Lung-Brain Interaction: Challenges and Strategies in ARDS and TBI Management

The management of acute respiratory distress syndrome (ARDS) in traumatic brain injury (TBI) patients presents unique challenges due to the need for lung-protective ventilation while maintaining cerebral perfusion. This article examines optimal ventilation strategies, oxygenation targets, fluid management, and adjunctive therapies to balance pulmonary and neurological outcomes in critically ill patients.

Introduction

The interplay between the respiratory and neurological systems is increasingly acknowledged in critically ill patients, particularly in the context of acute respiratory distress syndrome (ARDS) and traumatic brain injury (TBI). In polytrauma patients, these conditions often coexist, posing significant challenges in the intensive care unit (ICU). TBI patients may develop ARDS due to an exaggerated inflammatory response and impaired lung mechanics, or as a direct consequence of pulmonary contusions or aspiration. Conversely, TBI can significantly affect respiratory function through hypoventilation or pulmonary capillary hypertension caused by adrenergic stress, further complicating management strategies (Barretto et al. 2020). When both conditions coexist, mortality rates and outcomes worsen (Svedung et al. 2019).

Management strategies aim to minimise complications arising from the coexistence of these pathologies (Abdussalam 2017). Standard lung-protective ventilation strategies, including low tidal volume and optimised positive end-expiratory pressure (PEEP), help prevent ventilator-induced lung injury but may also lead to hypercapnia. Some studies suggest that permissive hypercapnia can be beneficial in select patients by inducing cerebral vasodilation. However, hypercapnia and acidosis may promote cerebral oedema and exacerbate brain injury. Additionally, high PEEP levels may hinder cerebral venous return, raising intracranial pressure (ICP) and compromising cerebral perfusion pressure (CPP) (Chesnut et al. 2017).

One of the greatest challenges in managing patients with severe TBI and ARDS is balancing lung-protective ventilation with the adjustments necessary to maintain blood gases within a range that prevents secondary brain injury due to hypoxaemia or hypercapnia (Huang et al. 2021). Prone positioning can improve pulmonary function and oxygenation; however, it may also increase intracranial pressure (ICP) (Roth et al. 2014). Early tracheostomy may also be pivotal in preventing complications. Despite advances in understanding these interactions, critical gaps remain, particularly due to the lack of standardised protocols and guidelines for ventilation strategies in neurocritical care (Chacón-Aponte et al. 2022). An individualised approach is therefore essential to simultaneously protect both the brain and the lungs (Robba et al. 2020).

Through this synthesis of current evidence, we aim to provide a comprehensive framework for understanding and addressing the complexities of lung-brain interaction in critical care settings.

Considerations in TBI

The brain consumes approximately 20% of available oxygen and receives about 15% of cardiac output. Its metabolism is predominantly aerobic, with an oxygen consumption of 150–160 μmol/100 g/min (Heuer et al. 2017). In adults, normal ICP ranges from 10 to 15 mmHg, while sustained values of ≥18 mmHg are associated with poor outcomes in TBI patients. Cerebral perfusion pressure (CPP) is calculated as the difference between mean arterial pressure (MAP) and ICP, typically maintained within 60–80 mmHg (Heuer et al. 2017).

TBI is caused by an external physical force that disrupts the balance between energy supply and metabolic demands (Robba et al. 2024). It has a global annual incidence of approximately 27 million cases (Kaur et al. 2018) and is a leading cause of mortality and disability, particularly in individuals under 40 years of age.

Primary brain injury occurs at the moment of impact and results from focal damage (including intracranial haematomas, skull fractures, lacerations, contusions, and penetrating injuries) as well as diffuse mechanical injury (Soto et al. 2022). Secondary injuries arise from a complex interplay of systemic and cerebral events that can worsen the primary injury. This process involves cerebrovascular alterations, disruption of the blood-brain barrier (BBB), cerebral oedema, and increased ICP, all of which significantly impact patient outcomes. In this context, hypoxaemia and hypercapnia can further compromise neurological outcomes in TBI patients who develop ARDS. Sustained low CPP values (<50 mmHg) increase the risk of cerebral hypoperfusion and neuronal injury, whereas excessively high values can exacerbate perilesional oedema and secondary brain injury (Treggiari et al. 2007).

ARDS and its Impact on Patients With TBI

ARDS is characterised by acute hypoxaemia with non-hydrostatic pulmonary oedema, marked decreased lung compliance, and increased work of breathing. It is associated with a mortality rate of approximately 50% (O'Leary 2016). Histopathological studies reveal neutrophilic infiltrates, oedema, haemorrhage, and hyaline membrane formation in the lungs (Mouret et al. 2019).

The impact of ARDS on TBI is associated with a longer stay in the ICU (an additional 4 to 6 days), prolonged mechanical ventilation (an extra 5 to 7 days), and an increased risk of intracranial hypertension (up to 50% in fatal TBI cases with neurogenic oedema), further compromising neurological recovery. The management of patients with both TBI and ARDS requires careful balancing, optimising pulmonary oxygenation without compromising cerebral pressure and perfusion. Multimodal neurological monitoring is recommended to guide ventilation and other interventions to minimise the risk of neurological complications (Della Torre et al. 2017).

In an experimental study, the combined effects of acute intracranial hypertension (AICH) and ARDS on lung and neuronal injury were evaluated. Twenty-eight animals were divided into four groups: control, AICH, ARDS, and ARDS+AICH. AICH was induced using an intracranial balloon catheter, while ARDS was induced via oleic acid infusion. Haemodynamic parameters, oxygenation, pulmonary and brain tomography, and markers of neuronal damage such as neuron-specific enolase (NSE) and S100B protein were assessed.

The results demonstrated that animals with AICH exhibited increased extravascular lung water and pulmonary density, exacerbating oedema and ventilatory deterioration. ARDS, in turn, caused hippocampal damage and cerebral oedema. Elevated levels of NSE and S100B indicated brain dysfunction, highlighting the pathological interaction between the lungs and the brain. Additionally, a significant increase in Hounsfield units (HU) in the lungs indicated heightened pulmonary water content and decreased aeration. AICH inherently increases lung density, but ARDS led to even more marked changes, reflecting regions of compromised ventilation—possibly due to interstitial oedema, partial alveolar collapse, or increased lung density (Ziaka et al. 2022).

Plasma concentrations of S100B and NSE proteins, as well as inflammatory cytokines IL-1β and IL-6, were elevated in all experimental groups compared to controls, with a more pronounced increase in ARDS cases. These findings suggest that ARDS may exacerbate brain injuries in patients with intracranial hypertension, possibly through pulmonary inflammation that could affect the nervous system via humoral, cellular, and neuronal mechanisms (López-Aguilar et al. 2013).

Impact of Mechanical Ventilation in TBI

Protective Ventilation: Low Tidal Volume and High PEEP

A protective lung ventilation (PLV) strategy, involving low tidal volume (Vt) and high positive end-expiratory pressure (PEEP), has demonstrated effectiveness in reducing respiratory complications in patients with ARDS. However, its application in patients with acute neurological compromise remains controversial, as permissive hypercapnia and elevated airway pressures can increase intracranial pressure (ICP) and compromise cerebral perfusion pressure (CPP). Although PEEP improves oxygenation by preventing atelectrauma, levels above 12 cmH₂O may adversely affect cerebral dynamics—particularly in patients with limited cerebrovascular reserve and reduced intracranial compliance. Therefore, PEEP application should be individualised to minimise adverse haemodynamic and neurological effects (Perez Nieto et al. 2021).

In the absence of conclusive evidence, the PROLABI study evaluated whether a protective lung ventilation strategy could improve clinical and neurological outcomes in this population. This multicentre, controlled, open-label clinical trial included 190 adult patients with acute brain injury without ARDS at admission (TBI, subarachnoid haemorrhage, intracerebral haemorrhage, or ischaemic stroke). Patients were randomly assigned to protective ventilation (VT 6 mL/kg PBW, PEEP 8 cmH₂O) or conventional ventilation (VT >8 mL/kg PBW, PEEP 4 cmH₂O). The composite primary outcome at 28 days (mortality, ventilator dependence, and ARDS development) was more frequent in the protective ventilation group (61.5% vs. 45.3%; RR 1.35; p=0.025), with increased mortality (28.9% vs. 15.1%) and ventilator dependence. No short- or long-term neurological benefits were observed, and the protective strategy was associated with higher central venous pressure and PaCO₂ levels (~35 vs. ~38 mmHg). The study concluded that protective ventilation, in the absence of ARDS, did not improve clinical or neurological outcomes and may even be harmful, emphasising the need for larger studies to confirm these findings (Mascia et al. 2024).

“Ventilatory management in patients with acute brain injury poses a significant clinical dilemma: protecting the lungs without compromising cerebral perfusion” (Robba et al. 2025)

Another important aspect to consider is that, in a large observational trial, elevated values of plateau pressure (Pplat), peak pressure, and driving pressure were significantly associated with ICU and 6-month mortality, but not with neurological outcomes (Robba et al. 2025).

Pulmonary Volume Recruitment Manoeuvres

Pulmonary volume recruitment manoeuvres (VRM) impact intracranial pressure (ICP), cerebral perfusion, and oxygenation. A VRM that involved raising peak airway pressure to 60 cmH₂O for 30 seconds resulted in an increase in ICP from 13 ± 5 mmHg to 16 ± 5 mmHg and a decrease in cerebral perfusion pressure (CPP) from 72 ± 8 mmHg to 60 ± 10 mmHg. Jugular venous oxygen saturation (SJO₂) dropped significantly from 69 ± 6% to 59 ± 7%. Although arterial oxygenation improved transiently, this benefit was short-lived. The rise in ICP is likely attributable to reduced venous return caused by elevated intrathoracic pressure. These results suggest that high-pressure VRMs can compromise cerebral haemodynamics in neurological injury, warranting strict monitoring and additional strategies to prevent cerebral ischaemia (Bein et al. 2002). Moderate-pressure alveolar recruitment manoeuvres may be safer concerning cerebral perfusion (Picetti et al. 2019).

Oxygen Targets

Safe PaO₂ values for patients with ARDS range between 60 and 90 mmHg (Nielsen et al. 2025), but these may not be adequate for patients with TBI. A study analysing 1,006 measurements of cerebral (PbtO₂) and arterial oxygenation (PaO₂) in TBI patients found that a PaO₂ ≥94 mmHg was necessary to maintain PbtO₂ above 20 mmHg, a threshold higher than that recommended by the Brain Trauma Foundation (60 mmHg). Additionally, 41.7% of the measurements showed an abnormal BOx ratio (<0.15), suggesting impaired cerebral oxygen delivery despite normal PbtO₂ levels (Dellazizzo 2019). Hyperoxia has been linked to increased mortality, with PaO₂ ≥100 mmHg associated with higher risk (OR 1.03; 95% CI: 1.01–1.05), indicating the need for more conservative and individualised oxygen therapy strategies (Rezoagli et al. 2022).

Impact of PaCO₂

Permissive hypercapnia, a consequence of the protective ventilation strategy (low tidal volume), has been associated with better outcomes in patients with ARDS (O'Croinin et al. 2004). However, patients with acute brain injury are highly susceptible to cerebrovascular autoregulation changes mediated by PaCO₂. Hypercapnia may lead to hyperaemia and increased cerebral oedema, correlating with higher mortality when unaccompanied by adequate compensation and respiratory acidosis (Svedung et al. 2019). Conversely, hypocapnia can induce cerebral arterial vasoconstriction, reducing brain tissue oxygenation and increasing the risk of ischaemia (Martineau et al. 2025). Normocapnia remains the preferred target to avoid adverse effects (Taccone et al. 2020).

Prone Positioning

Elevating the head >30° promotes cerebral venous drainage and minimises venous outflow interference caused by intrathoracic pressure (Alarcon et al. 2017). In patients with moderate to severe ARDS, prone positioning improves survival, but it significantly increases ICP, as demonstrated in a study analysing 119 prone sessions in 29 acute brain injury patients. ICP increased from 9.5 ± 5.9 mmHg in the supine position to 15.4 ± 6.2 mmHg in the prone position (p < 0.0001), underscoring the need for careful monitoring (Roth et al. 2014).

Fluid Therapy

In ARDS patients, a systematic review demonstrated no significant reduction in mortality (RR 0.92; 95% CI 0.82–1.02) but reported an increase in ventilator-free days (mean difference 1.82 days; 95% CI 0.53–3.10) and a reduction in ICU length of stay (−1.88 days; 95% CI −0.12 to −3.64) (Silversides et al. 2017). On the other hand, in the CENTER-TBI trial on fluid management, a positive fluid balance was associated with worse clinical outcomes. For every 0.1 L increase in daily positive balance, there was an increase in ICU mortality (OR 1.10; 95% CI: 1.07–1.12) and a higher likelihood of an unfavourable functional outcome at 6 months (OR 1.04; 95% CI: 1.02–1.05), as measured by the GOSE scale (Rezoagli et al. 2022).

Neuromuscular Blockers

In ARDS, neuromuscular blockers did not significantly reduce 28-day mortality (RR 0.90; 95% CI: 0.78–1.03) or 90-day mortality (RR 0.81; 95% CI: 0.62–1.06). However, a significant reduction in the risk of barotrauma was observed with the use of cisatracurium (Ho et al. 2020). On the other hand, a systematic review evaluating the use of neuromuscular blocking agents (NMBAs) in patients with TBI demonstrated that bolus administration of NMBAs was effective in controlling ICP increases related to stimulating procedures, such as tracheal suctioning and physiotherapy. However, retrospective evidence suggested potential adverse effects associated with continuous NMBA infusion, including extracranial complications (Sanfilippo et al. 2015).

ICP Monitoring

Continuous monitoring of ICP and CPP is essential in moderate to severe TBI patients under mechanical ventilation to balance lung-protective strategies with neuroprotective measures (Randall et al. 2017). A target ICP below 18 mmHg and a CPP above 60 mmHg are recommended to improve survival and functional outcomes (Meyfroidt et al. 2022).

Early Tracheostomy

Early tracheostomy (≤7 days) in TBI patients may facilitate mobilisation and reduce ventilator-associated pneumonia (VAP) risk (OR 0.59, 95% CI 0.35–0.99), increase ventilator-free days (MD 1.74, 95% CI 0.48–3.00), and decrease ICU length of stay (MD -6.25, 95% CI -11.22 to -1.28) without affecting 30-day mortality (Bertini et al. 2023).

The different management strategies and goals for patients with TBI and ARDS are shown in Figure 1.

Challenges and Future Research

The systemic inflammatory response syndrome (SIRS) induced by ARDS can exacerbate brain dysfunction. Future studies should evaluate targeted anti-inflammatory therapies, such as corticosteroids used in specific ARDS aetiologies, aiming to reduce damage without compromising immune function (Heuer 2017). Determining the ideal relationship between positive end-expiratory pressure (PEEP) and ICP in TBI patients is essential to avoid cerebral hypoperfusion while preventing pulmonary hypoxaemia (Pelosi 2011). Validation of biomarkers such as troponins, BNP, and inflammatory proteins to predict pulmonary and cardiac dysfunction in TBI-ARDS patients is needed through prospective studies (Jayasimhan et al. 2021). Sympathetic hyperactivity in TBI may exacerbate ARDS and neurogenic cardiomyopathy, and clinical trials should assess the role of beta-blockers and autonomic modulators in patient outcomes (Mrozek 2020). The effectiveness of interventions like optimised ICP management and corticosteroid therapy should be investigated to reduce pulmonary oedema secondary to acute brain injury (Schizodimos et al. 2020). Integrating artificial intelligence and big data analytics may improve the prediction of ARDS development in TBI patients, allowing for early and personalised interventions (Orenuga et al. 2025).

Conclusion

The management of ARDS in TBI patients requires a delicate balance between lung-protective strategies and neuroprotective measures. While protective ventilation can mitigate pulmonary injury, its potential impact on cerebral haemodynamics necessitates individualised approaches. Current evidence underscores the need for standardised protocols that consider both respiratory and neurological outcomes. Further research should focus on optimising ventilation strategies, integrating multimodal monitoring, and exploring targeted interventions to improve survival and neurological recovery in this challenging patient population.

Acknowledgments

We would like to express our gratitude to Dr Jose Antonio Carmona Suazo for his invaluable teachings to this day.

Conflict of Interest

None.