h and 8.2 L within 48 h). The investigators concluded that intravenous hydration patterns alone could not account for the development of PNec in this cohort of patients.8 In a small retrospective study of 35 patients with severe AP, Gardner et al9 introduced the term early uid resuscitation, dened as the administration of 33% or more of the initial 72-hour uid volume within the rst 24 hours of hospital admission, and late uid resuscitation as administering less than 33% of this volume, regardless of the amount of uid administered in the initial 72-hour period. The investigators reported that patients in the early resuscitation group experienced less mortality and tended to have lower rates of persistent organ failure when compared with patients with late resuscitation. There was also a trend toward larger amounts of uid given during the rst 72 hours in the early resuscitation group (12.2 L vs 7.7 L). In a recent randomized controlled trial from China by Mao et al, 115 patients with severe AP (APACHE-II score 8 and hematocrit 44%) were randomly assigned to slow or rapid hemodilution.10 The amount of uid used in the rapid hemodilution group was signicantly larger than that used in the slow hemodilution group both in the admission day (4.8 L vs 3.9 L) and the rst hospital day (5.8 L vs 4.8 L, respectively). Both sepsis and mortality rates were signicantly higher in the rapid hemodilution group (34% vs 15% for mortality). The authors concluded that rapid hemodilution could increase the incidence of sepsis and in-hospital mortality in severe AP patients and suggested that hematocrit should be maintained between 30%40% during the acute response stage. In the rst study featured in this issue of Clinical Gastroenterology and Hepatology, Warndorf et al11 analyzed retrospective data from a large cohort of 436 patients with AP following the above denitions of early and late uid resuscitation. Early resuscitation was found to be associated with decreased SIR system scores, decreased organ failure at 72 hours (but not at 24 h), a lower rate of intensive care unit admission, and a shorter length of stay. Of note, the average amount of crystalloid uids was signicantly higher in the early resuscitation group when compared with the late resuscitation group (3.5 L vs 2.4 L in the rst 24 h). This study is limited by being retrospective, involving only a single center, and including patients over a long time period (24 y), during which concepts of uid resuscitation and intensive care unit care have changed dramatically. The investigators selected to stratify patients
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:633 634

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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 8

using ratios of uid volumes, because such an approach eliminates reliance on absolute uid volumes, which do not correct for patient size and intravascular volume. On the other hand, this trial represents a large study to assess the impact of early uid resuscitation on clinical outcomes in AP and conrms expert opinion and clinical practice guidelines. Many questions regarding the actual parameters of early uid replacement, however, remain unanswered. What is the optimal rate, volume, and duration for uid resuscitation? How frequently do complications secondary to uid resuscitation (ie, pulmonary edema or sepsis) occur? What type of intravenous uid improves outcome? Which clinical marker should guide resuscitation? The second study featured in this issue of Clinical Gastroenterology and Hepatology is the rst prospective, randomized controlled trial on early uid resuscitation.12 This is a 4-arm, randomized controlled trial, which compared the effect of a goal-directed uid resuscitation vs standard uid resuscitation during the rst 24 hours of hospitalization of 40 consecutive patients with AP. The impact of 2 different crystalloid uids (Lactated Ringers vs normal saline) on early systemic inammation was also assessed. Results revealed that similar uid volumes were infused using either the goal-directed uid resuscitation protocol or standard uid resuscitation strategies (4.3 L vs 4.6 L in the rst 24 h), which precluded adequate evaluation of the goal-directed protocol. Patients resuscitated with Lactated Ringers, however, had reduced systemic inammation, based on CRP levels, compared to those that received saline. The investigators thus suggested that Lactated Ringers might offer improved pH-homeostasis and electrolyte balance when compared to normal saline. This study is limited by being small; therefore, the impact of Lactated Ringers on systemic inammation, although promising, should be interpreted with caution. How do we manage patients with early AP in our clinical practice? Our initial efforts focus on prompt diagnosis and initiation of uid hydration in the emergency room, followed by early assessment of disease severity based on admission laboratory work and the presence of 2 or more of the 4 SIR system criteria, in addition to triaging patients to the appropriate level of care. We advocate the administration of 1 to 2 L of crystalloids, preferably Lactated Ringers (approximately 20 mL/kg) wide open in the emergency room, followed by a continuous infusion of 150 to 300 cc/h (approximately 3 mL/kg/h) for the rst 24 hours. This resuscitation scheme may be even more rigorous in patients with a high hematocrit level at admission ( 44%), high blood urea nitrogen level ( 20 mg/dL), or a high SIR system score, in the absence of signicant cardiac or renal disease. After the initial 24 hours of care, assessment of patients at bedside and review of repeat laboratory work guides further uid replacement. A maintenance rate of about 2 mL/kg/h is used in those patients who respond to early hydration vs a rate of 3 mL/kg/h in patients refractory to initial uid resuscitation. Our clinical practice in patients undergoing ERCP, who are at moderate-to-high risk for postERCP pancreatitis includes placement of prophylactic pancreatic duct stents, and the infusion of 1 to 2 L of intravenous uids wide open at the end of the procedure in the recovery area. In summary, early uid resuscitation is a universally accepted paradigm for improving clinical outcomes in AP, which can be broadly applied even in small community medical centers. The optimal parameters of uid resuscitation, however, are still unclear and further randomized controlled trials to assess different uid solutions and infusion rates are needed. Despite previous unsuccessful attempts, the development of effective pharmacologic therapies for AP

is also of great importance. Barriers to such approaches include the dynamic and variable nature of AP, the fact that severe AP is a rare clinical outcome, difculty in identifying suitable candidate drugs, and the cost of selective anti-inammatory agents. It is imperative, however, to move forward with smaller phase I/II trials to establish safety and efcacy based on surrogate end points. Only the most promising pharmacologic agents with an excellent safety prole and rapid onset of action can then transition to phase III large-scale trials.

JOHN Y. NASR, MD GEORGIOS I. PAPACHRISTOU, MD Division of Gastroenterology, Hepatology and Nutrition Department of Medicine University of Pittsburgh Pittsburgh, Pennsylvania
References
1. Fagenholz PJ, Castillo CF, Harris NS, et al. Increasing United States hospital admissions for acute pancreatitis; 1988 2003. Ann Epidemiol 2007;17:491 497. 2. Gardner TB, Vege SS, Pearson RK, et al. Fluid resuscitation in acute pancreatitis. Clin Gastroenterol Hepatol 2008;6:1070 1076. 3. Bassi D, Kollias N, Fernandez-del Castillo C, et al. Impairment of pancreatic microcirculation correlates with the severity of acute experimental pancreatitis. J Am Coll Surg 1994;179:257263. 4. Forsmark CE, Baillie J, AGA Institute Clinical Practice and Economics Committee; AGA Institute Governing Board. AGA Institute technical review on acute pancreatitis. Gastroenterology 2007; 132:20222044. 5. Banks PA, Freeman ML, Practice Parameters Committee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006;101:2379 2400. 6. Brown A, Baillargeon JD, Hughes MD, et al. Can uid resuscitation prevent pancreatic necrosis in severe acute pancreatitis? Pancreatology 2002;2:104 107. 7. Eckerwall G, Olin H, Andersson B, et al. Fluid resuscitation and nutritional support during severe acute pancreatitis in the past: what have we learned and how can we do better? Clin Nutr 2006;25:497504. 8. Muddana V, Whitcomb DC, Khalid A, et al. Elevated serum creatinine as a marker of pancreatic necrosis in acute pancreatitis. Am J Gastroenterol 2009;104:164 170. 9. Gardner TB, Vege SS, Chari ST, et al. Faster rate of initial uid resuscitation in severe acute pancreatitis diminishes in-hospital mortality. Pancreatology 2009;9:770 776. 10. Mao EQ, Fei J, Peng YB, et al. Rapid hemodilution is associated with increased sepsis and mortality among patients with severe acute pancreatitis. Chin Med J 2010;123:1639 1644. 11. Warndorf MG, Kurtzman JT, Bartel MJ, et al. Early uid resuscitation and reduced morbidity in acute pancreatitis. Clin Gastroenterol Hepatol 2011;9:705709. 12. Wu B, Hwang J, Gardner T, et al. Early uid resuscitation strategies in acute pancreatitis: a randomized-controlled trial. Clin Gastroenterol Hepatol 2011;9:710 717.

Conicts of interest The authors disclose no conicts. doi:10.1016/j.cgh.2011.03.010

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