COVID-19-Related ARDS: Comparison
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InAcutracranial hypertensione respiratory distress syndrome (ARDS) is a common finding in severe traumatic brain injury, and requires treatment in the intensive care unit with intracranial pressure monitoring and, when possible, the application of multimodal neuromonitoring. A three-tier approach is suggested in current rec-ommendations, with higher tier therapies having more significant side effects. Researchers explain the rationale for this approach, they analyze the benefits and risks of each therapeutic mo-dality, and they discuss how to adapt the therapy to the resources available, based on the most recent recommendationsheterogeneous syndrome historically characterized by the presence of severe hypoxemia, high-permeability pulmonary edema manifesting as diffuse alveolar infiltrate on chest radiograph, and reduced compliance of the integrated respiratory system as a result of widespread compressive atelectasis and fluid-filled alveoli. Coronavirus disease 19 (COVID-19)-associated ARDS (C-ARDS) is a novel etiology caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may present with distinct clinical features as a result of the viral pathobiology unique to SARS-CoV-2.

  • brain trauma
  • intracranial hypertension
  • neuromonitoring
  • COVID-19
  • acute respiratory distress syndrome
  • mechanical ventilation

1. Introduction

Acute respiratory distress syndrome (ARDS), as initially described, defined patients with similar clinical and pathologic findings: refractory hypoxemia; diffuse alveolar infiltrates on chest X-ray; severely reduced lung compliance; and, in those who did not survive, heavy lungs at autopsy, characterized by diffuse alveolar injury with hyaline membranes [1]. As its manifestations appeared superficially similar regardless of etiology, it was reasoned that treatment should be essentially the same, and this quickly became a universally accepted approach [2].
Randomized trials of therapy for such a pathologically and mechanically defined entity, however, might require up to one thousand patients to demonstrate survival benefit. Consequently, the need to establish definitions broad enough to permit sufficient enrollment with smaller numbers became evident [3]. Definitional simplification that excluded such hallmark features of ARDS as low respiratory compliance succeeded in facilitating enrollment for clinical studies, of course, but this came at the expense of specificity. In a recent study, for example, 14% of patients meeting the definition for ARDS had no identifiable pulmonary lesions at post mortem examination [4]. As a result, randomized trials incorporating these simplified definitions have included patients with an extraordinary range of respiratory mechanics and severity of illness. Yet, conducting such trials has led to the impression among many clinicians that “ARDS” represents a distinct disease-like entity [5].
Whether all patients with ARDS should be treated similarly and without discrimination regarding etiology is not a new question but rather one with renewed immediacy. The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has overwhelmed intensive care units with cases of respiratory failure meeting the broadened diagnostic criteria for ARDS [6]. While the number of patients requiring invasive mechanical ventilation for ARDS secondary to COVID-19 (C-ARDS) has declined over time [7], mortality in this population remains high [8]. Many have argued that C-ARDS should be managed no differently than ARDS of any other etiology, ignoring that the viral pathogenesis of SARS-CoV-2 may lead to a distinct form of ARDS that diverges from “typical” ARDS. For C-ARDS patients requiring mechanical ventilation, current guidelines, derived from studies of ARDS primarily caused by bacterial pneumonia and septic abdominal disease [9], may not be universally appropriate.

2. “Typical” ARDS

ARDS is currently defined by the Berlin Definition (Table 1) [6] and is characterized by high-permeability pulmonary edema and widespread compressive atelectasis. In response to injury, immune cells trigger an inflammatory response that leads to disruption of the alveolar–capillary barrier [10]. Accumulation of protein-rich fluid in alveolar and interstitial spaces inhibits pulmonary surfactant [11] which, along with increased hydrostatic pressures from extravascular lung water, results in collapse of underlying lung units. Physiologically, this manifests as (1) severely impaired gas exchange, with refractory hypoxemia and hypercarbia secondary to intrapulmonary shunt and reduced functioning surface for gas exchange [12][13][14]; and (2) severely reduced lung compliance. Histologically, this initial phase manifests as “diffuse alveolar damage,” a constellation of findings involving damage to the alveolar lining and endothelium, the presence of hyaline membranes, interstitial and alveolar edema, and inflammatory infiltrate [15].
Table 1. Berlin Definition of Acute Respiratory Distress Syndrome. CXR, chest X-ray; CT, computed tomography; PaO2/FiO2, partial pressure of arterial oxygen to fraction of inspired oxygen ratio; PEEP, positive end-expiratory pressure; CPAP, continuous positive airway pressure.
TimingWithin 1 week of known clinical insult or new or worsening respiratory symptoms
Chest imagingBilateral opacities on CXR or CT not fully explained by effusions, lobar/lung collapse, or nodules
Origin of edemaRespiratory failure not fully explained by cardiac failure or fluid overload
OxygenationMild200 mm Hg < PaO2/FiO2 ≤ 300 mm Hg with PEEP or CPAP ≥ 5 cm H2O
Moderate100 mm Hg < PaO2/FiO2 ≤ 200 mm Hg with PEEP ≤ 5 cm H2O
SeverePaO2/FiO2 ≤ 100 mm Hg with PEEP ≥ 5 cm H2O
Studies using quantitative computerized tomography (CT) have demonstrated that not only is the ARDS lung heterogeneous, with normally aerated units co-existing alongside non-aerated ones [16], but that the location of non-aerated units is strongly influenced by gravity, owing to the compressive forces of overlying edematous lung tissue. For that reason, radiographic densities appear to migrate from the paravertebral region when supine to the parasternal region when prone [17]. These studies have further shown that, in ARDS, compliance of the integrated respiratory system is determined primarily by the number of aerated lung units [18]; in other words, low compliance in ARDS is due in large part to the lungs being “small” not “stiff” [19]. Collectively, these findings gave rise to the concept of the “baby lung”, a construct drawing similarity between the volume of aerated tissue in the low-capacity lung of ARDS and the volume of aerated tissue in the lung of a healthy child [20]. As total chest dimensions remain unaltered by ARDS, tissue density inversely parallels the capacity of the baby lung. This concept has important implications. First, the severity of gas exchange impairment is intrinsically linked to the quantity of non-aerated tissue, with shunt fraction and physiologic dead space increasing, and PaO2 decreasing, as the percentage of non-aerated lung rises [21]. Therefore, in typical ARDS, oxygenation and compliance are expected to deteriorate in direct proportion to one another. Additionally, the loss of ventilatory capacity means that the entire workload of ventilation is concentrated in an overtaxed baby lung, increasing the risk for progressive injury and further loss of functional lung units [22]. Protective strategies for ventilation have therefore been directed towards expanding the size of the baby lung through alveolar recruitment with the intent of distributing workload among a greater number of functional lung units, while avoiding exposure to (and unnecessary repetition of) tidal cycles that excessively strain vulnerable structural microelements. While imperfect, as there is significant heterogeneity within the ARDS population, we use the term “typical” to collectively refer to ARDS described in the pre-COVID ARDS literature, which predominantly focused on patients with bacterial pneumonia and intra-abdominal disease.

3. Viral Pathogenesis of SARS-CoV-2

Appreciation for the viral pathogenesis unique to SARS-CoV-2 underpins a solid understanding of physiologic disparities between C-ARDS and non-COVID ARDS. SARS-CoV-2 expresses multiple structural proteins on its viral envelope, including the spike protein, a glycoprotein that mediates binding to host cells [23]. Cellular tropism is determined not only by the expression of angiotensin converting enzyme 2 (ACE2) receptors on the surface of host cells [24], which the spike protein binds to directly, but also the presence of transmembrane serine protease (TMPRSS2), which cleaves spike protein and facilitates viral uptake [25]. Following the release of the viral ribonucleoprotein into the cytoplasm, viral replicases use endoplasmic reticulum membranes to form double membrane vesicles for ″protected″ viral RNA transcription (termed replication factories) [26][27]. ACE2 receptors are expressed widely throughout the body, but their concentration is especially high in the pulmonary vascular endothelium and respiratory tract. As a result, the cells first targeted by SARS-CoV-2 following inhalation are those located in the nasopharynx and upper airway (e.g., multiciliated cells or sustentacular cells of the olfactory mucosa) [28][29]. When host immunity fails to clear SARS-CoV-2 infection, it spreads to the lower respiratory tract, either by aspiration of viral particles from the oropharynx or gradual progression throughout the tracheobronchial tree; in some cases, it may bypass the upper respiratory tract altogether [30]. Upon reaching the alveoli, SARS-CoV-2 primarily affects alveolar type 2 (AT2) cells which, in health, are tasked with both production of pulmonary surfactant and regeneration of AT1 cells (which constitute the majority of the alveolar epithelium) [31]. Following infection, host cells initially attempt to control viral spread through innate immunity. Cytoplasmic pattern recognition proteins detect RNA fragments of SARS-CoV-2, triggering the release of interferons, pro-inflammatory cytokines and leukocyte recruitment [32]; additional cytokine release occurs when damage-associated molecular patterns in host cells are released in response to injury [33]. If the innate immune response is dysfunctional, infection will spread, increasing the risk for severe COVID-19; alternatively, if the adaptive B and T cell responses to innate cytokine and chemokine release are absent, uncontrolled inflammation may ensue [34]. Alveolar cell injury or death causes disruption of the alveolar epithelium, thereby setting off an imbalance between coagulation activation and fibrinolysis [26][35]. Fibrin-rich alveolar exudates form hyaline membranes, which prevent further fluid accumulation into the injured alveoli but also hinder the alveolar–capillary oxygen transport [26][36]. Diffuse alveolar damage is followed by small-vessel endothelial activation and injury secondary to hypoxia, cytokines, chemokines, damage-associated molecular patterns, and direct infection by the virus [26][37][38]. Diffuse endotheliitis with inflammatory cell infiltrates may induce widespread endothelial cell apoptosis, pyroptosis, and microcirculatory dysfunction contributing to C-ARDS and also promoting extrapulmonary organ/system failure [26][37]. Release of the endothelial tissue factor can activate the extrinsic coagulation pathway [39]. Extracellular RNA, DNA, and exposed collagen can also activate factor XII and the intrinsic coagulation pathway [40]. Concurrently, platelets seal off the area of endothelial damage to prevent vascular leakage and secrete coagulation-sustaining factors [41] (Figure I1).
Jcm 11 04896 g001 550
Figure 1. Severe coronavirus disease 19 is characterized by immune cell-mediated hypercoagulability and hypofibrinolysis. Hypoxia, cytokines, chemokines, damage-associated molecular patterns, and direct infection by the virus contribute to alveolar and endothelial cell death, and disruption of the alveolar–capillary barrier. Exposed extracellular matrix can trigger both the extrinsic coagulation (via tissue factor (TF)) and the intrinsic coagulation (via collagen/RNA). Recruited monocytes (with virus-activated NLP3 inflammasomes) and neutrophils amplify the inflammatory response, as well as the activation of coagulation by expressing active tissue factor (TF) and releasing neutrophil extracellular traps (NETs), respectively. Complement activation by the virus promotes active TF expression by neutrophils, and differentiation of cytotoxic CD-16+ T cells. NETs recruit platelets, which are subsequently activated by NET histones and the C3a and C5a complement fragments; this results in platelet release of cytokines. Activated platelets secrete coagulation-sustaining factors. The immunothrombotic process leads to diffuse small-vessel thromboses and thrombocytopenia. Concurrently, increased expression of plasminogen activator inhibitor (PA1) attenuates fibrinolysis. AT1, alveolar type 1 cell; AT2, alveolar type 2 cell; ET, endothelial cell; PRR, pattern recognition receptor; IL, interleukin; CCL, CC chemokine ligand; IFN, interferon. Reproduced in part with permission from [26]; copyright (2022) by Springer Nature.
In the context of COVID-19 immunothrombosis (Figure 1), recognition of SARS-CoV-2 through pattern recognition receptors of monocytes results in the release of activated tissue factor at sites of virus localization [26][42]. SARS-CoV-2 stimulates the NLPR3 inflammasome, with consequent production of interleukin (IL) 1 beta (IL-1-β) and IL-18 [42][43]. Concurrently, there is increased release of IL-6 from the alveolar epithelium, which in turn stimulates the production of clotting factors in the liver and tissue factor in the endothelium [26]. Complement activation by SARS-CoV-2 results in (1) upregulated expression of tissue factor by neutrophils [26][44]; and (2) differentiation of a CD-16 expressing T cell subpopulation, promoting immune complex-induced degranulation, microvascular endothelial cell injury, and release of IL-8 and chemokines [26][45]. Activated neutrophils release neutrophil extracellular traps (NETs), which directly activate factor XII and bind von Willebrand factor to promote recruitment of platelets [42]. NET histones, and complement fragments C3a and C5a, activate platelets, while neutrophil elastase and myeloperoxidase inactivate anticoagulants such as tissue factor pathway inhibitor [42]. NET-associated platelets activate the intrinsic coagulation pathway and release large amounts of pro-inflammatory cytokines [42]. Immune-activated platelets (through pattern recognition receptors) also propagate the innate immune response and immunothrombosis by releasing platelet factor 4 and high-mobility group box 1 protein, as well as platelet-derived extracellular vesicles [46]. Immunothrombotic mechanisms are further enhanced by hypofibrinolyis secondary to increased expression of plasminogen activator inhibitor [26][47] (Figure 1). Systemic hyperinflammation is the sine qua non of C-ARDS and may be especially prominent in subsets of patients with (1) risk factors such as age, obesity, cardio-respiratory comorbidity, diabetes, and immunosuppression [26][48][49]; (2) genetic predisposition (e.g., variants at chemokine receptor genes or genes involved in interferon induction and amplification) [26][50][51][52][53][54]; and (3) autoantibodies against type I interferons [55][56]. Besides C-ARDS, severe and potentially lethal COVID-19 may also have extrapulmonary manifestations including gastrointestinal symptoms, acute cardiac, renal, and liver injury, rhabdomyolysis, coagulopathy, cardiac arrhythmias, and circulatory failure [26][57]. Lastly, while some studies have demonstrated systemic inflammation in C-ARDS to be less robust than non-COVID ARDS [58][59], pro-inflammatory responses are tightly linked to injury of the pulmonary vascular endothelium and immunothrombosis, both of which are distinct pathophysiologic features of C-ARDS in terms of their severity and ubiquity [30].

4. Distinct Patroduction

hologic Features of C-ARDS

 

                  Severe ubstraumatic brain injury (TBI) is defined as “an alantial clinical and biologic heterogeneity exists within the ARDS population [[60]]. Subphenotyperation in brain function, or other evidence of brain pathology, caused by an external force”,s with distinct clinical features and responses to therapy have been identified with respect to the initial site of injury (pulmonary or extrapulmonary) [[61]] causing a drop in Glasgow Coma Scale (GCS) to £ 8  nd biologic markers of inflammation (hypo- or hyperinflammatory) [[162]].   A common characteristic of severe TBI is intracranial hypertension (ICH), which ranges, in d It should thus come as little surprise that properties unique to the SARS-CoV-2 virus itself might result in a form of ARDS with distinctive pathophysiology, or that even amongst patients with ARDS of a single etiology (e.g., C-ARDS), there might be a significant diversity of findings and responses to treatment (Table 2). 

 

 

Classical ARDS

C-ARDS

Etiology

Diverse, pulmonary or extrapulmonary (e.g. bacterial or viral pneumonia, severe trauma, aspiration, sepsis, etc.)

SARS-COV-2 infection of alveolar type 2 cells (primarily)

Hypoxemia (PaO2/FiO2 ≤300 mmHg at a PEEP level of ≥5 cmH2O)

Acute onset (e.g. within <48 hours after the clinical insult), or progressive onset (i.e. within 7 days after the clinical insult)

Progressive onset (i.e. within 7 or more days after the onset of COVID-19 symptoms)*

Lung compliance at hypoxemia onset

Usually low (e.g. <40 cmH2O/L)

Usually high (e.g. >40 cmH2O/L)

Recruitment potential

Low or high, depending on the extent / nature of lung unit involvement and associated atelectasis

Initially low – may increase with disease progression and development of edema and atelectasis

Functional-to-anatomical shunt ratio / hyperperfusion of gasless tissue *

Usually 0.5-2.0 / No

Usually > 2.0 / Yes

Alveolar capillary microthrombosis / new vessel growth

Present / present

Diffuse (~9 times more prevalent) / marked (2.7 times higher)

Clinical benefit from lung-protective ventilation

Proven

Highly likely

Clinical benefit from prone positioning

Proven

Highly likely

Clinical benefit from corticosteroids

Likely; more high-quality evidence needed

Proven

Clinical benefit from targeted anti-inflammatory interventions

Uncertain; lack of intervention-specific evidence

Proven

Clinical benefit from ECMO

Likely

Possible; high-quality evidence still needed

 

Table 2. Comparatiffverent cohorts, from 50-80% presentation of major characteristic features of classical ARDS and C-ARDS. ofARDS, acuthe cases ande respiratory distress syndrome; C-ARDS, coronarries the virus disease (COVID) 19-related ARDS; SARS-COV-2, severiske of cerebral herniationacute, respiratory syndrome coronavirus 2; [2][3][4][5].PaO2/FiO2, Aoxygen escalating approach has been adoarterial partial pressure-to-fraction of inspired oxygen fraction ratio; PEEP, posited for theive end-expiratory pressure; ECMO, extracoreatment ofporeal membrane oxygenation. ICH*, [6][7][8][9][10][11][12]May predispose to (Figure 1)early, iprofoun which, the different treatment modalities ard hypoxemia and the conceptual risk of pre-intubation, patient self-inflicted lung injury.

 

 

                  Re prioritized according to their efficacy and relative risks of their applicationorts comparing the pathologic features of C-ARDS to other forms of viral- or non-viral [6][8][10][12][13][14].ARDS Moare difficult to control, refractory ICH, will require higher tier therapiesfraught with conflicting results, as accounting for the stage of disease and evolution of practice patterns over time is challenging. One theme that carry the highest risk of complications. A prerequisitehas consistently emerged, however, is the near-universal presence of pulmonary vascular abnormalities in patients with C-ARDS [[63]].

 

                  fThor the application of these treatments is considered the admission ofugh often present, pulmonary vascular lesions are not a dominant histopathologic feature of usual ARDS and are seldom widespread in post-mortem lung specimens [[64],[65]].  theIn patient to the intensive care unit (ICU)s with C-ARDS, however, they not only occur commonly [[66],[67]] whebut are these interventions can be applied in the safest possible wayextensive, occupying greater than 25% of the lung parenchyma in over half of the patients examined at autopsy in one study [[68]]. BWhile microvasic support measures applied in the ICU are considered tier zerocular thrombi may be a shared histologic finding among all patients with ARDS caused by pulmonary viruses, including Influenza A and SARS-CoV-1 [[69]], wthile initial treatments targeting the ICHe extent of micro-thrombosis appears to be far greater in patients with C-ARDS [[70]]. Thin particular are considered as tier one treatments (Figure 1).  Es prevalence tends to uncouple gas exchange from mechanical properties, calling into question the specifics of ventilation management guidelines developed from clin though these interventions are not free of complications, a significant effect on survival has recently been attributed to treatments beyond this levelical trials in the non-C-ARDS setting. Furthermore, the thrombotic burden is not confined to the microcirculation; the incidence of large-vessel pulmonary emboli is higher in patients with C-ARDS than in those of ARDS secondary to other viral and non-viral etiologies [[1571],[1672]]. For this reason, tier twoOther pulmonary vascular derangements observed at autopsy include severe endothelial injury [[71],[72]] and the pree therapies reqsence of dilated/engorged capillaries [[73]].

 

                  Studire increased caution, clinical experience and warrant special consideraties incorporating dual-energy computerized tomographic angiography (CTA), digital subtraction CTA, and high-resolution CT have further extended these findings. Pulmonary vascular abnormalities on [17].

Figure 1. CT, most notably vessel enlareatment modalities included in the tiered approach to igement, are common in patients with COVID-19 and may even be present prior to the development of C-ARDS [[74]]. Entrlacranial hypertension. ICU:rged vessels suggestive of vasodilatation Icantensive Care unit; ETCO2: be frequently observed within an area of ground glass or Econd tidalsolidation [[75]], contrarbon dioxide partial pressure; ICP: Intracranial pressure; SpO2: Oxyy to the expected physiologic response to regional hypoxia (i.e., vasoconstriction). Perfusion imagein saturation; CPP: Cerebral perfusion pressure; Hb: Hemoglobin concentration; SerOsm:g confirms that a considerable fraction of opacified lung parenchyma demonstrates increased uptake (indicating blood flow) in spite of diminished or even absent ventilation [[76]]. SPerum osmolality; CSF: cerebrospfusion abnormalities, on the other hand, are detected in areas of normal lung density [[74]], with onal fluid; EVD: External ventricular drain; EEG: Electroencephalography; NMB: Neuromue study of mechanically ventilated C-ARDS patients reporting that perfusion defects were not only present in every patient studied, but that the median extent of vascular blocker; MAP: Mean arterial pressureabnormality approached 50% [[77]].

2

  

 

5. TRespier two therapies

2.1. Mild hypocapnia (PaCO2 32-35 mmHg)

Mos

ratory Mechanics and Gas Exchange in C-ARDS

 

                  Early in the clinicians treating pandemic, Gattinoni and colleagues reported novel findings in their first 16 patients with TBI know that C-ARDS; these patients had a relatively mhigh tidald hyperven compliance (averaging 50.2 ml/cm H2O) associated wilation is an effective and rapid wayth significantly elevated shunt fraction (0.50) [[78]]; furto reduce the ICP by inducing cerebral vasoconstrihermore, in the 8 patients they evaluated using quantitative CT, the ratio of shunt-fraction and reducing cerebral blood flowto gasless tissue was markedly higher (roughly 2.5 times) than those observed in usual ARDS [[1879].], However, it carries the risk of cerebral ischemia [19][20][21][22][23]consistent with hyper perfusion of gasless tissue.

 

                  One important point is that the basic component for the safe application of hyperChiumello and colleagues performed similar quantitative CT analysis in 32 consecutive C-ARDS patients receiving mechanical ventilation is the concomitant application of multimodal neuromonitoring that includes a focaland compared gas exchange, respiratory mechanics, and CT variables to those of two historical cohorts of usual ARDS: one matched 1:1 for PaO2/FiO2 (P/F) and global assne matched 1:1 for compliancess [[80]]. Comparent of the adequacy of cerebral oxygenationd to the C-ARDS cohort, the historical ARDS cohort matched for P/F [7][9][24].had Isignifican practice, advtly lower compliance values (39.9 versus 49.4 mL/cmH2O) ancd gas volumed neuromonitoring techniques are not always available in general ICUs, yet, ands on CT (930 mL versus 1670 mL). The historical ARDS cohort matched for compliance, on the other hand, had a higher P/F when compared to the C-ARDS cohort (160 versus 106.5 mmHg).

 

                  tThis limits the range of potentially useful interventions in many TBI patients. In view of such restrictionsese findings are well-explained by the pulmonary vasculopathy and diffuse, inflammation-triggered microthrombosis observed in COVID-related lung disease. In classical ARDS, airspace flooding, collapse, and based on current limited evidence, mild hyperventilation consolidation tend to parallel the severity of oxygenation impairment and fall in compliance. C-ARDS challenges this considered as an acceptable measure before escalating to other treatments. Still, close monitoring of the PaCO2ceptual framework; specifically, lung compliance may be well preserved in the early and mild stages of C-ARDS (at least in a major fraction of these patients), with severe hypoxemia  not occurring primarily as a ires of paramount importance in order to avoid lowering thult of airspace filling and lung unit drop-out, but as the consequence of increased perfusion to non-ventilated lung units [[73],[81],[82],[83],[84]]. Over PaCO2 to < 30 immHge, [25].

Lhowevering PCO2 , progression of C-ARDS fundamentay pose additional problems to trauma patients, besides the risk of brain ischemially alters the lung’s mechanical properties. In late phase ARDS, regardless of the cause, lung capacity becomes severely reduced and is characterized [24][26].by It his reasonable to avoid hypocapnia durgh dead space, limited recruitability, and low compliance [[85]].

 

                  As ming the first 24 hours after brain trauma, when the blood flow to the brain is known to be reducedht be expected from the loosely defined and oxygenation-based criteria for ARDS and the evolving nature of COVID-related lung injury, there is wide overlap between [27].the Hypomecapnia below 30 mmHg had better be kept as a temporizing measure for the cases of extremes in ICHhanics of C-ARDS and usual ARDS; indeed, several studies evaluating their comparative mechanical properties did not identify distinctive mean differences between cohorts [[86],[87]], which may in part ben signs of critical neuroworsening (F a function of the stage of illness in which such observations were made [[88],[89]].

 

6. Mechanigurcal Ve 2

)

ntilation in C-ARDS

 

                  The goals orf impending herninvasive mechanical ventilation are present. It can then be applied for a limited period of time, as a bridge to higher tier therapies, until other, more appropriin C-ARDS are to relieve excessive work of breathing, improve gas exchange, and avoid aggravation of existing lung injury. Repeated exposure to tidal cycles that cause excessive, fracturing strain of structural microelements is believed to be the proximate measures are applied. Subschanical stimulus for ventilator-induced lung injury (VILI) [[90]]; in requcently, a gradual return to normocapnia is advised, in order to avoid rebound ICH years, a better understanding of the biophysical causes of VILI has shifted our traditional focus from the inflation pattern of a single tidal cycle toward avoiding exposure to damaging levels of tidal energy and power [[1091]].

Figure 2. D At the befdsinition, causes, and management of critical neuroworsening. mGCS: motor Glasgow coma score; PLR: pupillary light reflex; SOL: spacede, however, the focus remains on attempting to restrain tidal plateau and driving pressures below defined numerical thresholds. Unfortunately, this well-intentioned objective is often pursued through application of inflexible ventilatory targets and without consideration of the stage of disease.

 

In occumany pying lesion; ICP: intracranial pressure; HOT: hyperosmolar therapatients with C-ARDS, ventilator strategies shown to be beneficial in clinical trials of unselected patients with ARDS will be appropriate; for others, however, they may not apply

2.2. Neuromuscular blockade (NMB)

. The mainbody concerns regarding the use of NMB are the increased risks forof C-ARDS literature has expanded at a remarkable pace throughout the pandemic, providing guidance in certain areas regarding optimal ventilator associated pneumonia and its associationmanagement. Knowledge gained through physiologic studies preceding the C-ARDS era must be applied judiciously in order to provide individualized care for patients with ICU - acquired neuromuscularARDS of any etiology—including those with COVID-19.

 

7. Tidal Volume in C-ARDS

 

                  Tweakness, otherwise termed ICU-neuromyopathnty years ago the ARMA trial [9] demonstrated a 9% absolute reduction in mortality [28][29].among Tmeche latter can significantly affect the quality of life of patients discanically ventilated ARDS patients randomized to an initial tidal volume of 6 mL/kg predicted body weight, forming the basis for what has become a standard of care codified in most ARDS guidelines [[92],[93]]. While larged from ICUs, and is related to tidal volumes that lead to excessive strain are undoubtedly misguided in any acutely injured lung [[94]], thseve post intensive care syndrome, which affectsral points are worth noting with respect to tidal volumore than 60%e selection in C-ARDS:

 

(1) Data frof ICU survivorsm the ARMA trial, [30]. Thderive are traumad primarily from patients who also presentith ARDS secondary to bacterial pneumonia and sepsis, may not be wholly translatable to patients with lung contusions, acute respiratory distress syndrome (ARDSARDS secondary to novel forms of viral pneumonia with unique pathologic features, such as C-ARDS.

 

(2) oEven in the ARMA tr abdominal compartment syndrome, and for whomial, tidal volumes could be liberalized if necessary to facilitate patient comfort and adequate ventilation.

 

(3) NMB isIn otherwise indicatedthree large randomized trials that preceded [31][32][33]. Tthe evARMA tridence for the effect of NMB on ICH is very limited, withal, no differences were found between patients treated with means of 7.2 mL/kg versus 10.6 mL/kg predicted body weight [[95]]; 7.2 mL/kg itversus size reportedly ranging withi10.4 ml/kg dry body weight [[96]]; and just 2-3 mmHg. Neuromuscular blocker7.3 ml/kg versus 10.2 ml/kg predicted body weight [[97]].

 

In usthe is justified during stimulating procedures such as tracheal suctiosubpopulation of C-ARDS patients with less alveolar injury and relatively preserved compliance, larger tidal volumes of 7-8 mL/kg predicted body weight may result in tolerable strain and bronchoscopy,energy input without the risk of VILI [[91]]. iIn such patients who are deeply sedat, enforcing low tidal volumes can unnecessarily increase dead space [[98]], lead. It can also be necessary during the application of cooling measures to lower body temperature, and, since muscular activity significantly contributes to CO2 p to reabsorption atelectasis from hypoventilation, and necessitate additional sedation to facilitate breathing comfort. However, as the severity of disease progresses and compliance declines, lower tidal volumes may be required to prevent the generation of strain that that exceeds critical threshodulds of injury.

 

8. Application of PEEP in C-ARDS

 

Since tion, NMB can also assist CO2he severity of gas exchange impairment and loss of compliantrolce in the baby lung [34].of ARDS reflect trial for NMB is currently suggested for patients in whom ICH is not controlled with tier one measures, with continued infusion reserved for those who show a favorable responshe reduced number of lung units available to accept ventilation, it is logical that interventions leading to an increase in the number of functional lung units should improve hypoxemia, reduce dead space, and increase compliance. Positive end-expiratory pressure (PEEP) is applied with the intent of achieving these goals by preventing collapse of unstable [35].

2.3. Assessment of static autoregulation – The mean arterial pressure (MAP) challenge

Calveoli and therebry stal pressure autoregulation can be severely impaired following TBIbilizing “recruitment”.  Expanding the ventilatory capacity in this manner additionally serves to distribute energy across a greater number of lung units, [36].perhaps Whdecreasile the assessment of dynamic pressure autoregulation requirng the quantity of damaging tidal energy transferred to the parenchymal matrix and reducing the risk of VILI [[19]].

 

Employing PEEP for thes special equippurposes of alveolar recruitment, static pressure autoregulation (sPAR) can be evaluated at the patient’s bedsidehowever, hinges on the assumptions that compromised gas exchange is due primarily to loss of otherwise functional lung units and that these collapsed, or fluid-filled, units will regain function in response to the application of end-expiratory pressure. [37][38].In C-ARDS, Wthen baseline CPP is above the lower breakpoint of sPAR and then raises further, the resulse assumptions may not hold true, and if they do, may be strongly dependent on the timing of the intervention [[99]].

 

Withing vasoconstriction decreases cerebral blood volume, and ICP may also drop. To perform the assessment, the clinician needs to maintain “otherwise stable conditions”, record baseline parameters, titrate vasopressors to a MAP rise of 10 mmHg, and observe and record the response for a maximum of 20 min. Subsequently, MAP/CPP needs to be adjusted, according to whether sPAR is intact or disrupted. The ideal positive response, comprises an ICP drop in response to the MAP rise the baby lung, the regional effects of PEEP are highly variable, as both recruitment and overdistension occur simultaneously as the lung expands. The net benefit of PEEP depends on whether recruitment of functional lung units outweighs overdistension within those that were already functional. When overdistension prevails, gas exchange is adversely affected as blood flow is directed away from overdistended lung units that previously participated in gas exchange, resulting in increased dead space and encouraging hypercarbia. The effects of net overdistension on oxygenation, on the other hand, are variable. Oxygenation may initially improve in response to increased PEEP despite net overdistension, especially if decreased cardiac output leads to reduction in blood flow through areas of intrapulmonary shunt, making the P/F ratio a poor surrogate for recruitment [[36100],[39101]].

T

 

When assessment of sPAR is associated with several clinical challenges.  To perform the test,PEEP results in significant net recruitment, respiratory compliance (a correlate of baby lung size) will improve.  However, when PEEP results in significant experience is required in treatingnet overdistension, compliance will fall as open lung units are shifted past the upper inflection point of their pressure-volume curve. Under these conditions, the increase in ICP caused by d energy input associated with higher PEEP serves only to increase the risingk of VILI and hemodynamic perturbations [[102]]. 

                  MAP 

In whrecen sPAR is disrupted. The adjustment of MAP/CPP is a clinical decision that needs to take into account the rt decades, lung protective strategies have focused on not only the use of low tidal volumes for ventilation, but also the application of higher PEEP [[92]]. “PEEP tablelats,” in whive risks ofch PEEP is increasing vasopressor infusion rate. Finally, similarly to dynamic pressure autoreguled in a stepwise fashion with respect to the inspired oxygen requirement, assume that impaired oxygenation status, sPAR is not stable over the is secondary to the loss of functional lung units. Based on their use in clinical course of TBI patients,trials, such tables are commonly used by clinicians managing ARDS to select PEEP [[103]]. aInd may require frequent reassessment many centers, this practice resulted in the early use of PEEP levels exceeding 14 cmH2O for C-ARDS [[39104]]. The adjustment of CPP may be particularly challenging in trauma patients who require In C-ARDS, however, impaired oxygen exchange is often strongly influenced by vascular dysfunction—not loss of functional lung units—in which case high vasopressor infusion rates to maintain a MAP of ≥ 70 mmHg (for example), or have clevels of PEEP are not beneficial. In one study of mechanically ventilated patients with C-ARDS, partitioned respiratory mechanics were measured at low and high levels of PEEP [[105]]. Concurmparent ARDSd to 5 cmH2O, a PEEP orf 15 camH2O resultediac dysfunction in reduced [40].

3. Tier three therapies

3.1. Therapeutic hypothermia

Lowerilung bcody temperaturempliance, increased lung strain, and in particular brain temperature, below 36 °C decreases the metabolic demandsan increased ventilatory ratio (i.e. a surrogate of physiological dead space defined as the quotient of measured over predicted product of minute ventilation and PaCO2 of[[106]]). brHain tissud PEEP in that study [[105]] be,en hence decreases cerebral blood flow, blood volume and ICP. At set in accordance with the P/F table used in a recent clinical trial [[107]] ithe cellular levewould have been 18 cmH2O. 

 

Whil,e hypothermia mitigates calcium induced neurotoxicityresponse to PEEP varies significantly among individual patients with C-ARDS [[100]], funeuronal apoptosis, inflammatory response, and cytotoxic oedemactional recruitment appears to be diminished relative to usual ARDS [[4180].] and Despite these experimental findings,likely is influenced by the stage of disease and timing of observation [[108]]. Sthese reports did not translate in positive clinical outcomesudies incorporating quantitative CT have either demonstrated minimal recruitment [42][43][44].of Based on these results,dditional lung units at higher levels of PEEP [[109]] or recurrent recommendations ruitment without simultaneous improvement in PaCO2, suggesting the use of mild hypothermia, targeting core boat recruited units are not functional/participating in gas exchange [[110]]. Indeedy, temperatures of 35–36 °C as tier three therapy. Temperatures of < 35 °C are higher levels of PEEP in C-ARDS have been reported to have deleterious effects on both gas exchange [[105],[111]] anotd recommendspiratory mechanics [[105],[109],[111],[112],[113]], consisted,nt with due to increased risk for systemic complicationnet overdistension. In the advanced stages of C-ARDS when consolidation is [43].

Whexten consideringve, even PEEP levels as low as 5 cmH2O hmaypothermia, the overall patient’s condition n be associated with markedly elevated airway plateau and driving pressures [[85]].

 

Theseds to be evaluated in view of the likely side effects. The latter may include impaired cardiac contractility, coagulation and platelet f data serve to underscore the importance of tailoring PEEP to the patient’s individual physiology. To minimize the hemodynamic and mechanical risks associated with PEEP, it should only be increased if doing so leads to demonstrable recruitment of function, increased risk for arrhythmias and infections, and significant fluid and electrolyte shifnal lung units. While all methods of PEEP titration are imperfect, targeting optimal compliance is a reasonable strategy. If an increase in PEEP results [45].in Thimprovesed system complications have been reported mainly in patients cooled down to 32–35 °C, while many of them are more pronounced duance (while tidal volume is held constant), aeratable lung capacity has increased and recruitment has occurred. Recruitment of functional lung units is additionally associated with reduced PaCO2 for a ging the rewarming phaseven minute ventilation as a result [46].of Thde targeted temperatures can be achieved in many patients with the use of external coolcreased dead space ventilation and increased surface area for gas exchange; while physiologic dead space is not routinely measured in clinical settings, the ventilatory ratio correlates reasonably well [[106]], ings easily measures. Cooling blankets or other devices with feedback control should be used when available, in order to avd, and can be tracked following adjustments in PEEP. Similarly, the recruitment to inflation (R/I) ratio is a bedside test that has been used to estimate lung recruitability in response to changes in PEEP [[114]]. 

 

9. Body Positioning

 

                  Lung tissue mass is not did lowering body temperature below the desired level, as westributed evenly, with 60% being located in the dependent (dorsal) half of the sterno-vertebral axis when supine [[115]]. In ARDS, the dorsal l as temperature shiftung is predisposed to compressive atelectasis [45].when Comsupared to other tier three treatments, temperature management may be more suitable for pine due to the weight of overlying edematous tissue. External compression of lower lung units by the abdominal contents and of medial lung units by the weight of the overlying heart may also occur [[116],[117]]. Atelectatsients without active bleeding and signs ofs results in relatively well-perfused but reversibly non-ventilated alveoli [[118]]. sThock, who are not candidates for surgical decompression.

3.2. Metabolic suppression with barbiturates

Be ventral lung, on the other hand, is predisposed to overdistension during passive ventilarbtiturates can induce on, not only because it receives a greater metabolic suppression than midazolam or propofol, and also have antiepileptic properties. By depressing braiproportion of that ventilation, but also due to the increased regional compliance of the anterior chest wall (relative to the posterior chest wall), which permits a greater degree of end-tidal distension of adjacent lung units [[119]].

 

                  In futhe pronce position, oxygen consumptionpreviously compressed dorsal and metabolism, they also reduce cerebral blood flow and ICHdial lung units are recruited, and previously gas-filled ventral lung units become less distended or collapse [6]altogether. Despite They have antiepileptic properties, bind to neuronal γ- aminobutyric acid alpha (GABAA)this tendency for collapse of ventral lung units, there is typically net recruitment, as the loss of ventral lung units is outweighed by recruitment of units in the dorsal region, which contains a greceptors and cause neuater mass of lung tissue [[120]]. Pronale hyperpolarization and inhibitionpositioning further results in better anatomical matching of the action potentilung and chest wall shapes and compliance along the vertical [47].axis, Ileadin addition, it has been shown that barbitg to less variation in size of individual pulmonary units [[119]] (Figurates reduce lactate and pyruvate production in the brain and inhibit lipid peroxidation mediated by free radical 2). Since the distribution of lung perfusion remains virtually unchanged in the prone position, these changes [48]. Threseult findings suggest that not only are barbiturates effective in the treatment of ICH, but they also possess significant neuroprotectivein more homogenous ventilation, with decreases in both venous admixture and dead space. Proning may also result in reduced lung stress (i.e. transpulmonary pressure) and strain (i.e. the tidal volume-to-end-expiratory lung volume ratio) [[121]], deffectscreasing the risk of VILI.

Figure 2. NDiagrammatic prevertheless, there is no evidence to support an improvement in clinical outcomes with their ussentation of physiological mechanisms associated with pronation in the acute respiratory distress syndrome (ARDS). (A) and (C) show the shape of lung units (i.e. alveoli) without the effect of gravity. (B) In the supine [49].

A plauosible argument for this discrepancy is that these sedatives have significant side effects, the most prominent being hemodynamiction, the volume of dorsal lung units is significantly smaller than the volume of ventral lung units, as a result of gravity and pleural pressure; thus, ventral lung units are more prone to overdistention and dorsal lung units are more prone to compromise, hypotension and myocardial depression. Consequently, their use is limited in trauma patients with shock or myocardial injury, since they may further increase vasopressor requirements for the maintenance of adequate CPession atelectasis. (D) In the prone position, gravity and pleural pressure result in a decrease in the volume of the ventral lung units and an increase in the volume of the dorsal lung units. (E) In the supine position, the ventral transpulmonary pressure (PTP) may substantially exceed the dorsal PTP. (F) Prone positioning reduces the ventral-to-dorsal PTP [50][51].gradient, Other side effects are immunosuppression, hepatic and renal dysfunction, and suppression of gut motility. At increased doses, barbiturates suppress the pupillary light reflex, in which case patient monitoring relies mainly on invasive measures or imaging. Finally, their use can lead to prolonged sedation deby augmenting the homogeneity of ventilation. (G) The reopening, dorsal lung units continue to receive most of the blood flow. (H) The ventral lung units may exhibit a greater tendency to collapse, but are still relatively underperfused. Reproduced in concordance with the Creative Commons Attribution License (CC-BY) from: Chen L, Zhang Y, Li Y, Song C, Lin F, Pan P. The Application of Awake-Prone Positioning Among Non-intubated Patients With COVID-19-Related ARDS: A Narrative Review. Front Med (Lausanne). 2022;9:817689.

 

The use to drug accumulation, and consequently to prolonged need forof prone positioning has increased significantly during the COVID pandemic, with 77% of mechanicallly ventilationed C-ARDS patients [52][53][54][55].with Dyskalemias, usually P/F < 100 being placed in the prone position [[122]] apcompear as hypokalemia ared to only 16% of usual ARDS patients with a P/F < 100 during the lopre-COVID era [[123]]. It remading phase and hyperkalemia during withdrawal; the latter may require renal replacement therapy in some casens one of the few interventions in severe ARDS associated with survival benefit, as demonstrated by a landmark study showing significant mortality reduction when patients with ARDS and a P/F < 150 were placed the prone position for least 16 hours daily [[56124][57]].

Whilen metabolic suppression with barbiturates is planned, a test dose should be administered first and the that trial preceded the advent of COVID, recent investigations performed in C-ARDS patient’s response should be recorded. A favorable response is characterized by ICP drop and concurrent maintenance of adequate CPP.  If this is achieved, then loadings also suggest a survival benefit, with one retrospective study demonstrating a small but statistically significant reduction in the risk of death when C-ARDS patients with a P/F < 200 were proned within the first 2 days of ICU admission [[125]].

 

                  Studoses can be administered. The endpoint of barbiturate administration should be ICP control, and the minimum effective dies that have investigated the physiologic effects of prone positioning in C-ARDS patients have generally reported improved oxygenation, with P/F increasing ≥ 20 mmHg in approximately 75% of patients [[122]]. Response should be used in order to minimize the keep side effects. Electroencephalographic monitoring should s to proning are heterogeneous though, and available data suggest that the mechanisms responsible for improved oxygenation may differ from those in usual ARDS.

 

Unlidkeally be applied, in order to titrate the barbiturate infusion rate to a usual ARDS, net recruitment of C-ARDS lungs following placement in the prone position is relatively modest and often negligible [[126]]. suImppression – burst pattern of >> 50%; further increase in barbiturate dose are unlikely to affect ICP roved system compliance, typically present when significant net recruitment occurs, has not been observed in most studies [[122],[126],[127]-[128],[58129]]. When therapeutic targets are fulfilled and barbiturates are to bile measurements of partitioned respiratory mechanics would be needed to conclude withdrawn, a gradual reduction over a few days is advised, so as to avoid hyperkalemia and rebound ICH.   

3.3. Decompressive craniectomy

De certainty that the lack of improvement in system compliance isn’t the result of decreased chest wall compliance in the prone position counterbalancing a simultaneous incompressive craniectomy lowers the ICP, and this has been confirmed by twoase in compliance of newly recruited lung, an absence of significant recruitment is suggested by other findings as well.

 

CO2 rexchandomized trialsge often improves in [59][60].the Cpromplications of craniectomy include infections, intracranial hemorrhage, seizures, transcranial hene position as a result of decreased dead space and recruitment of additional lung units. Most studies that have evaluated gas exchange in the prone position, however, have reported little change in the PaCO2 (or veniationtilatory ratio) [[122],[126],[127]-[128],[129]]. fCormation of subdural hygroma, and hydrmpared to usual ARDS, the changes in both respiratory system compliance and PaCO2 focephallus. These potential complications, along with owing prone positioning are significantly less in patients with C-ARDS [[83]]. In the riabsk of cranioplastyence of recruitment, the most plausible mechanism to explain [13]improved oxygenand the high baseline risk of a poor tion is better matching of ventilation/perfusion ratios of vaso-dysregulated tissue  [120]].

 

Timineurg may alsological outcom play a significant role in response to prone positioning [[83],[126]]. In unresolving ARDS, may hinder a decision for secondary decompression. These issues, as well asatelectasis and edema may evolve into significant dorsal consolidation and diffuse fibrosis; in this setting, there is minimal recruitment of dorsal tissue in the probable need for long term care, need to be thoroughly explained to the patients’ families. Decompressive craniectomy remainsne position--only increased ventral atelectasis. A significant percentage of such patients either experience worsened P/F ratio in the prone position or fail to meet the accepted criteria for “responsiveness” (improvement in P/F ≥ 20 mmHg)  [[128]].

10. Conclusion

                  Typica tier three therapy, while patients more likely to benefit are those with unilaterall ARDS is characterized by high-permeability edema, widespread atelectasis, and a loss of compliance that  relates directly to the reduced capacity of aerated lung units. COVID-19, a novel etiology of ARDS, has distinct pathology, previously fit,ic findings consistent with adequate social support, in the setting of adequate medical and social resources. It is also a rescue option in othersevere injury to—and dysfunction of—the pulmonary vasculature as a result of SARS-CoV-2-induced endothelial injury and immunothrombosis. The lungs of patients with C-ARDS may be more likely to overdistend than to recruit in response to customary levels of PEEP. A subpopulation of patients not responding to conservative treatmentswith C-ARDS may present with severely deranged gas exchange that is uncoupled from the comparatively mild parenchymal [13].

4. Conclusions

Tienjur two and three therapies for ICH in TBI are associated with significant adverse effects and complications. Therefore, these treatmentsy. Just as typical ARDS encompasses a broad range of clinical findings, so too does C-ARDS, often transitioning in its more advanced stages to a form indistinguishable from typical ARDS. Some have argued that all patients with ARDS, regardless of etiology, should be chosen when ICH poses a bigger threat to thetreated identically. This approach, however, ignores the physiologic variability that not only exists between patient. Current tier concepts allow for flexibility in the choics, but also within individual patients depending on the phase of therapye disease.

                 

                  Rand for patient-tailored approaches in different resource settings. Individualized approaches can be achieved by the use of imaging and neuromonitoring modalities, and future research should be oriented tdomized trials in ARDS have identified several interventions that lead to improved outcomes. These studies have enrolled patients with significant heterogeneity though and as such, a significant degree of heterogeneity in treatment effect is to be expected [[130]].  They repoward strengthening the evidence for these treatments and identifying patient profiles that can benefit from each one of themt the mean intervention effects observed in a population, but with regard to benefit wide individual variability exists.  Randomized trials have provided safe starting points from which to approach mechanical ventilation in the individual, but such rules are not inviolable. A more holistic approach, taking into consideration the unique physiology of individual patients, is warranted—as exemplified by C-ARDS.

                   

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