ARDS

Question 1

What is ARDS?

Answer 1

1. Respiratory failure is defined as an inadequate gas exchange by the respiratory system, resulting in arterial oxygen and/or carbon dioxide levels that cannot be maintained within their normal range.
2. Acute Respiratory Distress Syndrome (ARDS) is a type of RF, with an incidence of 5-15/100,000 and a mortality of up to 40%. Mortality is predominantly due to sepsis & multi-organ failure.
3. Its underlying aetiology is both a direct and indirect disruption of the normal physiology of the lung, and consequently a serious disruption of gas exchange and the potential for a local and systemic inflammatory response.
4. Chest radiography often demonstrates bilateral infiltration. The aetiology of ARDS is a triad of inflammation, mechanical injury, and hypoxia. Each component of the triad exacerbates the other two, creating a vicious cycle of disrupted physiology.

Question 2

Pugin et al 2008?

Answer 2

1. Pugin et al (1999) reported that the early phase of ARDS is associated with oedema fluid in the alveolar space which has significant levels of proinflammatory cytokines, IL-8 and neutrophil matrix metalloproteinases.

2. Histological examination of the lung parenchyma in an ARDS patient reveals substantial neutrophil accumulation and alveolar macrophage activation.
3. Migration of neutrophils is at first an appropriate inflammatory response to arrest and remove infective pathogens of the lungs.
4. However, secretion of proinflammatory cytokines by the neutrophils and macrophages amplifies the inflammatory response, contributing to an overwhelming lung inflammation and resultant systemic inflammation.

Question 3

Ware et al 2001

Answer 3

. Ware et al (2001) reported that this disruption also impairs fluid clearance from the alveoli, which gives a poor prognosis of survival.

Question 4

Greene et al 1999

Answer 4

Greene et al (1999) observed significant low surfactant levels in bronchioalveolar lavage in ARDS patients. Finally, loss of the epithelial barrier allows easy migration of pathogens and inflammatory cytokines into the systemic circulation.

Question 5

What is the multiple hit concept?

Answer 5

1. Fan et al (2006) created a mouse model of haemorrhagic shock (the primary insult) and the administered intratracheal LPS (secondary insult).

2. The primary insult activated polymorphonuclear cells (PMNs) which infiltrated the alveoli and induced toll-like receptor 2 (TLR2) upregulation in the alveolar macrophages.
3. This sensitises alveolar macrophages to a secondary inflammatory insult – i.e. it is a positive feedback mechanism.

Question 6

Peter et al 2008

Answer 6

1. In light of the importance of inflammation in the pathogenesis of ARDS, steroids have been proposed as a therapy strategy.
2. However, a meta-analysis by Peter et al (2008) suggests that while they may reduce mortality and the time on a ventilatory, there is no conclusive benefit to steroid treatment.

Question 7

What is mechanical damage?

Answer 7

Mechanical ventilation (MV) is a mainstay of ARDS treatment and is essential to sustain sufficient alveolar ventilation and maintenance of blood gasses.

However, MV has now been conclusively shown to paradoxically exacerbate lung injury and inflammation.

Question 8

Vanaeker et al (2007)

Answer 8

Vaneker et al (2007) demonstrated that MV in healthy mice induces reversible pulmonary and systemic cytokine elevation and leukocyte infiltration.

This was in the absence of endothelial injury, and demonstrates that the endothelium is capable of mechanotransduction. This may in part be due to the cyclic stretch induced by MV.

Question 9

Vlahakis et al 1999

Answer 9

Vlahakis et al (1999) cultured alveolar epithelial cells on deformable culture membranes and showed that stretching these cells increased secretion of proinflammatory cytokine IL-8

Pugin et al (2008) also demonstrated that cyclic stretch of alveolar type II cells led to dose-dependent acidification of the culture medium, due to increased Na+/K+ ATPase activity and a subsequent increase in glycolysis-dependent lactic acid production.

Question 10

Altemeier et al 2005

Answer 10

Mechanical ventilation also alters the gene transcription profile in response to an inflammatory insult

Question 11

What can mechanical injury caused by MV can be subdivided in 3 major categories

Answer 11

• Barotrauma: high airway pressures during positive pressure ventilation can cause gross injury which manifest as air leaks, e.g. subcutaneous emphysema.
• Volutrauma: high end-inspiratory volume leading to lung stretch and diffuse alveolar damage and pulmonary oedema
• Atalectatrauma: damage caused by repeated opening and closing of lung units, was first proposed by Robertson et al (1984). Opening of the collapsed airways requires relatively higher forces and a greater degree of alveolar stretch. The shear stresses produced might cause epithelial disruption.

Question 12

Wolthuis et al 2008

Answer 12

Many studies, including that by Wolthuis et al (2008) have shown that MV employing lower tidal volumes and positive end-expiratory pressure (PEEP) prevents pulmonary inflammation in patients without pre-existing lung injury. PEEP acts to prevent collapse of alveoli at end-expiration, and therefore prevents cyclical closing and reopening, thus limiting atalectatrauma.

Question 13

Trembley et al 1997

Answer 13

Tremblay et al (1997) demonstrated that after exposure of isolated rat lungs to lipopolysaccharide (LPS), expression of pro-inflammatory cytokines (TNFα, IL-1, IL-6) was highest in MV with high tidal volumes and zero PEEP, and was much attenuated through use of moderate tidal volume and high PEEP.

Question 14

Laffey et al 2004

Answer 14

Laffey et al (2004) reported that acute hypercapnic respiratory acidosis can reduce endotoxin-induced acute lung injury and be anti-inflammatory. Therefore, a possible protective strategy is to underventilate the lungs to generate a protective hypercapnic respiratory acidosis. Utilization of this “permissive hypercapnia” strategy in patients was associated with improved outcome in several clinical studies in adults with ARDS.

Question 15

Toole et al 2009

Answer 15

1. Toole et al (2009): Hypercapnic acidosis inhibits pulmonary epithelial wound healing by reducing cell migration via an NF-κB dependent mechanism that may involve alterations in matrix metalloproteinase activity.
2. Further, more recent studies have associated hypercapnia in ARDS with right ventricular failure due to pulmonary arterial hypertension. increasing acceptance of hypercapnia as being harmless or even potentially beneficial by virtue of rightward shift of the oxyhaemoglobin dissociation curve, systemic and microcirculatory vasodilatation, and inhibitory effects on neutrophils and other inflammatory cells

Question 16

ARDS is heterogeneous

Answer 16

1. One of the major problems presented by ARDS is the heterogeneity of pathology in alveoli of different part of the lungs.
2. Even in health there is heterogeneity in lung compliance.
3. This is accentuated in ARDS by differences between ‘dependent’ areas of the lung (where there is gravitational fluid accumulation), and ‘non-dependent’ areas of the lung.
4. Further, pneumonia lungs will have water logging due to increased permeability of epithelial lining. This means that there will be obstruction, making it difficult for alveoli to open meaning throughout the lung, different parts will have different pressure-volume loops.
5. This means, that despite providing same amount of pressure, some alveoli will only open partially and when you expire, they will not empty at the same rate as different parts will have different compliance, when you mechanically ventilate the lungs.
6. This means there will be more dead space in these lungs. This can lead to build up of CO2 and pressure in the lungs.
7. Dependent alveoli have reduced ventilation and reduced ability to empty.
8. Therefore, whilst PEEP may act to prevent collapse of non-dependent alveoli which empty well, it may actually induce damagingly excessive pressures and volumes in dependent alveoli which empty poorly which can lead to pneumothoraxes.
9. Studies have also demonstrated differences in cellular response to mechanical stress in dependent and non-dependent areas of lung.

Question 17

What is high frequency oscilattory ventilation?

Answer 17

HFOV

1. High frequency oscillatory ventilation (HFOV) is an alternative to conventional MV which aims to minimise mechanical injury to the lungs.
2. It delivers high frequency (~15Hz) but low tidal volume (~200ml) ventilation, superimposed on a high mean airway pressure.
3. This prevents cyclic stretch of the alveoli whilst preventing their collapse.
4. HFOV induces several flow profiles, including bulk convection, pendelluft, cardiogenic mixing and diffusion.
5. Pendelluft can lead to the hyperinflation of the lungs as part of the lung is trying to expire, and the other part is trying to inspire. In the past that caused the lungs to pop and cause pneumothorax.
6. Further, to use HFOV a neuromuscular blockade has to be used which increase the chances of an infection.

7. Downar et al (2006) reviewed the benefits of HFOV in ARDS and reported that it may improve oxygenation if used early.

8. However, a 2005 Cochrane Review concluded that there was insufficient evidence to support use of HFOV in ARDS.

Question 18

Surfactant in ARDS

Answer 18

1. Lung injury in ARDS results in ↑ hysteresis in the pressure-volume loop – indicating increased work of breathing and there is also decreased production of surfactant in ARDS.
2. Administration of surfactant to an ARDS patient can reduce the work of breathing, but this lacks clinically significant outcomes.

Question 19

Nitric oxide in ARDS

Answer 19

1. Nitric oxide is a vasodilator and can in some situations (e.g. HAPE) promote better V/Q matching.
2. Afshari (2010) reported on a meta-analysis of RCTs studying inhaled NO as a treatment in ARDS.
3. They concluded that inhaled NO may improve oxygenation in the first 24 hours but does not reduce mortality or improve any of the measured patient benefit outcomes.

Question 20

Hypoxia and ARDS

Answer 20

1. Inflammation can disrupt the alveolar epithelium, resulting in oedema and thickening of the diffusion barrier.
2. The loss of surfactant and atalectasis results in reduced alveolar ventilation. Thus, there is a substantial increase in the amount of shunt – perfusion of alveoli in the absence of sufficient ventilation.
3. It is this failure of ventilation and gaseous exchange which gives the hypoxaemia which characterises ARDS. Hypoxia can also play a causative role in ARDS.

4. Vuichard et al (2005) demonstrated that hypoxia can itself augment pathogen associated lung injury & inflammation and induce apoptosis of type II alveolar cells. Thus, there emerges a vicious cycle of inflammation, damage and hypoxia.

Question 21

Cell based therapy in ARDS

Answer 21

1. In light of the mixed evidence for the lung protective strategies discussed above, there is still much to be done to improve and treat patients with severe ARDS.
2. Cell-based therapy with allogeneic human MSCs has emerged as a promising approach to therapy for ALI and ARDS.
3. MSCs secrete multiple effector molecules, including anti-inflammatory cytokines, growth factors, and antimicrobial peptides.
4. These can reverse the major abnormalities of lung injury, including altered lung endothelial and epithelial permeability, impaired alveolar oedema fluid clearance, dysregulated inflammation, and infection.
5. In addition, in an experimental model, MSCs attached to the alveolar wall by connexin-43–based gap junctional channels and transferred mitochondria to endotoxin-injured alveolar epithelium, restoring alveolar ATP production and normalizing surfactant production and epithelial barrier properties.

Question 22

What is an example of neuromuscular respiratory failure?

Answer 22

• Phrenic neuropathy
• Guillain barre syndrome
  
  • Campylobacter jejuni (undercooked chicken) ascending paralysis
  • Autoimmune reaction, myelin sheath becomes attacked by antibodies that are shared by infections agents. You get sensory and motor neuropathy, to a point where they cannot breathe.

Question 23

Describe genetic mutation in pseudocholinesterase deficiency

Answer 23

• You give suxamethonuiun, occupies one ACh receptor at skeletal muscle junction stops receptor opening. In people who can’t metabolise the suxamethonium, then it stays there and can last 24 hours.
• Called suxamethonium apnoea
• Pseudocholinesterase is an enzyme present in the blood and certain organs which hydrolyses acetylcholine more slowly than acetylcholinesterase.
• It is produced in the liver and hydrolyses exogenous choline esters.