Mechanical Ventilation-induced Acute Kidney Injury [AKI]

Acute respiratory distress syndrome (ARDS), ventilation-induced lung injury (VILI), and protective mechanical ventilation (MV) are key aspects of respiratory failure management. ARDS is an inflammatory pulmonary edema caused by alveolar and endothelial injury, characterized by a breakdown in the alveolar-capillary barrier that results in the collapse of alveolar spaces. Clinically, ARDS manifests as acute hypoxemia, bilateral X-ray infiltrates, and decreased lung compliance. A global epidemiological study identified a 10.4% prevalence of ARDS among ICU admissions, with ICU and hospital mortality rates of 35.3% and 40.0%, respectively. ARDS survivors often experience long-term morbidity affecting the cardiovascular system, nerves, muscles, and the central nervous system. During the SARS-CoV-2 pandemic, ARDS statistics surged, placing an unprecedented burden on healthcare systems worldwide.

Mechanical ventilation serves as the primary supportive therapy for ARDS but can also exacerbate lung damage, a phenomenon referred to as VILI. VILI is primarily caused by alveolar overdistension (volutrauma) due to high tidal volumes and repeated opening and closing of unstable alveoli (atelectrauma) associated with insufficient positive end-expiratory pressure (PEEP). The late 1990s saw the first clinical trials definitively showing that lower tidal volumes improved survival rates in ARDS patients, highlighting the importance of VILI in determining ARDS outcomes. VILI also triggers a biological response characterized by lung and systemic inflammation, as well as damage to distant organs (biotrauma), which explains the role of protective ventilatory strategies in preventing organ failure and mortality.

In ARDS, a significant portion of lung units becomes unstable, collapses, and is excluded from ventilation. The collapse reduces the aerated lung size, resembling what is referred to as the "baby lung." Consequently, only this small "baby lung" receives the tidal volume, making it prone to overstretching and excessive strain. Moreover, lung infiltrates are unevenly distributed, concentrating exaggerated tensions in the healthy alveoli surrounding collapsed regions. To prevent VILI, two main ventilatory strategies have been employed: reducing tidal volume to mitigate volutrauma and optimizing PEEP to decrease atelectrauma, strain, and the uneven distribution of forces. While the protective role of low tidal volume is well-established, the role of PEEP remains a subject of ongoing debate.

The Role of PEEP in Protective Mechanical Ventilation

PEEP is defined as the maintenance of positive pressure at the airway opening at the end of expiration. Since the initial description of ARDS in 1967, PEEP has been observed to improve hypoxemia in ARDS patients by preventing alveolar collapse and recruiting collapsed lung regions, thus reducing intrapulmonary shunt. Another significant effect of PEEP is the reduction of the primary mechanisms responsible for VILI: 1) increasing the size of the "baby lung" through lung recruitment, reducing lung strain and stress; 2) keeping unstable alveoli open at end-expiration, thereby reducing opening and closing; and 3) promoting more uniform ventilation to decrease lung inhomogeneities and reduce injury at the interfaces between aerated and collapsed lung tissue.

These effects are more prominent in easily recruited lungs, while the risk of alveolar overdistension and VILI increases in less recruited lungs. Over the past 50 years, various strategies for determining appropriate PEEP levels have evolved, ranging from zero end-expiratory pressure (ZEEP) to implementing super PEEP strategies. One of the most well-known approaches is the ARDSNet PEEP/FiO2 table introduced by the National Institutes of Health ARDS Network in 1995. Although widely used, this method focused primarily on managing hypoxemia rather than preventing VILI. Subsequent trials, such as the ALVEOLI trial and the LOV trial, increased PEEP levels, but none demonstrated a mortality benefit for higher PEEP strategies.

The three largest trials comparing high versus low PEEP strategies (ALVEOLI, LOV, and EXPRESS) revealed no significant differences in mortality between the groups. A likely explanation is that higher PEEP benefits patients with substantial lung recruitability but may harm those with lower recruitability, resulting in a neutral overall effect. While higher PEEP consistently improved oxygenation across trials, improvements in respiratory compliance were less consistent. Additionally, smaller clinical studies have linked high PEEP with increased vasopressor requirements and greater fluid retention. These findings underscore the complexity of PEEP's effects on both lung mechanics and systemic physiology.

Cardiocirculatory Effects of PEEP

The hemodynamic effects of PEEP are complex and manifest in various ways in individual patients. These effects can be categorized into three primary aspects: 1) A decrease in right ventricle preload: PEEP increases pressure in the right atrium, impairing venous return. As PEEP levels gradually increase, the diameter of the inferior vena cava enlarges during both inspiration and expiration, reflecting an increase in transmural pressure and a reduction in venous return. 2) An increase in pulmonary vascular resistance: PEEP also elevates right ventricle (RV) afterload, opposing RV ejection during systole, potentially increasing RV end-diastolic volume and affecting left ventricle (LV) function downstream. These effects are influenced by factors such as lung recruitment, hyperinflation, and hypoxic vasoconstriction. 3) A decrease in left ventricle output and afterload: The primary effect of PEEP on the LV is mediated by a reduction in venous return, leading to decreased LV preload and cardiac output shortly after PEEP elevation. In patients with LV dysfunction, this reduction in afterload can enhance cardiac output and reduce myocardial oxygen demand.

In patients with acute lung injury, an increase in PEEP often results in decreased venous return and cardiac output, leading to a drop in mean arterial pressure. Intravenous fluids and/or vasoconstrictors are generally required to restore cardiac output. However, the ultimate impact of these interventions on abdominal venous congestion and tissue perfusion remains inadequately defined.

Despite the long-established awareness of PEEP's negative cardiovascular effects, its influence on intra-abdominal organs has received relatively little attention. One reason for this knowledge gap could be the challenges associated with bedside assessment of abdominal vascular flow. Over recent years, this gap has been bridged by the increased use and accessibility of Doppler ultrasonography in ICU settings. Experimental data indicate that PEEP induces redistribution of blood flow to the brain, heart, adrenals, and intestines while diminishing blood flow to the liver, pancreas, and stomach. Total renal blood flow appears to be relatively unaffected, but the redistribution of intrarenal blood flow may result in kidney dysfunction. The next sections will review the effects of PEEP on hepatic, renal, and intestinal blood flow, focusing on these three organs due to their significant role in organ dysfunction in ARDS patients.

Hepatic Blood Flow: Fujita et al. demonstrated that increasing PEEP from 5 to 10 cmH2O proportionally decreased hepatic blood flow and cardiac output without changes in mean arterial pressure. Hepatic oxygen supply and venous hemoglobin saturation were also reduced. In addition, hepatic and portal venous pressures increased with elevated PEEP, and hepatic dimensions expanded by 16-19% after applying a PEEP of 10 cmH2O. In an ARDS porcine model, Kredel et al. compared groups with 5 cmH2O PEEP and higher PEEP following a recruitment maneuver. Plasma transaminases, LDH, and bilirubin were elevated in the higher PEEP group. Brienza et al. found a strong association between mechanical ventilation with PEEP and liver dysfunction (OR 4.25; p=0.006) in critically ill patients. Recently, Huette et al. reported a progressive increase in portal pulsatility index from 9% to 45% when PEEP increased from 0 to 15 cmH2O in cardiac surgery patients, indicating venous congestion.

Renal Blood Flow: The development of acute kidney injury (AKI) is a major contributor to ICU morbidity and poor long-term outcomes. PEEP has been associated with reduced renal perfusion and glomerular filtration, as well as elevated levels of antidiuretic hormone, plasma renin, and aldosterone. These changes coincide with decreased natriuresis and water retention, which can contribute to venous congestion. A comprehensive retrospective cohort study by Geri et al. linked mechanical ventilation (MV) to renal function deterioration, with PEEP playing a significant role in this association due to renal venous congestion. Dres et al. demonstrated that high PEEP correlated with higher AKI incidence and an increased need for renal replacement therapy in COVID-19 ARDS patients. In a study by Fogagnolo et al., a linear correlation was found between PEEP levels and the renal resistive index (R²=0.31; p=0.03), with 71% of patients showing non-continuous renal venous flow under high PEEP.

Intestinal Blood Flow: Lehtipalo et al. evaluated intestinal perfusion in a porcine model using invasive Doppler measurements, finding that hepatosplanchnic blood flow progressively declined as PEEP increased from ZEEP to 12 cmH2O. This was associated with a parallel increase in oxygen extraction. The effects of this maneuver were more pronounced when abdominal perfusion pressure dropped below 50 mmHg. Additionally, mechanical ventilation with positive pressure impeded lymphatic drainage from the interstitium, leading to interstitial fluid retention. In an endotoxemic porcine model, Lattuada et al. compared three groups (spontaneous ventilation, PEEP 5 cmH2O, and PEEP 15 cmH2O) and observed that increasing PEEP proportionally decreased lymphatic flow from the abdomen and increased liver and intestinal edema and inflammation. These effects were attributed to increased systemic capillary leakage and impeded abdominal lymph drainage. Experimental data suggest that PEEP-induced venous congestion in abdominal organs, resulting from reduced pressure gradients between the arterial and venous systems, leads to increased oxygen extraction, organ dysfunction, and local inflammation.

The most extensively studied pathological model of abdominal congestion is secondary to chronic global heart failure, which leads to reduced cardiac output, increased filling pressures, and fluid overload. In these patients, visceral edema can progress to severe complications such as cirrhosis, terminal renal failure, and intestinal dysfunction, with increased permeability to endotoxins and bacteria. This condition is exacerbated by a systemic inflammatory state, worsening the patient's prognosis. PEEP can induce a similar pathophysiological state through elevated right heart filling pressures, even in the absence of right ventricular dysfunction or hypervolemia. In ARDS patients, factors such as decreased oncotic pressure, increased vascular permeability due to inflammation, and elevated hydrostatic pressure (fluids and transfusions) contribute to the negative impact of venous congestion caused by PEEP. Fluid accumulation in encapsulated organs such as the liver and kidneys is poorly tolerated due to limited expansion, intensifying perfusion disturbances.

In terms of specific organ perfusion, venous congestion increases post-capillary pressure. If PEEP reduces cardiac output, precapillary pressure may also decrease, disrupting the balance between these factors and potentially leading to organ dysfunction. Doppler ultrasound (US) serves as an effective, non-invasive tool for evaluating arterial and venous abdominal vasculature, providing clinicians with valuable data on organ-specific blood flow. In