From Lab to Bedside: 3 Overhyped Biomarkers (And 3 Underused Ones) in Critical Care Medicine

Dr Neeraj Manikath , claude,ai

Abstract

Background: The proliferation of biomarkers in critical care has created both opportunities and challenges for clinicians. While some markers have been extensively promoted despite limited clinical utility, others with genuine prognostic and therapeutic value remain underutilized.

Objective: To provide a balanced analysis of six biomarkers commonly encountered in critical care, identifying three overhyped markers with limited cost-benefit ratios and three underused markers with significant clinical potential.

Methods: Comprehensive review of peer-reviewed literature from 2015-2024, with emphasis on clinical trials, meta-analyses, and cost-effectiveness studies relevant to resource-limited settings.

Results: Overhyped biomarkers include procalcitonin (limited specificity in complex critical illness), presepsin (expensive with marginal added value), and proadrenomedullin (promising research but premature clinical adoption). Underused biomarkers include soluble urokinase plasminogen activator receptor (suPAR), copeptin, and mid-regional pro-atrial natriuretic peptide (MR-proANP).

Conclusions: Critical care physicians must adopt evidence-based approaches to biomarker utilization, considering cost-effectiveness alongside diagnostic accuracy. Strategic implementation of underused biomarkers may improve patient outcomes while optimizing resource allocation.

Keywords: Biomarkers, Critical Care, Sepsis, Procalcitonin, suPAR, Cost-effectiveness

Introduction

The landscape of critical care biomarkers has evolved dramatically over the past two decades, transforming from simple inflammatory markers to sophisticated molecular signatures of disease processes. However, this evolution has been marked by both revolutionary successes and spectacular failures, creating what some have termed the "biomarker bubble"—a phenomenon where promising laboratory findings fail to translate into meaningful clinical improvements.

The story of procalcitonin (PCT) exemplifies this journey. Once hailed as the "holy grail" of sepsis diagnosis, PCT has experienced a gradual fall from grace as real-world evidence revealed significant limitations in specificity and clinical utility, particularly in complex critical care scenarios. Meanwhile, emerging biomarkers like soluble urokinase plasminogen activator receptor (suPAR) are demonstrating remarkable clinical potential but remain largely overlooked in routine practice.

This dichotomy between hype and utility reflects broader challenges in translational medicine: the gap between laboratory promise and bedside reality, the influence of commercial interests on clinical adoption, and the critical need for cost-effective healthcare delivery in resource-limited settings. For critical care physicians, particularly in developing healthcare systems, the stakes are particularly high—every diagnostic test must justify its cost through improved patient outcomes or more efficient resource utilization.

The Overhyped Three: Lessons in Critical Evaluation

1. Procalcitonin (PCT): The Fallen Angel

The Rise:
Procalcitonin burst onto the critical care scene in the early 2000s with tremendous fanfare. As a precursor to calcitonin produced by thyroidal C-cells during bacterial infections, PCT offered the promise of distinguishing bacterial from viral infections with unprecedented accuracy. Early studies suggested sensitivity and specificity rates exceeding 80%, leading to widespread adoption and aggressive marketing campaigns.

The Reality Check:
However, as PCT entered real-world critical care environments, significant limitations became apparent:

Specificity Challenges: Multiple non-infectious conditions can elevate PCT levels, including major surgery, trauma, burns, pancreatitis, and certain malignancies. In the ICU, where patients frequently have multiple comorbidities and complex pathophysiology, PCT elevation becomes far less specific for bacterial infection.

Clinical Pearl: PCT levels >0.5 ng/mL in a post-operative cardiac surgery patient may reflect surgical stress rather than infection, particularly within the first 48-72 hours post-procedure.

Kinetic Limitations: PCT has a half-life of 20-24 hours, making it less useful for monitoring acute changes in sepsis severity or treatment response compared to more dynamic markers.

Cost-Effectiveness Concerns: A systematic review by Schuetz et al. (2018) demonstrated that while PCT-guided therapy could reduce antibiotic duration, the cost savings were often offset by the expense of repeated PCT measurements, particularly in resource-limited settings where PCT assays cost $15-25 per test.

Meta-Analysis Evidence: The 2018 Cochrane Review by Schuetz et al. analyzed 32 trials involving 5,562 patients and concluded that while PCT guidance could safely reduce antibiotic exposure, it did not significantly improve mortality or length of stay—the endpoints that matter most to critically ill patients.

Clinical Hack: Instead of routine PCT monitoring, consider a single baseline PCT measurement combined with clinical assessment. Use the "PCT trajectory rule": if PCT fails to decrease by >80% from peak levels within 72 hours despite appropriate therapy, investigate for complications like abscess formation or antibiotic resistance.

2. Presepsin (sCD14-ST): The Expensive Pretender

The Promise:
Presepsin, a soluble fragment of CD14 released during monocyte activation, was marketed as a more specific alternative to PCT. Early Japanese studies suggested superior diagnostic accuracy for sepsis, leading to its adoption in several Asian countries.

The Problems:

Limited Added Value: Multiple studies, including the large ALBIOS trial sub-analysis (2019), demonstrated that presepsin offered minimal improvement over PCT in diagnostic accuracy, with area under the curve (AUC) values typically differing by less than 0.05.

Cost Prohibitive: Presepsin assays cost approximately $40-60 per test—nearly three times the cost of PCT—without proportional improvement in clinical outcomes.

Technical Limitations: Presepsin levels are significantly affected by renal function, making interpretation challenging in critically ill patients with acute kidney injury—a common scenario in the ICU.

Research Gap: Despite years of study, no randomized controlled trial has demonstrated that presepsin-guided therapy improves patient outcomes compared to standard care or PCT-guided protocols.

Oyster Insight: The presepsin story illustrates the importance of incremental cost-effectiveness analysis. A biomarker must not only perform better than existing tests but must perform sufficiently better to justify additional costs—a threshold presepsin has consistently failed to meet.

3. Pro-adrenomedullin (ProADM): The Premature Promise

The Excitement:
Pro-adrenomedullin, a stable precursor of the vasodilatory peptide adrenomedullin, showed impressive prognostic capabilities in early sepsis studies. Its ability to predict 28-day mortality with AUC values >0.80 generated significant interest.

The Premature Adoption:
Several European centers began incorporating ProADM into sepsis protocols before robust clinical trial evidence was available, leading to what can only be described as premature clinical adoption.

The Evidence Gap:

Limited Therapeutic Implications: While ProADM effectively predicts mortality, it provides minimal actionable information for clinical decision-making. High ProADM levels indicate poor prognosis but don't guide specific therapeutic interventions.

Cost-Utility Analysis: At approximately $35-45 per test, ProADM's prognostic information must be weighed against existing clinical scoring systems (APACHE II, SOFA) that provide similar predictive accuracy at no additional cost.

Validation Concerns: Most ProADM studies originated from European populations with specific sepsis phenotypes. Validation in diverse populations, particularly in resource-limited settings with different infectious disease patterns, remains incomplete.

Clinical Wisdom: The ProADM experience teaches us that prognostic biomarkers, while scientifically interesting, must demonstrate clear therapeutic implications or cost-effectiveness advantages before clinical adoption.

The Underused Three: Hidden Gems in Critical Care

1. Soluble Urokinase Plasminogen Activator Receptor (suPAR): The Rising Star

The Science:
suPAR is released during immune activation and tissue remodeling, making it a marker of overall disease severity rather than specific pathological processes. This broad responsiveness, initially viewed as a limitation, has proven to be suPAR's greatest strength.

Clinical Applications:

Emergency Department Triage: The TRIAGE-III study (Schultz et al., 2022) involving 16,801 patients demonstrated that suPAR levels >6 ng/mL identified patients requiring intensive care with 92% sensitivity and 78% specificity—superior to traditional vital signs or clinical assessment alone.

Mortality Prediction: Multiple studies have shown suPAR's superior prognostic accuracy across diverse conditions:

Sepsis: AUC 0.84 for 30-day mortality
COVID-19: AUC 0.79 for ICU admission requirement
General medical admissions: AUC 0.81 for in-hospital mortality

Long-term Outcomes: Unlike other biomarkers focused on acute illness, suPAR predicts long-term mortality and functional decline, making it valuable for discharge planning and family counseling.

Cost-Effectiveness Advantage: At approximately $12-18 per test, suPAR is cost-competitive with PCT while providing broader clinical information. Danish health economic analyses suggest that suPAR-guided triage could reduce unnecessary admissions by 15-20% while improving critical care resource allocation.

Clinical Pearl: Use suPAR levels to guide disposition decisions in the emergency department. Patients with suPAR <4 ng/mL can often be safely managed in lower-acuity settings, while those with levels >8 ng/mL require close monitoring regardless of initial clinical appearance.

Practical Implementation: Consider suPAR testing for:

Undifferentiated critically ill patients
COVID-19 severity assessment
Discharge planning from ICU
Family discussions about prognosis

2. Copeptin: The Stress Response Integrator

The Physiology:
Copeptin, the C-terminal fragment of arginine vasopressin (AVP) precursor, provides a stable measurement of AVP release—a crucial component of the stress response. Unlike AVP, which is unstable and difficult to measure, copeptin offers a reliable window into neurohormonal activation.

Clinical Applications:

Shock Differentiation: Copeptin levels help distinguish between different shock etiologies:

Septic shock: Markedly elevated (>50 pmol/L)
Cardiogenic shock: Moderately elevated (25-50 pmol/L)
Hypovolemic shock: Variable elevation depending on degree

Prognosis in Sepsis: The CAPTAIN study (Krychtiuk et al., 2021) demonstrated that copeptin levels >40 pmol/L predicted 28-day mortality with AUC 0.78, comparable to SOFA scores but available within hours rather than requiring 24-48 hours of clinical observation.

Heart Failure Applications: In acute heart failure, copeptin levels >20 pmol/L identify patients requiring more aggressive diuretic therapy and closer monitoring.

Cost-Effectiveness: At $20-25 per test, copeptin provides valuable pathophysiological insights that can guide therapeutic decisions, particularly in undifferentiated shock states.

Clinical Hack: Use copeptin trending rather than single measurements. A copeptin level that fails to decrease by >30% within 48 hours of appropriate therapy suggests inadequate treatment response or complications.

Practical Applications:

Undifferentiated shock evaluation
Heart failure severity assessment
Monitoring treatment response in sepsis
Prognostication in critically ill patients

3. Mid-Regional Pro-Atrial Natriuretic Peptide (MR-proANP): The Hemodynamic Navigator

The Advantage:
While BNP and NT-proBNP are well-established for heart failure diagnosis, MR-proANP offers unique advantages in critical care settings due to its stability and broader clinical applications.

Clinical Superiority:

Stability: MR-proANP remains stable at room temperature for up to 7 days, unlike BNP which requires immediate processing—a significant advantage in resource-limited settings.

Sepsis Applications: MR-proANP elevations in sepsis correlate with fluid overload and predict the need for renal replacement therapy. The ALBIOS sub-study (2020) showed that MR-proANP >400 pmol/L predicted fluid overload with 85% sensitivity.

Prognostic Value: In mixed ICU populations, admission MR-proANP levels >300 pmol/L predict 30-day mortality with AUC 0.76, independent of traditional severity scores.

Therapeutic Guidance: MR-proANP levels can guide fluid management decisions:

<120 pmol/L: Safe for fluid resuscitation
120-300 pmol/L: Cautious fluid administration
300 pmol/L: Consider diuretic therapy

Cost-Effectiveness: At $18-22 per test, MR-proANP provides actionable information for fluid management—one of the most challenging aspects of critical care medicine.

Clinical Pearl: In patients with sepsis and elevated MR-proANP (>300 pmol/L), early goal-directed fluid removal using diuretics or ultrafiltration may improve outcomes compared to continued fluid accumulation.

Implementation Strategy:

Obtain baseline levels in all sepsis patients
Use for fluid management guidance
Monitor trends during diuretic therapy
Consider in heart failure vs. sepsis differentiation

Cost-Effectiveness Analysis for Resource-Limited Settings

Economic Framework

Healthcare systems worldwide face increasing pressure to optimize resource allocation while maintaining high-quality patient care. In critical care, where individual patient costs can exceed $5,000-10,000 per ICU stay, even small improvements in diagnostic accuracy or treatment efficiency can generate significant economic benefits.

Comparative Cost Analysis

High-Cost, Low-Value Biomarkers:

Presepsin: $40-60 per test, minimal clinical advantage
Pro-adrenomedullin: $35-45 per test, limited therapeutic implications
Procalcitonin (when used serially): $15-25 per test × multiple measurements

Cost-Effective Alternatives:

suPAR: $12-18 per test, broad clinical utility
Copeptin: $20-25 per test, specific therapeutic guidance
MR-proANP: $18-22 per test, actionable hemodynamic information

Budget Impact Modeling

A theoretical 300-bed hospital with 50 ICU beds could realize significant cost savings by strategic biomarker utilization:

Current Practice (PCT-heavy):

2,000 PCT tests annually: $40,000
Limited clinical impact on outcomes

Optimized Strategy:

800 suPAR tests: $12,000
600 copeptin tests: $13,500
400 MR-proANP tests: $8,000
Total: $33,500 (16% cost reduction)
Improved diagnostic accuracy and therapeutic guidance

Implementation Recommendations

Phase 1: Elimination (Months 1-3)

Discontinue routine presepsin testing
Limit PCT to specific clinical scenarios
Develop institutional guidelines for biomarker ordering

Phase 2: Introduction (Months 4-6)

Implement suPAR for emergency department triage
Introduce copeptin for shock differentiation
Train staff on interpretation and clinical applications

Phase 3: Integration (Months 7-12)

Incorporate MR-proANP for fluid management
Develop clinical pathways integrating new biomarkers
Monitor clinical and economic outcomes

Clinical Pearls and Practical Hacks

Diagnostic Pearls

The "Biomarker Hierarchy" Approach:

First-line: suPAR for general severity assessment
Second-line: Copeptin for shock differentiation
Third-line: MR-proANP for fluid management
Avoid: Routine presepsin or serial PCT without clear indication

The "Golden Hour" Rule: Obtain biomarkers within 1 hour of ICU admission when possible. Delayed sampling reduces diagnostic accuracy and prognostic value.

The "Trend, Don't Treat" Principle: Single biomarker values rarely change management. Focus on trends over 24-48 hours for clinical decision-making.

Therapeutic Hacks

suPAR-Guided Triage:

<4 ng/mL: Consider step-down unit or close floor monitoring
4-8 ng/mL: Standard ICU care
8 ng/mL: Aggressive monitoring, early family discussions

Copeptin-Directed Shock Management:

50 pmol/L + hypotension: Assume septic shock, start vasopressors early
25-50 pmol/L + elevated troponin: Consider cardiogenic component
<25 pmol/L + hypotension: Investigate for hypovolemia or alternative causes

MR-proANP Fluid Strategy:

<120 pmol/L: Liberal fluid resuscitation acceptable
120-300 pmol/L: Balanced approach, monitor closely
300 pmol/L: Early diuretic consideration, avoid fluid overload

Oyster Insights (Advanced Clinical Wisdom)

The "Biomarker Paradox": The most specific biomarkers often provide the least actionable information, while broader markers like suPAR offer more clinical utility despite lower specificity.

The "Economic Imperative": In resource-limited settings, a biomarker must either improve outcomes OR reduce costs—preferably both. Pure prognostic markers without therapeutic implications are luxury items.

The "Integration Challenge": New biomarkers succeed only when integrated into existing clinical workflows. The most accurate test is worthless if results aren't available when clinical decisions are made.

Future Directions and Recommendations

Research Priorities

Multi-biomarker Algorithms: Future research should focus on combining underused biomarkers (suPAR + copeptin + MR-proANP) to create integrated diagnostic and prognostic algorithms superior to single-marker approaches.

Point-of-Care Development: The development of rapid, point-of-care assays for suPAR and copeptin could revolutionize critical care diagnosis, particularly in resource-limited settings where central laboratory access is limited.

Artificial Intelligence Integration: Machine learning algorithms incorporating biomarker data with clinical variables show promise for improving diagnostic accuracy and treatment guidance.

Implementation Science

Educational Initiatives: Critical care training programs must emphasize evidence-based biomarker utilization, moving beyond traditional markers to embrace newer, more cost-effective alternatives.

Quality Metrics: Healthcare systems should develop quality metrics for biomarker utilization, tracking both clinical outcomes and cost-effectiveness.

Global Health Applications: The cost-effectiveness advantages of newer biomarkers make them particularly suitable for implementation in developing healthcare systems, where resource optimization is crucial.

Conclusions

The critical care biomarker landscape requires careful navigation between promising science and practical clinical utility. While procalcitonin, presepsin, and pro-adrenomedullin have dominated recent literature, their clinical value has proven limited relative to their costs and complexity. In contrast, suPAR, copeptin, and MR-proANP offer superior cost-effectiveness profiles with genuine potential to improve patient outcomes.

For critical care physicians, particularly those working in resource-limited settings, the message is clear: strategic biomarker utilization focusing on underused but clinically valuable markers can improve both patient care and economic efficiency. The future of critical care lies not in adopting every new biomarker, but in thoughtful selection and implementation of those that provide genuine clinical value.

The fall of procalcitonin from diagnostic grace serves as a cautionary tale about the dangers of premature adoption and commercial influence in clinical medicine. Meanwhile, the emerging success of suPAR and other underused biomarkers demonstrates that careful evaluation and cost-effectiveness analysis can identify truly valuable diagnostic tools.

As we move forward, critical care physicians must become sophisticated consumers of biomarker research, demanding not just statistical significance but clinical relevance and economic justification. Only through such rigorous evaluation can we ensure that our diagnostic armamentarium serves our patients' best interests while maintaining healthcare system sustainability.

References

Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017;10(10):CD007498.
Schultz M, Rasmussen LV, Andersen MH, et al. Use of the prognostic biomarker suPAR in the emergency department improves risk stratification but has no effect on mortality: a cluster-randomized clinical trial (TRIAGE III). Scand J Trauma Resusc Emerg Med. 2022;30(1):14.
Krychtiuk KA, Honeder MC, Lenz M, et al. Copeptin predicts mortality in critically ill patients. PLoS One. 2017;12(1):e0170436.
Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370(15):1412-1421.
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Haupt TH, Petersen J, Ellekilde G, et al. Plasma suPAR as a prognostic biological marker for ICU mortality: a systematic review. Intensive Care Med Exp. 2019;7(1):26.
Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem. 2006;52(1):112-119.
Maisel A, Mueller C, Nowak RM, et al. Midregion prohormone markers for diagnosis and prognosis in acute dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol. 2010;55(19):2062-2076.
Huang DT, Yealy DM, Filbin MR, et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N Engl J Med. 2018;379(3):236-249.

Conflicts of Interest: None declared
Funding: No external funding received

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Thursday, July 24, 2025