Colloids in acute pancreatitis: Microcirculatory advantage or inflammatory mirage

Abstract

The quest for optimal fluid resuscitation in acute pancreatitis continues to challenge clinicians, balancing perfusion, inflammation, and safety. The recent randomized controlled trial published in World Journal of Gastrointestinal Surgery by Costea et al compared Dextran 40 Plus Ringer’s lactate solution with Ringer’s lactate solution alone in mild-to-moderate acute pancreatitis. While dextran-enhanced therapy significantly reduced C-reactive protein at 72 hours, it did not accelerate systemic inflammatory response syndrome resolution or improve clinical outcomes. This paradox rekindles debate on whether early biochemical improvement truly mirrors microcirculatory recovery. Physiologically, dextran may enhance capillary flow and protect the endothelial glycocalyx; however, these benefits appear transient and clinically neutral within current dosing limits. This editorial examines the evidence landscape, critiques methodological aspects, and situates the trial within the evolving paradigm of moderate, goal-directed fluid therapy. Ultimately, colloid supplementation may refine hemodynamic precision but remains an “inflammatory mirage” until larger, mechanistically informed trials confirm patient-centered benefit.

Key Words: Acute pancreatitis; Fluid resuscitation; Colloids; Dextran 40; Ringer’s lactate; Microcirculation; C-reactive protein

Core Tip: Fluid resuscitation remains the cornerstone of acute pancreatitis care; however, the ideal composition remains unsettled. A recent randomized trial comparing Dextran 40 Plus Ringer’s lactate vs Ringer’s lactate alone demonstrated lower C-reactive protein but no difference in systemic inflammation or organ failure. This editorial explores why the apparent biochemical benefit may not translate into clinical improvement, highlighting the intricate interplay between microcirculation, endothelial integrity, and inflammatory signaling. The piece highlights how this study refines, not resolves, the colloid debate, underscoring the need for individualized, goal-directed hydration strategies guided by hemodynamic and perfusion markers rather than fixed formulas.

This editorial refers to “Fluid therapy strategies in acute pancreatitis: Randomized controlled trial comparing dextran and Ringer’s lactate” by Costea et al, 2025; https://dx.doi.org/10.4240/wjgs.v17.i11.109869.

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INTRODUCTION

Acute pancreatitis (AP) remains one of the most frequent and unpredictable emergencies in gastroenterology. Despite major advances in imaging, nutritional support, and critical care, mortality in severe forms still approaches 15%-20%[1]. Early fluid resuscitation is universally recognized as a determinant of outcome; it mitigates pancreatic ischemia, maintains capillary perfusion, and limits systemic inflammatory response[2]. Yet, what constitutes optimal fluid therapy remains contentious.

Balanced crystalloids, particularly Ringer’s lactate solution (RLS), are currently preferred over normal saline because of their superior acid-base profile and possible anti-inflammatory effect[3,4]. By contrast, colloids such as dextran, gelatin, and hydroxyethyl starch (HES) offer theoretical advantages, sustained intravascular retention and microcirculatory enhancement, but have been shadowed by safety concerns, including renal toxicity and coagulopathy[5,6].

Against this backdrop, Costea et al[7] recently published a study in World Journal of Gastrointestinal Surgery, which conducted a single-blind randomized controlled trial evaluating dextran 40 combined with RLS vs RLS alone in mild-to-moderate AP. It is important to note that the full data for this study are currently in press and thus unavailable for independent scrutiny; the following discussion and conclusions based on its findings should therefore be considered provisional. Their finding, lower C-reactive protein (CRP) at 72 hours without improvement in systemic inflammatory response syndrome (SIRS) or organ failure, presents a physiological paradox. Can early biochemical attenuation reflect a meaningful clinical advantage?

This editorial explores that question by examining mechanistic plausibility, evidence coherence, and future research trajectories, while acknowledging that definitive judgment on clinical significance must await the publication of the final trial data.

EVIDENCE LANDSCAPE AND RECENT DEVELOPMENTS

Fluid therapy in AP has evolved from aggressive empiricism toward physiologically guided moderation. The landmark ERICA trial demonstrated that moderate resuscitation (5-10 mL/kg/hour) reduced complications compared with aggressive protocols[8]. Subsequent meta-analyses confirmed that overhydration increases pulmonary edema, abdominal compartment syndrome, and mortality[9,10].

Crystalloids remain the backbone of therapy. RLS, a balanced solution containing lactate as a buffer, counteracts metabolic acidosis and exerts mild anti-inflammatory effects by reducing nuclear factor kappa B activation in acinar and endothelial cells[11]. This has led major societies, including the American College of Gastroenterology (2024) and the Japanese Pancreas Society (2021), to recommend RLS as first-line fluid[12,13].

Colloids re-entered the discussion when microcirculatory dysfunction was recognized as an early pathogenic event in AP. Pancreatic capillaries lose perfusion due to endothelial swelling, leukocyte adhesion, and glycocalyx degradation[14]. Dextran 40, a low-molecular-weight polysaccharide, improves capillary flow by reducing erythrocyte aggregation and plasma viscosity[15]. In animal models, it restored pancreatic oxygenation and limited necrosis[16]. Clinically, however, evidence is scarce and heterogeneous. Albumin infusion has shown benefits in hypoalbuminemic or septic contexts[17], whereas HES has been linked to renal injury and excess mortality[18].

The Costea trial thus fills an important niche, testing a theoretically safer colloid in the early, non-severe spectrum of AP under standardized goal-directed hydration[7]. Table 1 summarizes trials collectively highlighting the evolution from aggressive to goal-directed resuscitation and the unresolved question of whether colloid supplementation confers clinical benefit beyond biochemical attenuation.

Table 1 Summary of key trials in fluid therapy for acute pancreatitis.

Ref.	Design/n	Intervention	Primary outcome	Main finding
Myburgh et al[6], 2012	RCT (249 patients)	Moderate vs aggressive RLS	Major complications	Aggressive resuscitation increased fluid-overload events (20.5% vs 6.3%); interim analysis showed no reduction in progression to moderately severe/severe pancreatitis
Buxbaum et al[9], 2017	RCT (60 patients)	Early aggressive vs standard RLS	Clinical improvement time	Aggressive hydration hastened clinical improvement (70% vs 42% at 36 hours); no volume-overload events were reported in this cohort
Garber et al[15], 2018	RCT (41 patients)	HES + crystalloid vs crystalloid alone	Intra-abdominal hypertension	The HES group had lower IAP and earlier negative fluid balance; safety concerns for colloids persist
Yang et al[16], 2004	RCT (120 patients)	Various colloids vs crystalloids	Inflammatory response	Colloid (HES combinations) groups had more rapid reduction in inflammatory markers and IAP; renal/Long-term safety signal was heterogeneous
Costea et al[7], 2025	RCT (108 patients)	Dextran 40 + RLS vs RLS alone	CRP and SIRS at 72 hours	Lower CRP at 72 hours (median 43 mg/L vs 171 mg/L; P < 0.001) with dextran arm; no statistically significant difference in organ failure, ICU admission, or mortality (in-press data)

CRP: C-reactive protein; HES: Hydroxyethyl starch; IAP: Intra-abdominal pressure; ICU: Intensive care unit; RCT: Randomized controlled trial; RLS: Ringer’s lactate solution; SIRS: Systemic inflammatory response syndrome. Data are derived from randomized controlled trials cited in the main text.

CRITICAL APPRAISAL

The investigators randomized 108 patients with mild-to-moderate AP to receive either dextran 40 + RLS (1:3 ratio) or RLS alone. Both groups followed identical hemodynamic and biochemical monitoring protocols. The dextran arm achieved significantly lower CRP at 72 hours, but rates of SIRS resolution, organ failure, complications, and mortality were comparable[7]. Although the authors reported a significantly lower SIRS rate at 72 hours (3.6% vs 20.8%; P = 0.008), this early difference was not sustained throughout the observation period and did not translate into improved overall outcomes.

Strengths include a randomized design, blinded outcome assessors, and adherence to Consolidated Standards of Reporting Trials standards. The study captured inflammatory kinetics over 72 hours and included a 3-month follow-up, rare among small trials.

Limitations are equally clear. First, the single-center nature and modest sample size limit the power to detect clinical differences. Second, inclusion of only mild-to-moderate cases excludes those most likely to benefit from enhanced microcirculation. Third, CRP reduction, though statistically significant, represents a surrogate marker with uncertain prognostic value when uncoupled from SIRS or organ failure. Finally, the lack of mechanistic endpoints (e.g., microvascular imaging, glycocalyx biomarkers) constrains physiological interpretation.

Taken together, the study’s biochemical signal may reflect transient rheologic effects rather than true endothelial recovery. The absence of renal or coagulation toxicity is reassuring, suggesting dextran 40’s safety in this context, but the clinical neutrality tempers enthusiasm.

MICROCIRCULATION, INFLAMMATION, AND THE CLINICAL PARADOX

Why might dextran 40 lower CRP without improving outcomes? The answer likely lies in the temporal disconnect between microvascular correction and systemic inflammation. Early AP involves a cascade of capillary leakage, hemoconcentration, and cytokine release[19]. Dextran’s plasma-expanding effect may transiently restore perfusion, reducing hepatic CRP synthesis, yet fail to halt downstream cytokine amplification once SIRS is established. Moreover, RLS itself exerts anti-inflammatory effects through lactate-mediated inhibition of neutrophil activation[11], potentially obscuring incremental benefits from colloids. When both arms receive RLS, dextran’s advantage may be diluted.

The study also re-emphasizes the pitfalls of relying solely on CRP. While convenient, CRP lags behind real-time inflammation and correlates imperfectly with organ failure[20]. Procalcitonin, interleukin 6 (IL-6), or direct perfusion metrics might better reflect treatment efficacy. Importantly, dextran’s theoretical microvascular benefits require intact renal clearance and endothelial integrity. In severe AP, where glycocalyx destruction and capillary plugging dominate, macromolecular colloids may no longer reach the target compartment[21]. This highlights the delicate interplay among fluid composition, microcirculatory restoration, and systemic inflammation - an equilibrium that remains central to improving outcomes in AP (Figure 1).

Figure 1 Proposed mechanisms linking fluid composition to microcirculatory and inflammatory outcomes in acute pancreatitis. Balanced crystalloids Ringer’s lactate solution improves macrocirculatory stability, mitigates acidosis, and exerts anti-inflammatory effects through lactate-mediated suppression of neutrophil activation. Colloid solutions such as dextran 40 enhance microvascular shear, reduce erythrocyte aggregation, and may transiently preserve endothelial glycocalyx integrity, supporting capillary perfusion. Both pathways converge on reducing inflammatory biomarkers (e.g., C-reactive protein), yet a persistent barrier - represented by sustained endothelial injury, cytokine amplification, and capillary leak - limits translation of biochemical improvement into clinical endpoints. This framework illustrates why early biochemical responses may not correspond to meaningful reductions in organ failure or systemic inflammatory response syndrome. CRP: C-reactive protein; NF-κB: Nuclear factor kappa B; RBC: Red blood cell.

At a cellular level, pancreatic acinar injury provokes intense endoplasmic reticulum stress and activation of the unfolded protein response, amplifying oxidative and inflammatory cascades[22]. These early intracellular events may prime the systemic inflammatory reaction that later manifests as endothelial dysfunction and capillary leak. Furthermore, emerging evidence suggests that persistent nociceptive and neurogenic signaling can sustain inflammatory activation even after the initial insult has subsided, linking molecular stress to prolonged clinical symptoms[23]. Such insights emphasize that microcirculatory restoration alone may be insufficient unless upstream cellular and neuroinflammatory triggers are concurrently addressed.

Nevertheless, recent meta-analyses emphasize that biochemical attenuation alone seldom translates into tangible clinical benefit. Improvements in surrogate markers such as CRP or hematocrit reduction do not consistently predict decreases in persistent organ failure, intensive care unit stay, or mortality. This reinforces that patient-centered outcomes must remain the ultimate benchmark for fluid therapy success[24,25].

Mechanistically, early glycocalyx degradation triggers leukocyte adhesion and microcapillary plugging, reducing perfusion despite adequate macrocirculation. Colloids may transiently preserve glycocalyx thickness and improve microvascular shear, but this benefit wanes once systemic inflammation amplifies permeability and interstitial edema[24,25]. To confirm whether colloids truly restore perfusion rather than merely alter laboratory indices, future studies could integrate bedside microcirculatory monitoring, such as sublingual videomicroscopy, contrast-enhanced ultrasound, or near-infrared spectroscopy, to visualize real-time perfusion dynamics. Such translational endpoints may finally clarify whether dextran confers a genuine microcirculatory advantage or only a biochemical illusion.

ECONOMIC AND SAFETY PERSPECTIVE

From a safety standpoint, dextran 40 demonstrates a more favorable renal profile than older HES solutions, which have been linked to acute kidney injury and higher mortality in patients who are critically ill[18]. This is high-certainty evidence (grade: High). A landmark 2013 meta-analysis demonstrated that HES significantly increased mortality and acute kidney injury in critically ill adults[26]. This evidence underpins the 2024 European Society of Intensive Care Medicine guideline, which strongly recommends against the use of synthetic colloids (strong recommendation, high-certainty evidence)[27]. When used in moderate doses and short infusion durations, dextran-induced coagulopathy and anaphylactoid reactions remain infrequent. By contrast, human albumin, although physiologically appealing for its oncotic and antioxidant properties, remains costly and is generally reserved for patients with hypoalbuminemia or cirrhosis.

Costea et al[7] reported no nephrotoxicity or coagulation derangements with dextran supplementation. While total hospitalization costs were numerically lower in the colloid arm, this was not a pre-specified economic analysis and should be interpreted as a preliminary observation. A definitive claim of cost-effectiveness cannot be made without a formal budget-impact or cost-utility analysis. Such an analysis would need to weigh the modest direct cost of dextran against the expenses of intensified monitoring it necessitates, and then contrast this with potential savings from reduced intensive care unit admissions or shorter hospital stays - data that are currently unavailable. Therefore, from a health-economic perspective, a carefully titrated dextran-crystalloid regimen is best viewed as a potentially cost-neutral intervention for selected patients, rather than a cost-saving one. Its economic viability is contingent upon avoiding the significant costs associated with rare but serious complications, which mandate vigilant monitoring and strict adherence to individualized resuscitation targets.

CLINICAL AND RESEARCH IMPLICATIONS

Clinically, the findings of Costea et al[7] counsel caution rather than conversion. Routine colloid supplementation in all cases of AP cannot yet be justified. Current evidence continues to favor early, moderate, and goal-directed resuscitation with RLS, carefully titrated to dynamic indicators such as hematocrit (≤ 44%), blood urea nitrogen trajectory, urine output, and capillary refill time[8,12,22]. Nevertheless, selective use of colloids could be considered in specific clinical phenotypes, patients with pronounced hemoconcentration, documented microcirculatory dysfunction on contrast-enhanced ultrasonography, or persistent tissue hypoperfusion despite adequate crystalloid therapy.

FUTURE TRIAL DESIGN FRAMEWORK

To move the field beyond biochemical surrogates, future studies should adopt adaptive, multicenter randomized designs that integrate both mechanistic and clinical endpoints. Serial assessment of endothelial and glycocalyx integrity markers (syndecan-1, heparan-sulfate fragments, IL-6 kinetics) and bedside perfusion monitoring with contrast-enhanced ultrasound or sublingual videomicroscopy could objectively link microvascular improvement to patient outcomes. Stratification by disease severity (mild, moderately severe, and severe AP) will help identify phenotypes most likely to benefit from colloid-enhanced resuscitation. Economic and safety analyses remain essential, as dextran’s lower cost and absence of nephrotoxicity in the present trial[7] must be balanced against theoretical coagulation risks and monitoring demands.

Ultimately, precision-guided fluid therapy, dynamically adjusted by hematocrit, blood-urine-nitrogen trend, and tissue perfusion rather than fixed volumes, offers the most promising path to translate biochemical benefit into tangible clinical recovery.

CLINICAL PERSPECTIVE: WHEN TO CONSIDER COLLOID-CRYSTALLOID COMBINATION

Colloid-crystalloid combination therapy may be considered in selected patients with pronounced hemoconcentration (hematocrit ≥ 45%) or documented microcirculatory dysfunction on contrast-enhanced ultrasonography, particularly when tissue hypoperfusion persists despite adequate crystalloid resuscitation. By contrast, it should be avoided in those with established organ failure, renal impairment, or coagulopathy, where macromolecular colloids may exacerbate endothelial injury. When used, dextran supplementation must be incorporated into a goal-directed strategy, with volumes titrated to dynamic perfusion indicators such as capillary refill, urine output, and hematocrit trend, followed by reassessment every 6-12 hours. Importantly, colloid use should be confined to the initial resuscitation phase and discontinued once hemodynamic stability and satisfactory urine output are achieved.

To operationalize these triggers in routine practice, hemoconcentration should be interpreted using both absolute and relative criteria. A hematocrit value ≥ 45% represents clinically meaningful hemoconcentration[2]; however, because baseline hematocrit varies with age and chronic comorbidities, a failure of the admission hematocrit to decrease by at least 3-5 percentage points after initial crystalloid resuscitation provides a more dynamic and individualized indicator of impaired plasma volume expansion. Microcirculatory dysfunction on contrast-enhanced ultrasonography may be defined by reproducible perfusion abnormalities, including a > 20% reduction in perfusion index compared with a reference organ (e.g., spleen or renal cortex), a prolonged time-to-peak enhancement exceeding 12-15 seconds, or a quantifiably reduced wash-in slope[19]. These abnormalities should be considered clinically significant only when they persist after an initial 2-4 hours window of adequate crystalloid optimization. In such cases, a short course of colloid supplementation may be justified as part of a goal-directed resuscitation strategy.

CONCLUSION

Colloid therapy in AP continues to oscillate between physiologic appeal and clinical skepticism. The study by Costea et al[7] provides high-quality, hypothesis-generating evidence: Dextran 40 + RLS modestly improves early inflammatory markers without altering clinical outcomes. These findings reinforce that less may be more; carefully titrated balanced crystalloids remain the safest default. Yet, the notion that restoring microcirculation could influence disease trajectory remains scientifically compelling.

The next generation of trials should integrate real-time perfusion monitoring, biomarker-guided endpoints, and individualized fluid algorithms to determine if physiologic plausibility translates into tangible patient benefit. Until then, the current evidence reinforces that the cornerstone of AP management remains early, moderate, and goal-directed fluid resuscitation with balanced crystalloids. This strategy must be dynamically tailored to the individual patient's hemodynamic and perfusion profile, rather than relying on fixed-volume formulas or unproven colloid supplements. Future research should focus on identifying distinct AP phenotypes that may derive genuine benefit from individualized colloid supplementation.