Acute Respiratory Distress Syndrome (ARDS): Causes, Symptoms, and Pathophysiology

Assignment Task

Acute Respiratory Distress Syndrome (ARDS) is a severe form of respiratory failure resulting from injury to the lung tissue (Matthay et al, 2019). It is characterised by severe hypoxemia, increased lung permeability, and the accumulation of fluid in the alveoli leading to decreased lung compliance. The initial insult leads to widespread inflammation of lungs resulting in damage to alveolar cells thus impairing gas exchange. There is loss of surfactant leading to alveolar collapse (Sarkar et al, 2018). This in turn leads to decreased oxygenation of the blood as the body attempts to compensate. It is commonly caused by aspiration, trauma, pulmonary infection and sepsis (Son et al, 2017).

The lung injury causes release of pro-inflammatory cytokines such as tissue necrosis factors (TNF) and interleukins (IL)-1, IL-6 and IL-8. These cytokines attract neutrophils to the lungs, where they activate and release toxic mediators that cause damage to the alveolar epithelium and capillary endothelium (Vassiliou et al, 2020). Protein escapes from the vascular space when the capillary endothelium is damaged. The oncotic gradient that promotes fluid resorption is lost, and fluid floods into the interstitium, overwhelming the lymphatics. The ability to increase alveolar fluid clearance may also be compromised. Alveolar air space is filled with debris from degenerating cells proteinaceous oedema fluid. Neutrophils, fibrin and red cells thus forms a hyaline membrane. Furthermore, functional surfactant is lost, causing alveolar collapse (Vassiliou et al, 2020).

With ARDS, the damaged lung undergoes a complex three phase process: exudative, proliferative and fibrotic (Sinha et al, 2021). Firstly, the exudative phase of ARDS is distinguished by diffuse alveolar damage and lung endothelial injury, both of which result in a higher permeability of the alveolar-capillary barrier. Increased capillary permeability causes protein-rich fluid to enter and accumulate in the alveolar and interstitial space. Alveolar oedema caused by ARDS primarily affects dependent portions of the lungs, resulting in atelectasis and poor aeration (Swenson et al, 2021). Secondly, in the fibrotic phase the turnover of surfactants increases. Further fibrosis consisting of the deposition of collagen within the alveolar, interstitial and vascular spaces will result in long term lung disease with impaired gas exchange (Swenson et al, 2021). Thirdly, in the proliferative phase pulmonary oedema starts getting reabsorbed and body attempts to repair alveolar epithelial type ll cells. These alterations are effectively induced by a complex interplay of a pro-inflammatory as well as an anti-inflammatory mediator (Chen et al, 2017). The specific type 1 alveolar cells are generally irreversibly injured. Space is replaced by the protein deposition, cellular debris, fibrin and can produce a hyaline membrane. Type 2 cells generally proliferate with the regeneration of some of the epithelial cells thus remodelling the alveolar structure. (Chen et al, 2017).

Another factor that can cause severe respiratory depression/ ARDS is Tricyclic antidepressant (TCA) overdose (Odigwe et al, 2016). TCAs have been shown to impair pulmonary function by reducing pulmonary compliance, increasing airway resistance, and causing bronchospasm. TCA overdose inhibits sodium channels in the myocardium and respiratory muscles, which leads to decreased contractility and impaired ventilation. This can result in hypercapnia and respiratory acidosis, leading to hypoxemia (Odigwe et al, 2016). Additionally, TCA overdose can cause significant hypotension, which can lead to decreased perfusion of the lungs, resulting in tissue damage and worsening ARDS. This contributes to reduction in oxygen delivery to body tissues, leading to multiple organ failure. TCA overdose can lead to a range of cardiovascular effects, including hypotension, tachycardia, and arrhythmias, which can contribute to poor prognosis by reducing cardiac output and impairing pulmonary circulation. This can lead to hypoxemia and impaired gas exchange, which can further exacerbate lung injury and increase the risk of ARDS (Odigwe et al, 2016). Referring to Billy’s case, billy has hypotension 100/50 and Tachycardia 140 which could indicate he has symptoms of TCA overdose with his history of depression and chronic back pain.

The first step in stabilising a patient with severe ARDS is to improve oxygenation and gas exchange to avoid worsening, hypoxia and organ damage. The distribution of oxygen to tissues is vital for cells to survive (Umbrello, et al 2017). Patients with Acute Respiratory Distress Syndrome have lungs that are less aerated, also known as a ‘baby lung’. In ARDS lungs have low compliance due to atelectasis, inflammation and oedema (Gattinoni et al, 2019). In addition to damage to his lungs Billy is also obese. Since Billy is 160kg and 172cm tall, BMI is calculated by weight/height2, there Billy’s BMI is 54.1 which is considered morbidly obese (Nuttall, 2015). Obesity can cause changes in lung function and respiratory mechanics, such as decreased lung compliance and increased airway resistance due to the expansion of the stomach causing compression on the lungs (Dixon et al, 2018). Therefore, obese patients with ARDS may require higher airway pressures to achieve adequate ventilation and oxygenation. Effective management of ventilation in obese patients requires a comprehensive approach that includes lung protective ventilation strategies, use of PEEP optimisation of oxygenation and ventilation, and close monitoring for the development of barotrauma (De Jong et al, 2020). Strategies to reduce the risk of barotrauma in obese patients include limiting the use of high tidal volumes and considering the use of prone positioning or recruitment manoeuvres to improve lung function and reduce atelectasis (De Jong et al, 2020). A lung protective strategy is using low tidal volume ventilation with a high PEEP to prevent regional overdistension in patients with Acute Respiratory Distress Syndrome (Umbrello et al, 2017). With the low tidal volume strategy, it can decrease the work of breathing and prevent atelectasis of a collapsed lung to enhance gas exchange. A low tidal volume ventilation in association with PEEP can help restore adequate oxygenation, limit oxygen toxicity and prolong life (Matthay, M et al, 2019). It also reduces shunting, thus increasing oxygen delivery. This can prevent barotrauma and volutrauma (Matthay, M et al, 2019).

Tidal volume (VT) is a key ventilation parameter that affects the lung mechanics and gas exchange in ARDS patients. LTVV (Low Tidal Volume Ventilation) involves using smaller tidal volumes (6 mL/kg ideal body weight or less) to reduce the risk of over-distension of the lungs, which can cause further injury to the lung tissue. The use of low tidal volumes has been shown to reduce the incidence of barotrauma and improve oxygenation, as well as reduce the risk of ventilator-associated pneumonia (VAP) and nosocomial infections (Umbrello et al 2017).

Positive end-expiratory pressure (PEEP) is a key ventilation parameter that is used to prevent alveolar collapse and improve oxygenation in ARDS patients. PEEP works by increasing the transpulmonary pressure, which prevents alveolar collapse and improves oxygenation (Suarez-Sipmann et al 2019). Therefore, it is recommended to use a PEEP level >12 cm H2O in ARDS (Matthay et al, 2019).

The respiratory rate (RR) is another ventilation parameter that must be considered in ARDS patients. The RR mainly affects the CO2 elimination. The goal of RR is to maintain normocapnia, which is defined as a PaCO2 of 35-45 mmHg. A higher RR can lead to hypocapnia as all the CO2 would be blown off due to the higher respiratory rate. (Matthay et al, 2019).

The FiO2, or the fraction of inspired oxygen, is another parameter to be considered in ARDS patients. The goal of FiO2 is to maintain adequate oxygen saturation (SpO2) while minimising oxidative stress, which can contribute to lung injury. High FiO2 levels can lead to an increase in oxidative stress and free radical formation, which can worsen the ARDS. Therefore, it is important to keep the FiO2 as low as possible while maintaining adequate oxygen saturation (Matthay et al, 2019).

Plateau pressure (Pplat) is another important ventilation parameter in ARDS patients. Pplat is defined as the pressure that is maintained in the lungs during the period of no airflow, and it represents the distending pressure in the lungs (Silva et al, 2018). High Pplat levels can cause barotrauma and volutrauma, which can lead to further lung injury and worsen the ARDS. To prevent this, it is crucial to keep the Pplat below 30 cm H2O in ARDS patients (Silva et al, 2018).

In addition to ventilator settings there are two common modes of ventilation used for patients with ARDS. SIMV Volume control and SIMV Pressure Control.

SIMV volume control ventilation is beneficial to obese patients with ARDS as it provides a set tidal volume with a set respiratory rate, which allows for better control of minute ventilation (De Jong et al, 2020). However, pressure control ventilation may also be beneficial in obese patients with ARDS as it allows for better control of the patient's inspiratory pressures, which can be useful in managing airway resistance and optimizing oxygenation (De Jong et al, 2020). Pressure control ventilation may be preferred in obese patients with ARDS who have restrictive lung disease or decreased lung compliance, as it provides a set peak airway pressure with variable tidal volume, which allows for better control of the patient's inspiratory pressures and helps avoid barotrauma. Pressure control ventilation may also be useful in obese patients with ARDS who require higher levels of positive end-expiratory pressure (PEEP) to improve oxygenation, as it allows for better control of the inspiratory-to-expiratory ratio and may reduce the risk of lung injury. Furthermore, Billy is retaining CO2 therefore Billy would benefit from pressure control with a higher respiratory rate to help blow off his CO2 (De Jong et al, 2020). In conclusion, the best mode of ventilation to employ for Billy would be SIMV pressure control ventilation.

Therefore, in order to treat Billy it is recommended that he should be ventilated on pressure control SIMV with low tidal volume 4-6ml/kg (IBW), respiratory rate of 18-22 bpm, a high PEEP between 10-20 and an FiO2 of 100% then try to titrate down below 60% if there is improvement.

Low tidal volume ventilation (LTVV) has been widely used in the treatment of ARDS in the last decade. The main goal of this treatment is to reduce lung injury, which is a significant factor in the high mortality rate of ARDS patients. In recent years, several randomised control trials have been conducted to evaluate the effectiveness of LTVV in patients with ARDS. These trials have found that using LTVV reduces the risk of lung injury and improves patient outcomes.

The first randomised control trial was the the ProVENT study, a randomised control trial conducted by Nijbroek et al (2022) evaluated 903 patients to review mortality of patients with ARDS. The randomised control trial compared a conventional tidal volume group (VT of 12 ml/kg of predicted body weight) and a low tidal volume group (VT of 6 ml/kg of predicted body weight). This study was conducted across 22 ICUs for 3 months in the Netherlands. The results of the study showed that LTVV was associated with a lower 28-day mortality rate compared to conventional tidal volume ventilation (23.1 versus 31.7%). The study's findings suggest that LTVV is preferred compared to traditional tidal volume ventilation. One of the strengths of the study is how it is a randomised control trial, which allows for greater transparency and reduces the potential for selection bias. Secondly, the study has a big sample size (903 patients). Thirdly, this study was a multi-centre study which the patients were enrolled in different hospitals hence there is a diverse amount of data collected for patients of all backgrounds. However, the study also has several limitations that should be considered when interpreting the results. Firstly, the study was conducted over a relatively short period of time (3 months), and it is unclear whether the benefits of low tidal volume ventilation would be sustained over a longer period of time. Secondly, the study did not address the issue of long-term survival or the quality of life of survivors, and further research is needed to determine the long-term effects of low tidal volume ventilation in patients with ARDS.

It is important to note that the study only had a short follow-up period, so it is unclear what the long-term effects of LTV on mortality may be. Additionally, the study only evaluated the use of LTV in the context of COVID-19 patients, so it is unclear how these results would apply to other patient populations.

The third randomised control trial conducted by Hirshberg et al (2018) evaluated 52 patients with ARDS across 4 ICUs. The patients were randomly assigned to receive either low tidal volume ventilation or traditional high tidal volume ventilation. The study found that LTVV improved oxygenation and compliance compared to high tidal volume ventilation. One of the strengths of the study is how it is a randomised control trial, which allows for greater transparency and reduces the potential for selection bias. However, the study has several limitations that should be considered when interpreting the results. Firstly, the study has a relatively small sample size hence limits the ability to generalise the results to a large population. Secondly, the study is conducted over a short amount of time (3 days) hence it is difficult to determine the long term effects of LTVV in improving patient outcomes.

There have been no further randomised control trials of LTVV in ARDS patients conducted in the last 7 years, therefore based off these three trials it can be concluded that LTVV is still the best option for patients with severe ARDS.

After Billy’s deterioration 24 hours since being in the ICU, it is worth to note that deterioration of patients with ARDS most frequently results from sepsis (Kim et al, 2016). Severe sepsis can be the result of major organ dysfunction or metabolic acidosis developing from an unknown cause (Hotchkiss et al, 2016). The pathophysiology of severe sepsis is complex and multifactorial, and it is characterised by an exaggerated and uncontrolled systemic inflammatory response to an infectious insult. This response is associated with increased levels of pro-inflammatory cytokines, such as tumour necrosis factor-α (TNF-α) and interleukin-1 (IL-1), which can result in widespread tissue damage and organ dysfunction (Gyawali et al, 2019). In the initial phases of sepsis, the body attempts to compensate for the vasodilation by increasing heart rate in an attempt to maintain Cardiac output (Gyawali et al, 2019).

Referring to Billy’s deterioration 24 hours since admission to the ICU, Billy’s body is showing signs of infection through his elevated temperature of 39 degrees Celsius, a normal human body temperature is 36.5 degrees (Gyawali et al, 2019). Billy is also noted to be in Sinus tachycardia with a heart rate at 130 beat per minute which is far beyond normal range of 60 to 100 beats per minute (Gyawali et al, 2019) and he is hypotensive 85/55 mmHg which he will soon need intotropes if his BP continues to down trend. In addition to Billy’s decreasing vital signs he is also becoming oliguric. Billy has a urine output of 20 mL for the last one hour since his deterioration and approximately 80 mL in total for the last 4 hours which is 0.5 to 1.5 mls/kg/hr. As a result, hypoxaemia from ARDS and vasodilation from sepsis his organs are starved of oxygen and blood. This is going to cause multiorgan failure. Kidneys are particularly sensitive to hypoxia and hypotension (Kim et al, 2016).

In order to treat Billy it is essential to understand the perfusion and ventilation ratio. The perfusion and ventilation ratio in patients with acute respiratory distress syndrome (ARDS) is an important aspect of respiratory physiology that can be used to assess the efficiency of gas exchange in the lungs (Sarkar et al, 2017). The ratio is calculated by dividing the alveolar ventilation (the amount of air reaching the alveoli) by the pulmonary blood flow (the amount of blood flowing through the lungs). In ARDS patients, the perfusion and ventilation ratio may be altered due to the presence of fluid build-up and inflammation in the lungs, which can impair gas exchange (Sarkar et al, 2017). In particular, the ratio may be reduced due to ventilation-perfusion (V/Q) mismatch, which occurs when there is an imbalance between the amount of air reaching the alveoli (ventilation) and the amount of blood flowing through the lungs (perfusion). VQ mismatch occurs due to the presence of alveolar consolidation, atelectasis, and pulmonary oedema, which impairs oxygen diffusion and carbon dioxide elimination. This leads to a reduction in arterial oxygen saturation and an increase in arterial carbon dioxide levels, which can cause hypoxemia, respiratory acidosis, and ultimately, multi-organ dysfunction (Sarkar et al, 2017).

VQ mismatch in ARDS can also cause physiological dead space, which is the portion of inspired air that does not participate in gas exchange due to poor perfusion. This can lead to an increase in alveolar dead space, which reduces the efficiency of gas exchange and increases the work of breathing (Sarkar et al, 2017). One study found that a reduced perfusion and ventilation ratio was associated with increased mortality in ARDS patients (Gattinoni et al., 2016).

The effects of sepsis can be limited with appropriate shock management (Gyawali et al, 2019). Billy is possibly in septic shock as he aspirated on day 1. Now Billy may have aspiration pneumonia leading to generalise sepsis and shock. Therefore, It is vital to start managing his sepsis. The goal to manage sepsis is to maintain a mean arterial pressure (MAP) of 65 mmHg, central venous pressure (CVP) to 8–12 mmHg and urine output of 0.5-1ml/kg/hr (Gyawali et al, 2019). Therefore, in order to manage Billy’s sepsis, vasopressors need to be used to maintain his MAP above 65 and increase Central venous pressure (CVP), along with IV fluid management to increase his urine output (Gyawali et al, 2019).

Fluid resuscitation intravenously is most commonly used as the first line of therapy for patients with sepsis (Casey et al, 2018). The rationale is to ensure there is adequate volume circulation, optimal venous return, reversal of hypovolaemia and to maximise cardiac output and stroke volume. The first line of treatment for sepsis is fluid resuscitation to restore perfusion and administering antibiotics (Malbrain et al, 2018). The target tissue perfusion is achieved by boluses of intravenous fluids (IVF), the ideal IVF to use is crystalloids, Hartmanns fluid administered at 30ml/kg given over one to three hours from initial presentation to the hospital. In addition, using a vasopressor such as norepinephrine to maintain a MAP >65 mmHg (Semler et al, 2016).

Intravenous fluid resuscitation is the ideal treatment according to multiple randomised trials using a protocol-based approach to treat sepsis patients. However, the choice of fluid used for resuscitation remains a subject of ongoing debate, with some researchers advocating for balanced crystalloids, while others support the use of saline. The SALT trial (2017) conducted by Semler et al (2017) determined the efficacy of balanced crystalloids compared to saline for fluid resuscitation therapy in the intensive care unit (ICU). The SALT trial was a randomised trial conducted from 2011 to 2015. The study enrolled 974 patients with sepsis to review using saline compared to crystalloids as the best practice therapy for patients with sepsis. The patients were randomly assigned to receive either balanced crystalloids (n = 520) or saline (n = 454) for fluid resuscitation. The crystalloid IV used in the ICU for saline was 0.9% sodium chloride and the crystalloid used was Hartmanns lactated Ringer’s solution. There were no major differences in the two groups except the group with saline appears to experience more adverse kidney events. Hence, it can be concluded that crystalloids are the preferred fluid to use for sepsis. One of the strengths of this trial is that it is a randomised control trial, randomised control trials reduce bias and allows for transparency. Secondly, this trial has a larger size sample of patients. However there are multiple limitations to be considered when coming to conclusions of the results. Firstly, this trial was conducted in a single ICU and only in one single centre study, hence it limits the ability to expand the discoveries to the general population.

In addition to fluid resuscitation, vasopressors are required for the management of sepsis treatment. Sepsis causes profound vasodilation leading to hypotension and decreased organ perfusion (Shi et al, 2020). This in turn causes ischaemic injury to various organs, in order to prevent this it is suggested to maintain a mean arterial pressure (MAP) >65. In order to maintain a MAP>65 inotropes such as noradrenaline are required (Shi et al, 2020).

In a study conducted by The VANCS 11 (2019), randomised control trial evaluated 250 patients compared whether vasopressin could be used instead of norepinephrine as a first line therapy for patients with sepsis. Patients in the study were allocated either norepinephrine or vasopressin. 71 patients (56.8%) were assigned to use vasopressin and 66 patients were assigned to use norepinephrine (52.8%). The results showed that there was a lower mortality rate in the group of patients using norepinephrine. The mortality rate after 28 days was 66.8% in the vasopressin group and 42.8% in the norepinephrine group. In conclusion, using vasopressin as a first line vasopressor therapy was not favoured overusing norepinephrine. Therefore, norepinephrine is still the first line vasopressor that is preferred for sepsis patients. This study is a randomised control trial which potentially reduces bias. In addition, the treating clinicians, the assessors and the patients were unaware of this trial at the time of conduction. However, the study only evaluated the use of vasopressors in cancer patients, so it is unclear how these results would apply to other patient populations. Additionally, this study was only undertaken in one hospital in a singular country hence it is difficult to apply the results to the generalised population.

A second study, the CENSER (2019) randomised trial evaluated 310 patients with the use of vasopressors, specifically norepinephrine, in patients with sepsis. The study found that early initiation of norepinephrine was associated with improved survival compared to delayed initiation. This trial was conducted in Thailand. The patients in the study were randomised into two separate groups. One group was using norepinephrine (n=155) and the second group was using the standard treatment (n=155). The results demonstrated that the mortality rate was lower in the group receiving early norepinephrine (15.5%) versus the standard treatment (21.9%). The discoveries from this trial confirm that administering norepinephrine early in the initial stages of sepsis along with fluid resuscitation can decrease the severe sepsis outcomes for patients. However, several limitations must be considered when interpreting the results. Firstly, the study was conducted in a single centre, limiting the ability to generalise the findings to a larger population. Another limitation of the study is the small sample size, which may impact the ability to detect significant differences in patient outcomes.

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