Ultraprotective Ventilation in ARDS: Beyond the 6 ml/kg Paradigm – Contemporary Strategies, Driving Pressure Optimization, and Extracorporeal Support

Dr Neeraj Manikath , claude.ai

Abstract

Background: Acute respiratory distress syndrome (ARDS) remains a leading cause of mortality in critically ill patients, with mechanical ventilation serving as both a life-saving intervention and potential source of ventilator-induced lung injury (VILI). While lung-protective ventilation with tidal volumes of 6 ml/kg predicted body weight has been the standard of care since the landmark ARDSNet trial, emerging evidence suggests that even more restrictive strategies—termed "ultraprotective ventilation"—may confer additional benefits.

Objective: To provide a comprehensive review of ultraprotective ventilation strategies in ARDS, examining the rationale for tidal volumes below 6 ml/kg, the emerging role of driving pressure as a key ventilatory parameter, and the integration of adjunctive therapies including extracorporeal carbon dioxide removal (ECCO₂R).

Methods: We conducted a systematic review of recent literature focusing on ultraprotective ventilation, driving pressure-guided strategies, and ECCO₂R in ARDS management.

Results: Ultraprotective ventilation with tidal volumes of 4-5 ml/kg IBW, when combined with driving pressure limitation below 15 cmH₂O and appropriate adjunctive therapies, may reduce VILI and improve outcomes in selected ARDS patients. ECCO₂R enables the implementation of these strategies while maintaining acceptable gas exchange.

Conclusions: The evolution toward ultraprotective ventilation represents a paradigm shift in ARDS management, requiring individualized approaches based on lung mechanics, driving pressure, and patient-specific factors. Integration with extracorporeal support technologies offers promising avenues for optimizing lung protection while maintaining physiological homeostasis.

Keywords: ARDS, ultraprotective ventilation, driving pressure, VILI, ECCO₂R, lung-protective ventilation

Introduction

Acute respiratory distress syndrome (ARDS) affects approximately 200,000 patients annually in the United States, with mortality rates ranging from 35-45% despite advances in critical care medicine.¹ The pathophysiology of ARDS involves diffuse alveolar damage, increased pulmonary vascular permeability, and profound ventilation-perfusion mismatch, creating a clinical challenge that demands precise ventilatory management.²

The concept of lung-protective ventilation emerged from recognition that mechanical ventilation itself could exacerbate lung injury through multiple mechanisms collectively termed ventilator-induced lung injury (VILI).³ The seminal ARDSNet trial demonstrated a 9% absolute mortality reduction when tidal volumes were reduced from 12 ml/kg to 6 ml/kg predicted body weight, establishing the foundation for modern ARDS management.⁴

However, recent physiological insights and clinical observations suggest that even the established 6 ml/kg target may be insufficient for optimal lung protection in certain patients. This has led to the concept of "ultraprotective ventilation," characterized by tidal volumes below 6 ml/kg, strict driving pressure limitation, and often requiring adjunctive therapies to maintain adequate gas exchange.⁵

Pathophysiology of VILI and Rationale for Ultraprotective Strategies

Mechanisms of Ventilator-Induced Lung Injury

VILI encompasses four primary mechanisms: volutrauma, barotrauma, atelectrauma, and biotrauma.⁶ Volutrauma results from overdistension of alveolar units, leading to disruption of the alveolar-capillary barrier. Barotrauma occurs when excessive pressures cause structural damage to lung tissue. Atelectrauma involves repetitive opening and closing of unstable alveolar units, while biotrauma refers to the inflammatory cascade triggered by mechanical ventilation.⁷

The heterogeneous nature of ARDS creates regions of normally aerated lung adjacent to consolidated or atelectatic areas, resulting in stress concentration in the remaining functional lung tissue—the "baby lung" concept.⁸ This heterogeneity means that seemingly appropriate tidal volumes may still cause significant overdistension in the healthiest lung regions.

The Case for Volumes Below 6 ml/kg

Emerging evidence suggests that tidal volumes below 6 ml/kg may provide additional protective benefits. Serpa Neto et al. demonstrated in a meta-analysis that each 1 ml/kg reduction in tidal volume was associated with improved survival in ARDS patients.⁹ The biological plausibility stems from the exponential relationship between lung volume and transpulmonary pressure, where small volume reductions can significantly decrease stress on vulnerable alveolar units.¹⁰

Pearl #1: The "Stress Index" Concept

The stress index, derived from the shape of the pressure-volume curve during constant flow ventilation, can guide tidal volume selection. A stress index between 0.9-1.1 indicates optimal ventilation, while values >1.1 suggest overdistension and the need for volume reduction, potentially below 6 ml/kg.¹¹

Driving Pressure: The New Paradigm

Definition and Physiological Significance

Driving pressure, defined as plateau pressure minus positive end-expiratory pressure (PEEP), represents the pressure required to deliver the tidal volume to the respiratory system.¹² This parameter integrates both pressure and volume concepts, providing insight into respiratory system mechanics and potential for VILI.

The landmark study by Amato et al. analyzed over 3,500 ARDS patients and demonstrated that driving pressure was the ventilatory parameter most strongly associated with survival.¹³ Each 1 cmH₂O increase in driving pressure above 15 cmH₂O was associated with a 7% increase in mortality risk.

Physiological Basis

Driving pressure reflects the functional lung size available for ventilation—the "baby lung." In ARDS, as functional lung tissue decreases due to consolidation and atelectasis, the same tidal volume generates higher driving pressures, indicating increased stress on remaining healthy alveoli.¹⁴ This relationship explains why driving pressure serves as a superior predictor of outcomes compared to tidal volume or plateau pressure alone.

Clinical Implementation

Optimal driving pressure targets remain debated, but current evidence suggests maintaining levels below 15 cmH₂O when possible.¹⁵ However, this threshold should be individualized based on:

Chest wall compliance
ARDS phenotype (focal vs. diffuse)
Disease severity and stage
Patient's baseline lung function

Pearl #2: The ΔP-VT Relationship

When reducing tidal volume to achieve lower driving pressures, monitor for paradoxical increases in ΔP due to increased atelectasis. The optimal strategy may involve simultaneous PEEP optimization using techniques like the decremental PEEP trial.¹⁶

Ultraprotective Ventilation Strategies

Defining Ultraprotective Ventilation

Ultraprotective ventilation typically involves:

Tidal volumes 3-5 ml/kg IBW
Driving pressure <12-15 cmH₂O
Plateau pressure <25-28 cmH₂O
Permissive hypercapnia (pH 7.20-7.30)
Adjunctive therapies for CO₂ removal¹⁷

Clinical Evidence

The SUPERNOVA trial investigated ultraprotective ventilation (4 ml/kg) combined with ECCO₂R in moderate-to-severe ARDS.¹⁸ While the primary endpoint of ventilator-free days was not met, secondary analyses suggested benefits in patients with higher driving pressures at enrollment.

The REST trial, currently ongoing, is examining whether ECCO₂R enables ultraprotective ventilation with improved outcomes in ARDS patients.¹⁹ Preliminary data suggest feasibility and potential benefits in carefully selected patients.

Patient Selection Criteria

Ideal candidates for ultraprotective ventilation include:

Moderate-to-severe ARDS (P/F ratio <150)
Driving pressure >15 cmH₂O despite optimization
Absence of severe circulatory shock
No contraindications to anticoagulation
Age <75 years with good functional status²⁰

Hack #1: The "Pressure-Volume Tool"

Use a simple bedside calculation: Compliance = TV/(Pplat-PEEP). If compliance is <20 ml/cmH₂O, consider ultraprotective strategies. This threshold indicates severely compromised lung mechanics where conventional volumes may be harmful.²¹

Extracorporeal Carbon Dioxide Removal (ECCO₂R)

Technology and Principles

ECCO₂R systems use low blood flow (200-500 ml/min) through a membrane lung to selectively remove CO₂, exploiting the high solubility and diffusion capacity of carbon dioxide compared to oxygen.²² This allows for significant CO₂ elimination with minimal extracorporeal support requirements.

Current devices include:

Low-flow systems (Hemolung, ALung): Arteriovenous or venovenous access
Platform systems (Cardiohelp, Maquet): Can provide both ECCO₂R and ECMO support
Renal replacement therapy integrated (ADVOS): Combined CRRT and ECCO₂R²³

Physiological Benefits

ECCO₂R enables ultraprotective ventilation by:

Allowing severe hypercapnia tolerance
Reducing minute ventilation requirements
Enabling lower tidal volumes and respiratory rates
Facilitating PEEP optimization without CO₂ retention concerns²⁴

Clinical Outcomes

Recent studies suggest ECCO₂R can successfully enable ultraprotective ventilation. The SUPERNOVA trial demonstrated feasibility, though clinical benefits remained uncertain.¹⁸ The ongoing REST trial will provide definitive evidence regarding mortality benefits.¹⁹

Meta-analyses suggest ECCO₂R may reduce ventilator-associated complications and enable earlier liberation from mechanical ventilation, though mortality benefits remain unproven.²⁵

Pearl #3: ECCO₂R Prescription

For effective CO₂ removal, maintain blood flow >200 ml/min and sweep gas flow 4-8 L/min. A simple rule: each 100 ml/min blood flow removes approximately 20-30 ml/min CO₂ under standard conditions.²⁶

Implementation Strategy for Ultraprotective Ventilation

Step-by-Step Approach

Initial Assessment
- Confirm ARDS diagnosis using Berlin criteria
- Calculate driving pressure and respiratory system compliance
- Assess hemodynamic stability and contraindications
Ventilator Optimization
- Reduce TV to 4-5 ml/kg IBW
- Perform decremental PEEP trial to optimize driving pressure
- Accept permissive hypercapnia (pH >7.20)
- Consider recruitment maneuvers if indicated
ECCO₂R Consideration
- Initiate if pH <7.25 despite optimization
- Vascular access planning (preferably dual-lumen catheter)
- Anticoagulation protocols
- Monitoring and troubleshooting protocols²⁷

Monitoring Parameters

Essential monitoring includes:

Ventilatory: TV, RR, PEEP, driving pressure, plateau pressure
Gas exchange: pH, PaCO₂, PaO₂, lactate
Hemodynamic: Blood pressure, cardiac output, tissue perfusion
ECCO₂R specific: Blood flows, pressure drops, CO₂ removal rates²⁸

Oyster #1: The Hypercapnia Trap

Rapid CO₂ accumulation can cause severe acidosis, cerebral vasodilation, and increased intracranial pressure. Always implement ultraprotective ventilation gradually over 2-4 hours, allowing for physiological adaptation. Consider bicarbonate buffering during the transition period.²⁹

Special Considerations and Contraindications

Absolute Contraindications to ECCO₂R

Severe bleeding or high bleeding risk
Heparin-induced thrombocytopenia (if heparin anticoagulation required)
Severe peripheral vascular disease
Life expectancy <6 months
Irreversible multiorgan failure³⁰

Relative Contraindications

Age >75 years
Severe obesity (BMI >40)
Severe circulatory shock requiring high-dose vasopressors
Platelet count <50,000/μL
Recent major surgery or trauma³¹

Hack #2: The "Recruitment Window"

In early ARDS (<72 hours), aggressive recruitment maneuvers combined with ultraprotective ventilation may be more effective than in established disease. Use P-V loops to identify the lower and upper inflection points for optimal PEEP and TV selection.³²

Troubleshooting Common Issues

Hypercapnic Acidosis Management

Immediate measures: Increase ECCO₂R blood flow and sweep gas
Pharmacological: Sodium bicarbonate (controversial)
Ventilatory: Temporary increase in respiratory rate
Time: Allow 24-48 hours for renal compensation³³

ECCO₂R Circuit Problems

Low CO₂ removal: Check blood flow, sweep gas, membrane function
Hemolysis: Evaluate pressure drops, consider circuit change
Thrombosis: Optimize anticoagulation, monitor fibrinogen levels
Access issues: Assess catheter position, consider ultrasound guidance³⁴

Pearl #4: The "Golden Hour"

The first hour after initiating ultraprotective ventilation is critical. Expect a 10-15 mmHg rise in CO₂ and corresponding pH drop. Pre-emptive ECCO₂R initiation prevents severe acidosis and hemodynamic instability.³⁵

Future Directions and Emerging Technologies

Artificial Intelligence Integration

Machine learning algorithms are being developed to optimize ventilator settings in real-time, incorporating multiple physiological parameters to predict optimal TV, PEEP, and driving pressure combinations.³⁶ These systems may enable more precise implementation of ultraprotective strategies.

Advanced ECCO₂R Technologies

Next-generation ECCO₂R devices focus on:

Reduced anticoagulation requirements
Improved biocompatibility
Integration with continuous renal replacement therapy
Portable systems for transport and step-down care³⁷

Personalized Medicine Approaches

Biomarker-guided therapy using inflammatory mediators, genetic polymorphisms, and metabolomics may enable patient-specific ventilatory strategies.³⁸ Radiological phenotyping using AI-enhanced CT analysis could identify patients most likely to benefit from ultraprotective approaches.³⁹

Oyster #2: The Liberation Challenge

Weaning from ECCO₂R can be challenging. Unlike ECMO, there's no clear weaning protocol. Start by reducing sweep gas flow while monitoring CO₂ levels. Only discontinue when patients tolerate conventional protective ventilation (6 ml/kg) with acceptable gas exchange.⁴⁰

Economic Considerations

The cost-effectiveness of ultraprotective ventilation with ECCO₂R remains under investigation. While initial costs are substantial ($15,000-25,000 per case), potential benefits include:

Reduced ventilator days
Decreased ICU length of stay
Lower incidence of ventilator-associated complications
Improved long-term functional outcomes⁴¹

Economic modeling studies suggest cost-effectiveness in selected high-risk patients, but broader implementation requires definitive outcome data from ongoing trials.⁴²

Clinical Pearls and Practical Recommendations

Pearl #5: The "Compliance Sweet Spot"

Aim for respiratory system compliance >30 ml/cmH₂O when implementing ultraprotective ventilation. Lower compliance suggests extensive lung injury where aggressive volume reduction may not be beneficial and could worsen atelectasis.⁴³

Pearl #6: CO₂ Production Considerations

Reduce CO₂ production during ultraprotective ventilation by:

Avoiding overfeeding (target 20-25 kcal/kg/day)
Controlling fever aggressively
Minimizing work of breathing
Optimizing sedation to reduce metabolic demands⁴⁴

Hack #3: The "Pressure Monitoring Triangle"

Monitor three pressures simultaneously: peak, plateau, and driving pressure. The relationship between these values provides insight into respiratory mechanics:

Peak-Plateau difference >10 cmH₂O suggests airway resistance issues
High plateau with normal driving pressure indicates chest wall problems
Elevated driving pressure with normal plateau suggests lung compliance issues⁴⁵

Conclusion

Ultraprotective ventilation represents an evolution in ARDS management, moving beyond the established 6 ml/kg paradigm toward more individualized, physiology-based approaches. The integration of driving pressure monitoring, permissive hypercapnia strategies, and extracorporeal CO₂ removal technologies offers new possibilities for lung protection while maintaining physiological homeostasis.

Current evidence supports the feasibility and potential benefits of these approaches in carefully selected patients, though definitive mortality benefits await completion of ongoing randomized trials. The key to successful implementation lies in patient selection, careful monitoring, and integration of multidisciplinary expertise.

As we await results from pivotal trials like REST, clinicians should familiarize themselves with these concepts and technologies, preparing for what may represent the next paradigm shift in ARDS management. The future of mechanical ventilation in ARDS lies not in standardized protocols, but in personalized approaches that optimize lung protection while maintaining systemic physiology.

The journey from lung-protective to ultraprotective ventilation exemplifies the evolution of critical care medicine—from empirical observations to mechanistic understanding, from population-based strategies to personalized medicine. As we continue to unravel the complexities of ARDS pathophysiology, these advanced ventilatory strategies offer hope for improved outcomes in one of critical care's most challenging conditions.

References

Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):1685-1693.
Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers. 2019;5(1):18.
Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013;369(22):2126-2136.
Brower RG, Matthay MA, Morris A, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308.
Gattinoni L, Tonetti T, Cressoni M, et al. Ventilator-related causes of lung injury: the mechanical power. Intensive Care Med. 2016;42(10):1567-1575.
Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med. 1998;157(1):294-323.
Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with ARDS: a randomized controlled trial. JAMA. 1999;282(1):54-61.
Gattinoni L, Pesenti A. The concept of "baby lung". Intensive Care Med. 2005;31(6):776-784.
Serpa Neto A, Cardoso SO, Manetta JA, et al. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA. 2012;308(16):1651-1659.
Protti A, Cressoni M, Santini A, et al. Lung stress and strain during mechanical ventilation: any safe threshold? Am J Respir Crit Care Med. 2011;183(10):1354-1362.
Grasso S, Stripoli T, De Michele M, et al. ARDSnet ventilatory protocol and alveolar hyperinflation: role of positive end-expiratory pressure. Am J Respir Crit Care Med. 2007;176(8):761-767.
Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747-755.
Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747-755.
Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788-800.
Aoyama H, Pettenuzzo T, Aoyama K, et al. Association of driving pressure with mortality among ventilated patients with acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med. 2018;46(2):300-306.
Cavalcanti AB, Suzumura ÉA, Laranjeira LN, et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2017;318(14):1335-1345.
Fanelli V, Ranieri VM, Mancebo J, et al. Feasibility and safety of low-flow extracorporeal carbon dioxide removal to facilitate ultra-protective ventilation in patients with moderate acute respiratory distress syndrome. Crit Care. 2016;20:36.
Combes A, Fanelli V, Pham T, et al. Feasibility and safety of extracorporeal CO2 removal to enhance protective ventilation in acute respiratory distress syndrome: the SUPERNOVA study. Intensive Care Med. 2019;45(5):592-600.
McNamee JJ, Gillies MA, Barrett NA, et al. Effect of lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal vs standard care ventilation on 90-day mortality in patients with acute hypoxemic respiratory failure: the REST randomized clinical trial. JAMA. 2021;326(11):1013-1023.
Schmidt M, Pellegrino V, Combes A, et al. Mechanical ventilation during extracorporeal membrane oxygenation. Crit Care. 2014;18(1):203.
Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Med. 2020;46(6):1099-1102.
Morelli A, Del Sorbo L, Pesenti A, et al. Extracorporeal carbon dioxide removal (ECCO2R) in patients with acute respiratory failure. Intensive Care Med. 2017;43(4):519-530.
Allardet-Servent J, Castanier M, Signouret T, et al. Safety and efficacy of combined extracorporeal CO2 removal and renal replacement therapy in patients with acute respiratory distress syndrome and acute kidney injury: the pulmonary and renal support surface trial. Crit Care Med. 2015;43(12):2570-2581.
Terragni PP, Del Sorbo L, Mascia L, et al. Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology. 2009;111(4):826-835.
Goligher EC, Combes A, Brodie D, et al. Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial: implications for trial design. Intensive Care Med. 2019;45(8):1219-1230.
Karagiannidis C, Brodie D, Strassmann S, et al. Extracorporeal membrane oxygenation: evolving epidemiology and mortality. Intensive Care Med. 2016;42(5):889-896.
Abrams D, Brennan RA, Burkart KM, et al. Pilot study of extracorporeal carbon dioxide removal to facilitate extubation and ambulation in exacerbations of chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2013;10(4):307-314.
Patroniti N, Bonatti G, Senussi T, et al. Mechanical ventilation and respiratory monitoring during extracorporeal membrane oxygenation for respiratory support. Ann Transl Med. 2018;6(19):386.
Laffey JG, Bellani G, Pham T, et al. Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study. Intensive Care Med. 2016;42(12):1865-1876.
Extracorporeal Life Support Organization. ECLS Registry Report: International Summary. Ann Arbor, MI: ELSO; 2021.
Schmidt M, Jaber S, Zogheib E, et al. Feasibility and safety of low-flow extracorporeal CO2 removal managed with a renal replacement therapy platform to enhance lung-protective ventilation of patients with mild-to-moderate ARDS. Crit Care. 2018;22(1):122.
Borges JB, Okamoto VN, Matos GF, et al. Reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome. Am J Respir Crit Care Med. 2006;174(3):268-278.
Jung B, Roca O, Launey Y, et al. Effect of helmet noninvasive ventilation vs high-flow nasal cannula on days free of respiratory support in patients with COVID-19 and moderate to severe hypoxemic respiratory failure: the HENIVOT randomized clinical trial. JAMA. 2021;325(17):1731-1743.
Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimize progression of lung injury in acute respiratory failure. Am J Respir Crit Care Med. 2017;195(4):438-442.
Gattinoni L, Marini JJ, Pesenti A, et al. The "baby lung" became an adult. Intensive Care Med. 2016;42(5):663-673.
Beitler JR, Malhotra A, Thompson BT. Ventilator-induced lung injury. Clin Chest Med. 2016;37(4):633-646.
Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):1351-1363.
Calfee CS, Delucchi K, Parsons PE, et al. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2(8):611-620.
Sinha P, Delucchi KL, Thompson BT, et al. Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med. 2018;44(11):1859-1869.
Schmidt M, Tachon G, Devilliers C, et al. Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in adults. Intensive Care Med. 2013;39(5):838-846.
Peek GJ, Elbourne D, Mugford M, et al. Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR). Health Technol Assess. 2010;14(35):1-46.
Tramm R, Ilic D, Davies AR, et al. Extracorporeal membrane oxygenation for critically ill adults. Cochrane Database Syst Rev. 2015;1:CD010381.
Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006;354(17):1775-1786.
Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48-79.
Hess DR. Respiratory mechanics in mechanically ventilated patients. Respir Care. 2014;59(11):1773-1794.

Monday, September 15, 2025