REVIEW. Current Controversies in Fluid Resuscitation in Acute Pancreatitis. A Systematic Review

Transcription

1 REVIEW Current Controversies in Fluid Resuscitation in Acute Pancreatitis A Systematic Review Guru Trikudanathan, MBBS,* Udayakumar Navaneethan, MD,Þ and Santhi Swaroop Vege, MDþ Abstract: Acute pancreatitis (AP) is a common inflammatory disorder of the pancreas resulting in considerable morbidity and mortality. Aggressive intravenous fluid resuscitation generally is recommended in all patients with AP and remains the cornerstone of management of these patients. However, the optimal rate, type, and the goal of resuscitation remain unclear. The purpose of this review was to give an insight about the pathophysiologic alterations in the pancreatic microcirculation that occur in AP, the markers for early recognition of severity of pancreatitis, the optimal fluid, and timing and extent of fluid resuscitation. An early elevated hematocrit, blood urea nitrogen, or creatinine should prompt clinicians to institute more intensive early resuscitation measures. Crystalloids are the currently recommended fluids for management of these patients. Current studies are underway to determine the optimal end points of fluid resuscitation that determine outcome. Key Words: acute pancreatitis, fluid resuscitation, crystalloids, colloids, hematocrit Abbreviations: AP - acute pancreatitis, BUN - blood urea nitrogen, CVP - central venous pressure, SAP - severe acute pancreatitis, SIRS - severe inflammatory response syndrome (Pancreas 2012;41: 827Y834) Acute pancreatitis (AP) is an acute inflammatory process involving the pancreas, frequently affecting the peripancreatic tissue and less commonly the remote organ systems. It accounts for nearly 220,000 hospitalizations annually in the United States and is considered the third most common gastrointestinal discharge diagnosis. 1,2 Acute pancreatitis represents a spectrum of disease ranging from mild, self-limited course needing only brief hospitalization to a rapidly progressive, severe, and fulminant illness culminating into multiorgan dysfunction, as categorized by the most widely accepted Atlanta classification. 3 Recently, 2 separate categories, namely, moderately severe pancreatitis 4 and critical acute pancreatitis, 5 have been proposed as a new addition to the existing Atlanta classification. Current epidemiological surveys estimate the mortality of AP to be around 2% to 5%, but it could be as high as 47% in the event of multiorgan dysfunction. 6 Despite significant strides made in critical care management during the last few decades, the mortality associated with AP has only gradually declined. 7 With the dawn of From the *Department of Internal Medicine, University of Connecticut Medical Center, Farmington, CT; Digestive Disease Institute, The Cleveland Clinic, Cleveland, OH; and Division of Gastroenterology, Department of Internal Medicine, Mayo Clinic, Rochester, MN. Received for publication June 17, 2011; accepted December 9, Reprints: Santhi Swaroop Vege, MD, Division of Gastroenterology, Department of Internal Medicine, 200 First St, S, W Mayo Clinic College of Medicine, Rochester, MN ( vege.santhi@mayo.edu). All authors contributed equally to the manuscript. The authors declare no conflict of interest. Copyright * 2012 by Lippincott Williams & Wilkins the molecular and genomic era of medicine, our knowledge of the complex pathophysiologic mechanisms has exponentially increased, but an effective agent continues to elude us. Therapeutic endeavors directed toward suppressing the pancreatic secretions have not proven to be effective in improving outcomes because of the dynamic and variable nature of AP. Supportive management through aggressive fluid resuscitation, appropriate analgesia, and monitoring for complications continues to remain the cornerstone in the management of AP. A recent small study attributed the decline in mortality observed during the past decade to the current practice of aggressive hydration. 8 The purpose of this review was to give an insight about the pathophysiologic alterations in the pancreatic microcirculation that occur in AP, the markers for early recognition of severity of pancreatitis, the optimal fluid, and timing and extent of fluid resuscitation as well as novel ways to monitor the safety and efficacy of fluid resuscitation. It is hoped that this review of this often overlooked but vital component of management of AP invigorates interest in gastroenterologists toward carefully designed trials to find the most optimum resuscitation strategy in AP. SEARCH CRITERIA In October 2011, an electronic database (MEDLINE, Scopus, and EMBASE) search of the literature from 1980 to the present was performed using the MeSH (Medical Subject Headings) terms acute pancreatitis, severe acute pancreatitis, acute necrotizing pancreatitis, pancreatic necrosis, and pancreatic microcirculation. They were combined with the Boolean operator AND with studies identified by searching the keywords fluid resuscitation, fluid therapy, hemoconcentration, hematocrit, and prognostic marker. Of the 893 citations obtained through the initial search, we excluded citations after reviewing the title and abstract if they were irrelevant to this topic. After preliminary exclusions, we then excluded case reports, letters to the editors and commentaries, and studies in pediatric population. Abstracts not published were removed from the analysis. We finally obtained 60 studies (case control = 22, cohort study = 12). The rest were animal studies used to elucidate the pathophysiology involved. The authors (G.T. and U.N.) independently assessed the full text of the articles selected. Full articles and recent technical guidelines from major gastroenterology societies were evaluated and included in our review. In addition, we incorporated our own research developments in this review article. Pathophysiology and Early Markers of Acute Pancreatitis Alterations in pancreatic microcirculation, such as arteriolar vasoconstriction, increased capillary permeability, and capillary perfusion failure, occur very early in the course of the disease secondary to the local recruitment of proinflammatory cytokines and vasoactive factors. 9,10 This leads to ischemia and Pancreas & Volume 41, Number 6, August

2 Trikudanathan et al Pancreas & Volume 41, Number 6, August 2012 circulatory stasis. 11 In addition to the derangements in the capillary blood flow, enhanced leukocyte-endothelial interaction leads to progression of systemic inflammation. This results in derangement of coagulation cascade leading to a proteasemediated state of hypercoagulability and activation of fibrinolysis. 12 Thus, changes in blood coagulation and blood viscosity impair the pancreatic microcirculation, exacerbating ischemia and reperfusion injury. Reperfusion injury accounts for major acinar damage, which culminates in intracellular activation of proteases and tissue destruction. 13 Early aggressive hydration may correct hypovolemia caused by third spacing and enhances pancreatic perfusion, thereby helping in restoration of pancreatic microcirculation. It further overcomes gut hypoperfusion, enabling the preservation of intestinal integrity and function. The management of AP is complicated by the failure to discriminate between mild from severe disease during the early stages, contributing to its unpredictable outcome. 14 Recent studies by Wu and Conwell 15 indicate that the incidence of organ failure to be maximum in the first day at 17%, declining to 5% and 2% on the second and third day of hospitalization. Recent evidence from critical care literature has shown that the median duration of stay for patients with AP before transferring to intensive care was 1 day. 16 Identification of simple parameters to predict the severity of AP has been an active area of research over the past decade or so, to aid critical decisions to be made within the first 24 to 72 hours, the so-called interventional window of AP. 14 The pathophysiologic role of fluid loss in determining the severity of AP and the crucial role of fluid replacement in the prognosis of the disease are evident from the fact that, of the 11 points in Ranson criteria of severity of AP, 4 are directly related to fluid resuscitation (urea, net fluid sequestration, base deficit, and decreased hematocrit). An effectual approach in management of AP would be to pursue a goal-directed resuscitation based on dynamic laboratory monitoring of simple parameters. 17 Further early recognition of patients refractory to initial rehydration would assist us to identify patients who are likely to benefit from intense hemodynamic monitoring in critical care setting. 17 Hemoconcentration at admission is a readily available laboratory test that has been studied as a potential early marker of severity for nearly 5 decades. 18 A hematocrit of 47 or greater on admission and/or failure of the admission hematocrit to decrease at 24 hours suggestive of severe impairment of pancreatic microcirculation was the best binary risk factor for the development of necrosis. 19 A subsequent prospective study by the same group identified patients with AP and determined that an admission hematocrit greater than or equal to 44 and/or a failure of the same to decrease within 24 hours was a significant predictor of both pancreatic necrosis and organ failure. 20 In a retrospective study to determine whether fluid resuscitation could avert pancreatic necrosis among patients with hemoconcentration at admission, 39 patients rehydrated with crystalloid solutions failed to demonstrate that fluid resuscitation prevents pancreatic necrosis. However, patients with inadequate fluid resuscitation as evidenced by persistence of hemoconcentration at 24 hours developed necrotizing pancreatitis. 21 Subsequent, follow-up studies failed to demonstrate the utility of hemoconcentration as a robust predictor of necrosis and organ failure. 22Y26 However, discordant results were attributed to the transfer status of the patients. 27,28 They concluded that early hemoconcentration was linked with increased mortality only among transferred patients who had a more severe disease at baseline with a trend toward less aggressive resuscitation. 28 They further emphasized that the impact of transfer status must be taken into account when assessing future prognostic markers. 28 The value of hematocrit at admission for the initial assessment for AP patients and its implications in the prognosis remain controversial. In a large, hospital-based cohort study, early changes in blood urea nitrogen (BUN) accurately predict outcome in AP. 17 They identified serial BUN measurements as the most valuable single routine parameter for predicting hospital mortality during the first 24 hours of hospitalization. They also validated BUN measurement for early prediction of mortality in patients with AP. 29 In this important study, they had combined data from 3 major pancreas centers, carefully avoided selection bias, and also excluded transferred patient from the final analysis. An accompanying editorial pointed out that they had not controlled for 2 potential confounders, namely, body mass index and medical comorbid conditions. 30 However, this was a major breakthrough, and they recommended careful monitoring of BUN to gauge the effectiveness of initial resuscitative measures. 19,29 An elevated creatinine of greater than 1.8 mg/dl within 48 hours of admission has a 35-fold likelihood of development of pancreatic necrosis (odds ratio, 34.5; 95% confidence interval, 7.3Y163). 31 The authors hypothesized that although both changes in BUN and creatinine from baseline are indicative of intravascular volume depletion, creatinine is less sensitive to minute changes in intravascular volume and is superior in reflecting visceral organ injury. 31 However, these findings could not be confirmed as an elevated creatinine of 2 mg/dl at any time during the first 48 hours after admission was not a marker of pancreatic necrosis. Instead, they concluded in their multicenter trial involving community hospitals that if the creatinine is normal, necrotizing pancreatitis is unlikely. 32 In an accompanying editorial, the differences in the study cohort were highlighted as responsible for the differences in the reported predictive parameters. Muddana et al 31 reasoned that there was a higher proportion of severe pancreatitis in their cohort, as reflected by a higher rate of pancreatic necrosis (27% vs 13%) and more severe outcome (26% vs 14%). Thus, serum creatinine is a superior predictor in populations with a higher incidence of severe patients. 33 In a recent study that explored whether early fluid resuscitation changed the outcome, early resuscitation was associated with decreased severe inflammatory response syndrome (SIRS), as well as reduced organ failure, a lower rate of admission to the intensive care unit (ICU), and a reduced length of hospital stay. 34 Thus, an early elevated hematocrit, BUN, or creatinine should prompt clinicians to institute more intensive early resuscitation measures. Combining one or all these parameters with intense monitoring of urine output and hemodynamics may provide optimal targets for future, goal-directed resuscitation in AP and warrants further clinical trials (Tables 1Y3). Type of FluidVCrystalloid Versus Colloids When it comes to choosing the resuscitation fluids, clinicians have a broad range of options. At the fundamental level, the choice is between a crystalloid fluid and a colloid. The most appropriate fluid for resuscitation in AP is yet to be determined. There have been multiple animal studies in the past that have looked at crystalloids, especially the lactated Ringer s solution and Ringer s ethyl pyruvate solution, and more recently the focus has been on hypertonic saline. In one of the early studies, high versus low volume of lactated Ringer s solution in pancreatic microcirculation in 14 dogs with bile-trypsin pancreatitis was investigated. They found that the pancreatic blood flow decreased significantly in the lowinfusion group in comparison with the high-infusion group. However, the vigorous fluid rehydration did not completely terminate the pathologic process * 2012 Lippincott Williams & Wilkins

3 Pancreas & Volume 41, Number 6, August 2012 Fluid Resuscitation in Acute Pancreatitis TABLE 1. Published Studies on Admission Hematocrit as a Marker for Pancreatic Necrosis (PNec) Study Nature of Study No. Patients Study Period, mo Outcome Baillargeon et al 19 (1998) Retrospective Hematocrit (Hct) Q47 on admission or a failure at admission Hct to decrease at approximately 24 h was a strong risk factor for PNec Brown et al 20 (2000) Prospective Admission hematocrit (Hct) Q44% and admission Hct that does not decrease at 24 h are strong risk factors PNec and organ failure Lankisch et al 24 (2001) Prospective Hemoconcentration does not significantly correlate with clinical outcome variables including organ failure and mortality rate. Its value lies in its high negative predictive value. In the absence of hemoconcentration, contrast-enhanced computed tomography may be unnecessary on admission Pezzili and Morselli-Labate 25 (2001) Retrospective Hct not a good marker for assessing necrotizing pancreatitis or useful in the assessment of the severity of the clinically established disease. Sex and idiopathic form of pancreatitis correlate with PNec Khan et al 26 (2002) Prospective 58 5 Urinary trypsinogen activation peptide is more accurate than Hct in determining the severity of AP. No association between a rise in Hct and failure of Hct to decrease in determination of severity Gan and Romagnuolo 35 (2004) Retrospective 200 Initial Hct is a significant predictor for PNec, severity of pancreatitis, length of stay, and need for intensive care. Lack of normalization of Hct does not predict the severity of pancreatitis Remes-Troche et al 22 (2005) Retrospective Despite high negative predictive value, hemoconcentration is not a useful marker to predict worse outcome in AP Gardner et al 23 (2006) Retrospective Admission Hct was a poor predictor for necrosis. In a community setting with low rates of necrosis, admission and 24-h Hct levels not helpful in predicting subsequent PNec Wu et al 27 (2009) Retrospective Early hemoconcentration predicted increased risk of mortality only among transferred patients Wu et al 28 (2010) Prospective Transfer status is a powerful confounder in the relationship between hemoconcentration and PNec Ringer s ethyl pyruvate solution is a novel resuscitation fluid that replaces the lactate in lactated Ringer s with the stable form of pyruvate. Pyruvate, being a potent antioxidant, reduces pancreatic edema and necrosis and ameliorates injury of distant organs in AP by down-regulating inflammation, thus improving survival in mice with necrotizing pancreatitis. 39 In a recently published randomized controlled trial comparing normal saline versus lactated Ringer s solution, patients with AP who were resuscitated with lactated Ringer s solution had reduced systemic inflammation compared with those who received saline. 40 Also, the administration of lactated Ringer s solution also reduced levels of C-reactive protein, compared with normal saline (51.5 vs 104 mg/dl, respectively). This trial holds promise about the potential role of lactated Ringer s solution as a resuscitation fluid in the future. Currently, hypertonic saline as a resuscitation fluid has come under scrutiny. Besides restoring the circulating volume, it is known to exert favorable effects on cardiac contractility, TABLE 2. Published Studies on Elevated BUN as a Marker for Pancreatic Necrosis (PNec) Study Nature of Study No. Patients Study Period, y Outcome Wu et al 17 (2009) Prospective, multicentric An elevated BUN on admission and a raised BUN after 24 h were independent predictors of mortality. Serial BUN was the most significant single prognostic marker in AP Faisst et al 83 (2010) Retrospective, single center Patients with elevated BUN on admission had a significantly longer stay in the ICU. BUN is a cheap predictor of ICU stay and probable survival in acute necrotizing pancreatitis Wu et al 29 (2011) Secondary analysis of 3 multicentric prospective studies 1043 V BUN 920 on admission or rise in BUN at 24 h correlates with mortality. Accuracy of serial BUN measurements was comparable to Acute Physiology and Chronic Health Evaluation II * 2012 Lippincott Williams & Wilkins 829

4 Trikudanathan et al Pancreas & Volume 41, Number 6, August 2012 TABLE 3. Published Studies on Admission Hematocrit as a Marker for Pancreatic Necrosis (PNec) Study Nature of Study No. Patients Study Period, y Outcome Talamini et al 36 (1996) Retrospective, single center Serum glucose 9250, serum creatinine 92 mg/dl, pathologic chest x-ray are significant predictors of death Talamini et al 37 (1999) Muddana et al 31 (2008) Lankisch et al 32 (2010) Retrospective multicentric Retrospective, single center Retrospective multicentric Chest x-ray showing pleural effusion and/or pulmonary parenchymal densification are 2 simple tests for identifying AP severity and predicting PNec and infected PNec within 24 h of admission Low admission Hct indicates low risk of PNec. An increase in creatinine within 48 h strongly associated with PNec An elevated creatinine at any time during the first 48 h of admission is not a marker for PNec during first attack of AP blood pressure, and peripheral tissue perfusion. 39,41,42 It significantly facilitates pancreatic microcirculation, by causing shrinkage of endothelial cells through the establishment of a potent osmotic gradient. It is also known to abrogate neutrophil priming by inhibiting intracellular signaling pathways and also cause down-regulation of neutrophil burst activity. This also results in inhibition of leukocyte adhesion and transmigration, besides enhancing the protective function of T cells following injury. The therapeutic effects of the hypertonic saline in dampening the overexuberant inflammatory response that accompanies AP have been evaluated in several experimental studies. 41Y47 Besides the favorable hemodynamic effects, transient hyperosmolar resuscitation seems to modulate the cytokines toward an anti-inflammatory profile. This attenuates the pancreatic damage (as demonstrated by decreased acinar cell loss, inflammatory infiltrate, fibroblast proliferation, and adipose involvement), besides limiting the end-organ damage due to AP. 39,46 Crystalloids are distributed in both the plasma and the interstitial compartments, and large spaces are thus required to restore the circulation. The infusion of massive amounts of crystalloid fluids to correct the hemodynamic perturbations in AP could lead to pulmonary edema, which could culminate in fatal respiratory distress syndrome. Hypertonic saline effectively reduces the volume of traditional isotonic fluid resuscitation, thus reducing the risk of lung edema in AP. Furthermore, aerosolized hypertonic saline has been shown to attenuate pancreatitis-induced pulmonary injury, by significant reduction in pulmonary endothelial permeability and inappropriate neutrophil sequestration within the alveoli. 43 Very recently, they have been shown to favorably modulate matrix metalloproteinase enzymes, which are important mediators of inflammation implicated in lung injury. They also influence the lung heat shock proteins, which are molecular chaperones that stabilize and refold damaged intracellular proteins and also inhibit the expression of proinflammatory genes. 44 As treatment for acute lung injury following AP still eludes, clinical trials evaluating the safety and utility of this treatment, especially when given early, are warranted. However, the potential adverse effects of aggressive hypertonic therapy, such as central pontine myelinolysis in hyponatremics and risk of renal failure as demonstrated in a clinical trial in burn patients, 48 have raised doubts in its safety in restoring volume deficits. This is likely to impact the acceptance of hypertonic saline as a valid therapeutic approach despite success in the experimental settings. Colloids are considered to be superior to crystalloids in the optimization of the hemodynamic response. However, intravascular volume overload, hyperoncotic renal impairment, coagulopathy, extravasation through leaky capillary membranes, and anaphylactic reaction could occur with the administration of any colloid. Colloids such as dextran enhance blood flow through the correction of hypovolemia from the drug s colloidal osmotic effect in drawing fluid from the interstitial to the intravascular spaces. They also improve microcirculation by reducing blood viscosity and impeding erythrocyte aggregation by maintaining them in a state of electronegativity and mutual repellency. Besides facilitating the passage of erythrocytes through small vessels, they are also known to possess antiplatelet and antifibrin properties. 49 In animal studies, it has been shown that besides inhibiting the progression of pancreatic necrosis by enhancing the pancreatic microcirculation, the inflammatory mediators have less access to the acinus. 50 Furthermore, the reduced trypsinogen activation prevented acinar necrosis and distant organ damage. 51Y55 The effect of isovolemic hemodilution with dextran 60 was evaluated in a phase 1 study involving 13 patients admitted with severe (Balthazar CT class E) nonbiliary pancreatitis. 56 Independent from the exchange procedure, conventional fluid resuscitation through lactated Ringer s solution was given to the patient to maintain a central venous pressure (CVP) at 6 T 2 mm Hg. Hematocrit was maintained between 28% and 32% (the optimal hematocrit to counteract ischemia of peripheral organs) with retransfusion of autologous packed red cells if necessary. No changes in the systemic hemodynamics during the exchange or adverse effects were encountered by the investigators. Interestingly, because of the improvement in the pancreatic microperfusion, 10 of the 13 patients had pain relief in the absence of analgesia during the procedure. After hemodilution, the progression of pancreatic necrosis was reported only in 2 patients, and new areas of necrosis did not evolve. The overall mortality was only 7.7% in this group, with a mean Ranson score of 5. In another human study, 32 patients with severe AP (SAP) were treated with dexamathasone 0.5 to 1 mg/kg per day for 3 to 5 days and dextran 40 at 500 to 1000 ml/d for 7 days besides standard therapy. Twenty-seven patients improved, 5 deteriorated, and 4 of them underwent surgery. Four eventually died. 49 The investigators stated that high-dose dexamathasone when used for a short period can inhibit multiple inflammatory mediators without untoward adverse effects, and dextran helps in microcapillary disorders. Another study in Chinese literature demonstrated improved survival in a group of patients receiving greater amount of colloids and greater ratio of colloids to crystalloid fluids during the first 72 hours. 57 It is well known that the disturbance of the pancreatic microcirculation and the consequent tissue hypoxia perpetuate progression from mild to severe pancreatitis. 58 A cell-free * 2012 Lippincott Williams & Wilkins

5 Pancreas & Volume 41, Number 6, August 2012 Fluid Resuscitation in Acute Pancreatitis hemoglobin-based oxygen carrier (HBOC-301) improves fluidity because of its colloid effects and delivers cell-free oxygen to oxygen-deprived tissue, thus improving pancreatic microcirculation and pancreatic oxygen tension. This was assessed by leukocyte adherence and decreased tissue damage as compared with normal saline in a rodent model. 59,60 Furthermore, a combination of isovolemic hemodilution with hydroxyethyl starch and addition of a plasmatic oxygen carrier (like cell-free bovine hemoglobin HBOC-301) preserved pancreatic microcirculation, reduced mortality, and improved pancreatic tissue oxygenation. 58 This beneficial effect of additional oxygen supply does not lead to enhanced lipid peroxidation as feared. 61 In the future, a combination of rheologic and O 2 -delivering therapy may represent a novel therapeutic option for the treatment of AP. 58 A very recent study published in Chinese literature evaluated the effects of intravenously administered 6% hydroxyethyl starch 130/0.4 (rapidly degradable) solution and furosemide on the outcome of AP patients. Of the 135 patients (54% of patients with a Ranson score Q3 and 61% with a Balthazar CT score QD) receiving this treatment, only 4% and 7% patients developed pancreatic and systemic complications, respectively. 62 To summarize, there is still no consensus on the optimal type of resuscitation fluid appropriate for the management of AP. The American Gastroenterological Association recommends crystalloid in most instances. They further suggested that Colloids may be considered in limited situations: packed red blood cells when the hematocrit falls below 25%, and albumin if the serum albumin level drops to G2 g/dl. 63 German experts have recommended a ratio of 1:3 for colloids and crystalloids strictly based on their clinical experience. 64 Until there are randomized trials demonstrating the superiority of colloids to crystalloids, our resuscitation strategy should be guided by the guidelines. Timing and Extent of Fluid Resuscitation There has been a paucity of studies that looked at the rate and the extent of fluid resuscitation in AP. There have been 2 recent studies reported from the Mayo Clinic that specifically evaluated the impact of aggressive initial rate of resuscitation in the outcomes of SAP. 34,65 In both studies, the investigators stratified patients by the proportion of resuscitation within the first 24 hours of presentation to the emergency room. Therefore, aggressive fluid resuscitation was defined as patients receiving one third (33%) or more of the initial 72-hour fluid volume within the first 24 hours of hospital admission, and nonaggressive fluid resuscitation as those receiving less than one third in the initial 24 hours regardless of the amount of fluid administered in the initial 72-hour period. They demonstrated that the 28 patients in the nonaggressive group experienced significantly higher mortality as compared with the 17 patients subjected to early aggressive resuscitation (17.9% vs 0%, P G 0.04). There was also a trend toward greater degree of organ failure in the nonaggressive group (42.9% vs 35.3%, P = 0.3). 34 Experts pointed out reversal causation bias should also be considered for the poor prognosis associated with the late resuscitation group in this study. 66 In the second study, 73 patients admitted sequentially for a year were prospectively identified, with 42 categorized under the aggressive group and 31 in the nonaggressive group. They concluded that less aggressive initial intravenous fluid resuscitation rate in the first 24 hours of admission was associated with significantly higher SIRS system scores and rates of organ failure and a trend toward longer hospitalizations and more frequent ICU admission. 65 Interestingly, the average amount of crystalloid fluids was significantly higher in the early resuscitation group when compared with the late resuscitation group (3.5 vs 2.4 L in the first 24 hours). In an accompanying editorial, experts pointed out that it was a retrospective single-center study over a long period (24 years) during which the concepts of fluid resuscitation and ICU care have changed phenomenally. 67 However, one may need to pay attention to the amount of fluids especially in patients with diminished cardiac reserve. In a Swedish retrospective study, it was concluded that patients receiving 4000 ml or more of fluids during the initial 24 hours (n = 32) developed more respiratory complications (pleural effusion, atelectases, and pneumonia) as compared with those who received less than 4000 ml (66% vs 53%, P G 0.001). 68 The authors, however, acknowledged that those who received more fluids were sicker and profoundly hypovolumic, which necessitated their transfer to the ICU. They pointed out that because during resuscitation pulmonary edema as a complication was not noted in any patient, it is debatable that overzealous hydration could be implicated for the pulmonary complications. 68 Mao et al 69 reported better survival rates by controlling the amount of fluid resuscitation within the first 72 hours in 83 patients with SAP. In a subsequent study by the same group, they further proposed a strategy of fluid therapy aiming at controlled fluid expansion and restoration of normal body fluid distribution with a hematocrit goal of 30% to 35% during fluid expansion. 70 The same group in a very recent study concluded that rapid hemodilution (hematocrit G35% within 48 hours of onset of SAP) was associated with increased incidence of sepsis and in-hospital mortality within the first 28 days. 71 This study design was criticized for some glaring flaws in study design and the small sample size. The method of randomization was not specified. Patients were using both colloids and 6% hydroxyethyl starch. Some result variables were not adequately reported, for example, the incidence of pancreatic necrosis. Besides, achieving the threshold hematocrit in 1 to 2 days was surprising and suggests massive hydration. In all the 3 studies, the group pointed out that rapid and massive hemodilution leads to tissue hypoxia and organ hypoperfusion, as well as multiple organ dysfunctions. The resultant fluid sequestration could cause severe pulmonary interstitial edema and also tissue hypoxia as oxygen delivery is severely compromised because of massive reduction in hematocrit. 70 A recent study that utilized the Japanese National Clinical database involving nearly 9489 AP patients concluded that administration of too much fluid volume in the initial 48 hours is associated with increased mortality. However, a relative increase in fluid volume during the initial 48 hours compared with the fluid received throughout hospitalization correlated with decreased mortality. 72 The preliminary reports from a very recent prospective cohort study involving 247 patients concluded that administration of more than 4.1 L during the initial 24 hour was significantly and independently associated with persistent organ failure, acute collections, and respiratory and renal insufficiency. They also reported that less than 3.1 L during the initial 24 hours was not associated with organ failure, local complications, or mortality in their preliminary observations. They hypothesized that although the development of pancreatic necrosis is an early phenomenon, initial fluid therapy cannot prevent it. 73 If we extrapolate the results of the FEAST trial conducted in sepsis 74 in AP, it is clear that bolus-fluid resuscitation with either crystalloids or colloids in patients with compensated shock without a clinical fluid deficit must be practiced with greater caution and with increased vigilance. 75 A recent editorial suggested the administration of 1 to 2 L of crystalloids, preferably lactated Ringer s (at 20 ml/kg) wide open upon presentation in the emergency room. They further advocated a continuous infusion of 150 to 300 ml/h (roughly * 2012 Lippincott Williams & Wilkins 831

6 Trikudanathan et al Pancreas & Volume 41, Number 6, August ml/kg per hour) for the first 24 hours. They recommended more rigorous resuscitation in patients with higher hematocrit on arrival (944%), higher BUN (920 mg/dl), or a higher SIRS score in the absence of intrinsic cardiac or renal comorbidities. After the first day, they have suggested a reassessment of the patient at the bedside, and subsequent laboratory panel should guide further resuscitation. A maintenance rate of 2 ml/kg per hour should be used in those who responded well to the initial resuscitation and 3 ml/kg per hour in those refractory to the initial resuscitation. 67 Fluid Volume Assessment and End Points for Resuscitation Vigilant monitoring of rehydration, cardiovascular, and renal and respiratory functions is essential for early detection of electrolyte imbalances and volume overload, especially in the elderly patients and in those with cardiovascular and renal comorbidities. 76 In mild AP, the adequacy of fluid resuscitation should be clinically monitored by vital signs, physical examination, hourly urinary output, and drop in hematocrit at 12 and 24 hour after admission. Adequate fluid resuscitation should maintain a mean blood pressure of 65 mm Hg 77 and produce a urine output of at least 0.5 ml/kg per hour in the absence of renal failure, 63 and monitoring of CVP is generally not needed. 6 Guidelines from Japan recommend intravenous fluid resuscitation at a rate of 60 to 160 ml/kg per 24 hours to maintain urine output greater than 1 ml/kg per hour. 15 Based on Ranson criteria, experts have proposed that a sequestration of 6 L of fluids is an independent predictor of severity, the minimal requirement in a 70-kg individual being around 6 L. They therefore recommended intravenous hydration at a rate of 250 to 300 ml/h. 14 This was further established in a recent study that showed that patients with AP are less vulnerable for pancreatic necrosis if they received an average of 284 ml/h in the first 6 hours since admission. 8 In SAP, the fluid responsiveness must be guided by preload and intravascular volume assessment by monitoring CVP and pulmonary artery wedge pressure. 6,78 Central venous pressure between 8 and 12 cm of water is recommended. 64 Recently, a small study demonstrated the utility of passive leg raising as a simple bedside test in predicting the fluid responsiveness in spontaneously breathing patients with AP or severe sepsis. 79 Their underlying principle was that passive leg rising is a simple reversible maneuver, which simulates rapid volume expansion by shifting venous blood from lower extremities toward the intrathoracic compartment. Recent studies have reported these pressure-based parameters are unreliable in accurately assessing the preload and volume responsiveness, because of the presence of confounders such as intra-abdominal pressure, mechanical ventilation, mediastinal edema, and pleural effusions, all of which results in an accentuation in intrathoracic pressure and cardiac filling pressure, despite an impairment of venous return. 80 In a recent study, the utility of PiCCO continuous cardiac output monitoring system (Pulsion Medical Systems, Munich, Germany), a well-established but technologically advanced intravascular monitoring system (incorporating sophisticated algorithms), to evaluate the adequacy of fluid volume replacement in AP patients was studied. 81 They reported the superiority of modern hemodynamic parameters such as intrathoracic blood volume index, global end diastolic volume index, and extravascular lung water index over CVP for optimizing fluid management in SAP. Despite the promising results, of these hemodynamic parameters, the use of excessively specialized equipment and expertise will preclude their wider clinical application, especially in secondary centers where the majority of AP patients are initially treated. At present, there is 1 active clinical trial ongoing in Germany (EAGLE, clinicaltrials.gov #NCT ) evaluating targeted fluid resuscitation in the critical care setting utilizing PiCCO. 81 The other trial, the Trial of Intravenous, Goal- Directed Early Fluid Resuscitation (TIGER, clinicaltrials.gov #NCT ), which compared a targeted approach to resuscitation that utilizes early changes in BUN to direct resuscitation parameters, has been terminated because the interim analysis has shown that the primary end point (prevalence of systemic inflammatory response syndrome) was lower than anticipated. Very few studies have been done to assess the physician s compliance with recommendations for aggressive fluid replacement. In a recent, multicentric prospective survey conducted in Italy, it was shown that a patient with mild or severe pancreatitis received an average of only 2.5 L of fluid per day (about 100 ml/h). 82 However, it was shown that the amount of fluids delivered was significantly higher in those with severe pancreatitis when compared with the mild form. 82 Further studies are mandated to draft a clearly defined optimum fluid resuscitation algorithm that when initiated early in the disease course would definitely improve the outcome from AP. Studies are also warranted to assess the physician s compliance with the guidelines. CONCLUSIONS AND FUTURE DIRECTIONS To conclude, the mortality from SAP with organ failure is still very high. Aggressive fluid resuscitation in patients with AP needs to be initiated with a therapeutic intent. Although early, a recent trial has demonstrated that lactated Ringer s solution is better than normal saline in decreasing SIRS in patients with AP; further large studies are needed to validate this observation and whether this decrease in SIRS translates to improved outcome in these patients. Also, studies are required to evaluate the volume of fluids to be administered according to different grades of severity. Current studies are underway to also determine the optimal end point of fluid resuscitation that determines outcome. REFERENCES 1. DeFrances CJ, Cullen KA, Kozak LJ. National Hospital Discharge Survey: 2005 annual summary with detailed diagnosis and procedure data. Vital Health Stat. 2007;13(165):1Y Lowenfels AB, Maisonneuve P, Sullivan T. The changing character of acute pancreatitis: epidemiology, etiology, and prognosis. Curr Gastroenterol Rep. 2009;11(2):97Y Bradley EL 3rd. A clinically based classification system for acute pancreatitis. 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7 Pancreas & Volume 41, Number 6, August 2012 Fluid Resuscitation in Acute Pancreatitis 9. Kusterer K, Poschmann T, Friedemann A, et al. Arterial constriction, ischemia-reperfusion, and leukocyte adherence in acute pancreatitis. Am J Physiol. 1993;265(1 Pt 1):G165YG Knoefel WT, Kollias N, Warshaw AL et al. Pancreatic microcirculatory changes in experimental pancreatitis of graded severity in the rat. Surgery. 1994;116(5):904Y Cuthbertson CM, Christophi C. Disturbances of the microcirculation in acute pancreatitis. Br J Surg. 2006;93(5):518Y Salomone T, Tosi P, Palareti G, et al. Coagulative disorders in human acute pancreatitis: role for the D-dimer. Pancreas. 2003;26(2):111Y Vollmar B, Menger MD. Microcirculatory dysfunction in acute pancreatitis. A new concept of pathogenesis involving vasomotion-associated arteriolar constriction and dilation. Pancreatology. 2003;3(3):181Y Tenner S. Initial management of acute pancreatitis: critical issues during the first 72 hours. 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8 Trikudanathan et al Pancreas & Volume 41, Number 6, August Kusterer K, Enghofer M, Poschmann T, et al. The effect of somatostatin, gabexate mesilate and dextran 40 on the microcirculation in sodium taurocholateyinduced pancreatitis. Acta Physiol Hung. 1992;80(1Y4):407Y Huch K, Schmidt J, Schratt W, et al. Hyperoncotic dextran and systemic aprotinin in necrotizing rodent pancreatitis. Scand J Gastroenterol. 1995;30(8):812Y Donaldson LA, Schenk WG Jr. Experimental acute pancreatitis: the changes in pancreatic oxygen consumption and the effect of dextran 40. Ann Surg. 1979;190(6):728Y Klar E, Foitzik T, Buhr H, et al. Isovolemic hemodilution with dextran 60 as treatment of pancreatic ischemia in acute pancreatitis. Clinical practicability of an experimental concept. Ann Surg. 1993;217(4):369Y Mao E, Li L, Qin S, et al. Therapeutic experience of fulminant acute pancreatitis in acute response stage [in Chinese]. 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