Optimum Fluid Therapy in Acute Pancreatitis Needs an Alchemist

Abstract

See “Lactated ringers vs normal saline resuscitation for mild acute pancreatitis: a randomized trial,” by Lee A, Ko C, Buitrago C, et al; NS-LR Study Group, on page 955. See “Lactated ringers vs normal saline resuscitation for mild acute pancreatitis: a randomized trial,” by Lee A, Ko C, Buitrago C, et al; NS-LR Study Group, on page 955. The 2009 discovery of water on the moon by India’s moon mission Chandrayan 1 and an on-board NASA’s mineralogy mapper boosted human’s quest for extraterrestrial habitats in exotic locales, for “water is life to creatures” (from Sanskrit Jivanam Jivinãm Jivaha) if not the elusive elixir of life. Thus, ancient civilizations settled around great rivers—the Tigris and Euphrates (Mesopotamia), Ganges (India), and Nile (Egypt). Water and electrolyte balance is essential for managing most critical illnesses and acute pancreatitis (AP) is no exception. The study by Lee et al1Lee A. Ko C. Buitrago C. et al.NS-LR Study GroupLactated ringers vs normal saline resuscitation for mild acute pancreatitis: a randomized trial.Gastroenterology. 2021; 160: 955-957Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar in the current issue of Gastroenterology has focused attention on this important issue. The human body is composed of approximately 60% water, distributed across compartments: approximately 67%–70% intracellular and approximately 30%–33% extracellular, 75% of the latter is interstitial and 25% intravascular.2Levitt M.F. Gaudino M. Measurement of body water compartments.Am J Med. 1950; 9: 208-215Abstract Full Text PDF PubMed Scopus (7) Google Scholar The intricate intercompartment balance is maintained by neurohumoral mechanisms and pressure dynamics. AP is a unique illness that starts locally within the pancreas but has a potential to affect distant organs in severe cases through a myriad of perturbations that include hyperinflammation, compromised vascular integrity, and redistribution of fluid.3Garg P.K. Singh V.P. Organ failure due to systemic injury in acute pancreatitis.Gastroenterology. 2019; 156: 2008-2023Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar AP may be associated with a fluid deficit owing to low intake and vomiting, which is easily manageable. More important, there is fluid shift to the interstitium owing to vascular leakage causing intravascular fluid volume contraction.4de-Madaria E. Garg P.K. Fluid therapy in acute pancreatitis - aggressive or adequate? Time for reappraisal.Pancreatology. 2014; 14: 433-435Crossref PubMed Scopus (12) Google Scholar Endothelial injury and increased vascular permeability leading to extravasation of protein-rich fluid has been shown in AP.5Dumnicka P. Maduzia D. Ceranowicz P. et al.The Interplay between inflammation, coagulation and endothelial injury in the early phase of acute pancreatitis: clinical implications.Int J Mol Sci. 2017; 18: 354Crossref Scopus (90) Google Scholar Extravasation of fluid may be mediated by changes in pressure dynamics e.g. decreased oncotic pressure due to hypoalbuminemia and increased hydrostatic pressure, best exemplified by cirrhosis of the liver. But that is not akin to vascular (capillary) leak. Classical capillary leak syndrome leads to leakage of plasma comprising of fluid and proteins into the interstitium, resulting in intravascular hemoconcentration, hypotension, tissue hypoperfusion, and organ dysfunction.6Siddall E. Khatri M. Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management.Kidney Int. 2017; 92: 37-46Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar Vascular injury involves disruption of adherens junctions and tight junctions between endothelial cells, possibly owing to hypercytokinemia.6Siddall E. Khatri M. Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management.Kidney Int. 2017; 92: 37-46Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar In severe AP, a similar pathologic state is likely to play a dominant role in mediating organ dysfunction with vascular leakage, fluid sequestration, and circulatory hypovolemia. Indirect evidences such as hemoconcentration, decrease in plasma proteins, edema and pleural effusion suggest vascular leak in AP.7Whitcomb D.C. Muddana V. Langmead C.J. et al.Angiopoietin-2, a regulator of vascular permeability in inflammation, is associated with persistent organ failure in patients with acute pancreatitis from the United States and Germany.Am J Gastroenterol. 2010; 105: 2287-2292Crossref PubMed Scopus (51) Google Scholar Among patients with AP, an admission hematocrit of ≥44% predicted persistent organ failure and pancreatic necrosis in a study of 1612 patients.8Koutroumpakis E. Wu B.U. Bakker O.J. et al.Admission hematocrit and rise in blood urea nitrogen at 24 h outperform other laboratory markers in predicting persistent organ failure and pancreatic necrosis in acute pancreatitis: a post hoc analysis of three large prospective databases.Am J Gastroenterol. 2015; 110 (Erratum in: Am J Gastroenterol 2016;111:1216): 1707-1716Crossref PubMed Scopus (77) Google Scholar Hemoconcentration by itself may suggest either vascular leakage or simply fluid deprivation. The patient’s fluid balance in the prior 24–48 hours could help differentiate between deprivation versus sequestration. Estimated median fluid sequestration is approximately 4 L/48 hours in AP.9Sinha A. Quesada-Vázquez N. Faghih M. et al.Early predictors of fluid sequestration in acute pancreatitis: a validation study.Pancreas. 2016; 45: 306-310Crossref PubMed Scopus (9) Google Scholar Thus, aggressive fluid administration has been suggested to prevent tissue hypoperfusion, but there are controversies regarding fluid type, volume, and rate of infusion. Five randomized controlled trials (RCTs) compared aggressive versus nonaggressive fluid therapy (Table).10Mao E.Q. Tang Y.Q. Fei J. et al.Fluid therapy for severe acute pancreatitis in acute response stage.Chin Med J (Engl). 2009; 122: 169-173PubMed Google Scholar, 11Mao E.Q. Fei J. Peng Y.B. Huang J. Tang Y.Q. Zhang S.D. Rapid hemodilution is associated with increased sepsis and mortality among patients with severe acute pancreatitis.Chin Med J (Engl). 2010; 123: 1639-1644PubMed Google Scholar, 12Wu B.U. Hwang J.Q. Gardner T.H. et al.Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis.Clin Gastroenterol Hepatol. 2011; 9: 710-717.e1Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar, 13Buxbaum J.L. Quezada M. Da B. et al.Early aggressive hydration hastens clinical improvement in mild acute pancreatitis.Am J Gastroenterol. 2017; 112: 797-803Crossref PubMed Scopus (68) Google Scholar, 14Cuéllar-Monterrubio J.E. Monreal-Robles R. González-Moreno E.I. et al.Nonaggressive versus aggressive intravenous fluid therapy in acute pancreatitis with more than 24 hours from disease onset: a randomized controlled trial.Pancreas. 2020; 49: 579-583Crossref PubMed Scopus (7) Google Scholar Two trials from China included patients with severe AP and showed worse outcomes with aggressive fluid therapy.10Mao E.Q. Tang Y.Q. Fei J. et al.Fluid therapy for severe acute pancreatitis in acute response stage.Chin Med J (Engl). 2009; 122: 169-173PubMed Google Scholar,11Mao E.Q. Fei J. Peng Y.B. Huang J. Tang Y.Q. Zhang S.D. Rapid hemodilution is associated with increased sepsis and mortality among patients with severe acute pancreatitis.Chin Med J (Engl). 2010; 123: 1639-1644PubMed Google Scholar Two RCTs included patients with mild AP: Wu et al12Wu B.U. Hwang J.Q. Gardner T.H. et al.Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis.Clin Gastroenterol Hepatol. 2011; 9: 710-717.e1Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar did not find any difference between goal directed and standard fluids, whereas Buxbaum et al13Buxbaum J.L. Quezada M. Da B. et al.Early aggressive hydration hastens clinical improvement in mild acute pancreatitis.Am J Gastroenterol. 2017; 112: 797-803Crossref PubMed Scopus (68) Google Scholar showed clinical improvement with aggressive fluid therapy. A recent RCT that included patients after 48 hours of onset of AP did not find any benefit of aggressive fluid therapy.14Cuéllar-Monterrubio J.E. Monreal-Robles R. González-Moreno E.I. et al.Nonaggressive versus aggressive intravenous fluid therapy in acute pancreatitis with more than 24 hours from disease onset: a randomized controlled trial.Pancreas. 2020; 49: 579-583Crossref PubMed Scopus (7) Google Scholar Thus, there was a benefit with aggressive fluids in mild AP only in 1 trial. Because there is no significant fluid sequestration in mild AP, the purported benefit of aggressive fluids could be related to better pancreas perfusion. Another speculative mechanism could be enhanced excretion of cytokines à la “forced diuresis” given intact fluid regulatory mechanisms in mild AP.15Graziani G. Bordone G. Bellato V. et al.Role of the kidney in plasma cytokine removal in sepsis syndrome: a pilot study.J Nephrol. 2006; 19: 176-182PubMed Google Scholar In contrast, significant systemic inflammation and endothelial injury develop early in the course of severe AP causing organ failure.3Garg P.K. Singh V.P. Organ failure due to systemic injury in acute pancreatitis.Gastroenterology. 2019; 156: 2008-2023Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Aggressive fluid therapy is likely to aggravate vascular leak leading to more sequestration, congestion and tissue hypoxia, and thus further organ dysfunction leading to a vicious cycle (Figure). Only 20% of crystalloids remain in circulation after 20–40 minutes of equilibrium. A few studies and a meta-analysis have indeed shown increased incidence of respiratory and kidney failure with aggressive fluids in AP.16Gad M.M. Simons-Linares C.R. Is aggressive intravenous fluid resuscitation beneficial in acute pancreatitis? A meta-analysis of randomized control trials and cohort studies.World J Gastroenterol. 2020; 26: 1098-1106Crossref PubMed Scopus (26) Google Scholar,17Li L. Jin T. Wen S. Shi N. et al.Early rapid fluid therapy is associated with increased state of noninvasive positive-pressure ventilation in hemoconcentrated patients with severe acute pancreatitis.Dig Dis Sci. 2020; 65: 2700-2711Crossref PubMed Scopus (18) Google Scholar The clinically relevant questions and answers are as follows: (i) Are fluid dynamics fundamentally different in mild and severe pancreatitis? The answer is yes and that is why fluid administration should be carefully and differentially recommended in mild and severe pancreatitis. (ii) Can aggressive fluid therapy prevent pancreatic necrosis and/or organ failure? Based on the available data, the answer is no. In fact, 2 studies showed worse outcomes with aggressive fluids.10Mao E.Q. Tang Y.Q. Fei J. et al.Fluid therapy for severe acute pancreatitis in acute response stage.Chin Med J (Engl). 2009; 122: 169-173PubMed Google Scholar,11Mao E.Q. Fei J. Peng Y.B. Huang J. Tang Y.Q. Zhang S.D. Rapid hemodilution is associated with increased sepsis and mortality among patients with severe acute pancreatitis.Chin Med J (Engl). 2010; 123: 1639-1644PubMed Google Scholar Another important issue is the type of fluids for replacement. Traditionally, normal saline (NS) has been the crystalloid of choice for resuscitation in many critical illnesses such as sepsis and trauma and so was the case in AP. However, concerns were raised about the adverse effects of NS particularly hyperchloremic nonanion gap acidosis and acute kidney injury. Many RCTs compared balanced crystalloid solution with NS but definite evidence of benefit with balanced fluid (Ringer’s lactate) came from the SMART trial in critically ill patients.18Semler M.W. Self W.H. Wanderer J.P. et al.Balanced crystalloids versus saline in critically ill adults.N Engl J Med. 2018; 378: 829-839Crossref PubMed Scopus (613) Google Scholar Of 7942 patients randomized to balanced crystalloids group, 14.3% had major adverse kidney events, as compared with 15.4% of 7860 patients given NS (odds ratio, 0.91; 95% confidence interval, 0.84–0.99; P = .04). Ringer’s lactate is an isotonic balanced crystalloid (osmolarity 273 mOsm/L, pH 6.5). In AP, 3 previous RCTs compared Ringer’s lactate with NS. Whereas Wu et al12Wu B.U. Hwang J.Q. Gardner T.H. et al.Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis.Clin Gastroenterol Hepatol. 2011; 9: 710-717.e1Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar showed some benefit with reduction in systemic inflammatory response syndrome, the other 2 trials by de-Madaria et al19de-Madaria E. Herrera-Marante I. González-Camacho V. et al.Fluid resuscitation with lactated Ringer's solution vs normal saline in acute pancreatitis: a triple-blind, randomized, controlled trial.United European Gastroenterol J. 2018; 6: 63-72Crossref PubMed Scopus (68) Google Scholar and Choosakul et al20Choosakul S. Harinwan K. Chirapongsathorn S. et al.Comparison of normal saline versus Lactated Ringer's solution for fluid resuscitation in patients with mild acute pancreatitis, a randomized controlled trial.Pancreatology. 2018; S1424-3903: 30083-30088Google Scholar did not find any significant benefit (Table). The latest study by Lee et al1Lee A. Ko C. Buitrago C. et al.NS-LR Study GroupLactated ringers vs normal saline resuscitation for mild acute pancreatitis: a randomized trial.Gastroenterology. 2021; 160: 955-957Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar from the same group that showed benefit of aggressive fluids in mild AP13Buxbaum J.L. Quezada M. Da B. et al.Early aggressive hydration hastens clinical improvement in mild acute pancreatitis.Am J Gastroenterol. 2017; 112: 797-803Crossref PubMed Scopus (68) Google Scholar is significant in this respect. They randomized 121 patients to Ringer’s lactate or NS. Although the authors did not find any significant difference in the primary outcome, that is, a decrease in systemic inflammatory response syndrome until 72 hours, they reported significantly shorter hospital stay and fewer intensive care unit admissions in patients given Ringer’s lactate. The strengths of their study include a well-designed protocol, reasonable sample size and inclusion of patients within 8 hours of diagnosis; thus, fluids were administered during the critical period when there is a window of opportunity to restore the intravascular volume and maintain adequate tissue perfusion. However, the study included patients with mild pancreatitis. Another issue is that the benefit shown was for secondary outcomes and, thus, these results should be taken as exploratory and hypothesis generating.Table 1Summary of Randomized Trials of Fluid Therapy Comparing Aggressive and Nonaggressive Fluid Replacement in APAuthors and yearAggressive (number and severity)Nonaggressive (number and severity)OutcomesCommentsAggressiveNonaggressiveMao et al 200936; severe AP40; severe APMechanical ventilation - 94.4%Mortality - 30.6%Mechanical ventilation - 65%, mortality - 10%HCT with rapid fluids was 35.6% and 38.5% with slower infusion.Worse outcome with rapid fluidsMao et al 201056; severe AP59; severe APSepsis - 78.6%Mortality - 33.9%Sepsis - 57.6%Mortality -15.3%Rapid hemodilution: HCT <35 slower hemodilution: HCT >35Worse outcome with rapid fluidsWu et al 201119 (Goal directed)2158% reduction in SIRS42% reduction in SIRSP = .85 for SIRSNo difference in the mean volume of fluid infused between the 2 groupsBuxbaum et al 2017273370% clinical improvement7.4% SIRS42% clinical improvement21.1% SIRSPatients had mild AP.Significant benefit seen with aggressive fluidsCuéllar-Monterrubio et al 2020434513.3% had SIRS at day 713.9% had SIRS at day 7Patients randomized after 64.5 and 65.2 hours of onset of AP; no difference in pancreatic necrosis or organ failureAuthors and YearRL (n)NS (n)Severity of AP (RL vs NS)OutcomesCommentsReduction in SIRS (RL vs NS)Reduction in CRP (RL vs NS)Wu et al (2011)1921Mild;31% and 19% had SIRS84% (31% to 5%) reduction vs 0 (19% to 19%)(P = .03)51 vs 104 mg/L (P = .018)Overall, favored RLPatients were included after a median of 9 and 5 days after onset of AP; study terminated prematurelyde-Madaria et al (2018)1921Mild,47.4% vs 66.7% had SIRS15.8% vs 42.9% (P = .06)28 vs 166 mg/L (P = .04)Overall, favored RLBorderline significance for SIRS reductionChoosakul et al (2018)2324Mild;34.8% vs 41.7% had SIRS26.1% vs 33.4% at 48 hours (P= 0.88)No difference in CRPOverall, no benefitLee et al (2020)6160Mild37/5% vs 32.2% at 24 hours41.9% vs 38.3% at 48 hoursNot studiedOverall, no benefit for primary outcome i.e. SIRS but favored RL for secondary outcomes of intensive care unit admission and hospital stay.82% of patients in RL group received approximately 2 liters of NS before randomizationAP, acute pancreatitis; CRP, C-reactive protein; HCT: hematocrit; NS, normal saline; RL, Ringer’s lactate; SIRS, systemic inflammatory response syndrome. Open table in a new tab AP, acute pancreatitis; CRP, C-reactive protein; HCT: hematocrit; NS, normal saline; RL, Ringer’s lactate; SIRS, systemic inflammatory response syndrome. What are the likely reasons for the superiority of Ringer’s lactate over NS? NS could lead to a large chloride load contributing to kidney injury.16Gad M.M. Simons-Linares C.R. Is aggressive intravenous fluid resuscitation beneficial in acute pancreatitis? A meta-analysis of randomized control trials and cohort studies.World J Gastroenterol. 2020; 26: 1098-1106Crossref PubMed Scopus (26) Google Scholar Acidosis owing to NS (pH 5.5) could promote inflammation.21Rajamäki K. Nordström T. Nurmi K. et al.Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome.J Biol Chem. 2013; 288: 13410-13419Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar Lactate has been shown to negatively regulate TLR induction of the NLRP3 inflammasome and production of IL1β, via ARRB2 and GPR81 and thus could down-regulate inflammation.22Hoque R. Farooq A. Ghani A. et al.Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity.Gastroenterology. 2014; 146: 1763-1774Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar Calcium in Ringer’s lactate could reduce early systemic inflammation by binding nonesterified fatty acids.23Khatua B. Yaron J.R. El-Kurdi B. et al.Ringer's Lactate prevents rarely organ failure by providing extracellular calcium.J Clin Med. 2020; 9: 263Crossref Scopus (18) Google Scholar There are many gaps in our knowledge with regard to fluid administration in AP. Assessment of fluid sequestration and intravascular volume deficit is generally guided by clinical and noninvasive parameters, which have a limited accuracy. Body impedance analysis for assessment of compartment-wise fluid distribution and blood volume measurement need to be tested for optimal guidance for fluid replacement in clinical practice. We need to have a standard definition of “aggressive fluids,” which has been variably defined. Based on multiple studies, we suggest 3 mL/kg/h would constitute aggressive and 1.5 mL/kg/h as nonaggressive. We need biomarkers to asses early on vascular leak to alert clinicians regarding fluid management. Given the current state, how do we solve the conundrum of fluid therapy in AP? We need trials which should include patients with predicted severe AP preferably within first 24–48 hours of onset, be adequately powered, and have clinically important outcomes, for example, development of organ failure and pancreatic necrosis. Until then, as a general guidance, the choice of fluid seems to be Ringer’s lactate, the volume should be around 3–4 L/24 hours and there should be predefined checkpoints at 6–8 hours to assess fluid status, especially in patients with severe AP, comorbid conditions, oliguria, and older age. Lactated Ringers vs Normal Saline Resuscitation for Mild Acute Pancreatitis: A Randomized TrialGastroenterologyVol. 160Issue 3PreviewAcute pancreatitis (AP) is a leading cause of hospitalization in the United States, resulting in significant morbidity and cost.1 In the absence of proven pharmacologic interventions, early aggressive intravenous hydration has been the mainstay of treatment; however, although clinical practice guidelines and expert opinion agree on fluid volume, equipoise remains regarding optimal type.1 Full-Text PDF