Slide 1

Thank you so much. Thank you very much for this kind invitation. I will deal with the clinical features and therapeutic options for ARDS. You’ve already heard something about this this morning but I’ll be quick.

Slide 2

I’m not directly involved in research about ARDS, so I tried to update myself and when I went to Pubmed and searched for only reviews in the English language in the last 5 years in core clinical journals about the MeSH term, Acute Respiratory Distress Syndrome I found about 100 results that astonished me because I didn’t think that the proportion was like this and to give you an idea to do the same research with the term ‘acute renal failure’ or another MeSH term it will give you about half of the results.

Slide 3

The clinical definition of ARDS means to include also the definition of acute lung injury, in fact these two terms are the extreme ranges of a condition that is characterised by a severe, an acute form of respiratory failure that complicates many medical and surgical pathologies, it’s very important to early treat and recognise this condition for the outcome of patients, as we will see.

Slide 4

Clinically patients present with dyspnoea and symptoms that are very close to signs of pulmonary oedema and this form is very aggressive and most of these patients will need intubation and admission to intensive care unit is mandatory.

Slide 5

What are the causes of acute lung injury and ARDS? We see that we will have direct lung injury and so direct aggression to lung parenchyma and indirect lung injury. Direct lung injury can be pneumonia or pulmonary trauma. Whereas, indirect lung injury will see sepsis and severe polytrauma and so indirect involvement of lung on a systemic pathology.

Slide 6

But as happened for acute kidney injury in the recent years, about 20 years ago scientific community felt the need for a set definition criteria for acute lung injury and ARDS because the pathology was too vague to be included in clinical trials and to be understood correctly in the clinical setting. So, they defined essentially 3 points to define acute lung injury and ARDS. The first radiological. Patients needed to have new, bilateral diffuse, patchy or homogeneous pulmonary infiltrates. There had to be no signs of fluid overload, heart failure and chronic lung disease and pulmonary artery occlusion pressure had to be less than 18mmHg. The oxygenation. This is a very important point. The ratio between PaO2 and FiO2 (inspired fraction of oxygen) needed to be less than 300 mmHg to define to acute lung injury and less than 200 to define ARDS.

Slide 7

The point with these criteria is that they simplify things and as we know, about what is happening with acute kidney injury we know that a simplifying definition has to be reliable in order to help clinicians to have the tools to identify patients and to enrol them in clinical studies.

Slide 8

This set of definitions had some strengths because first of all, it recognised that the severity of ARDS was an evolving severity, so they identified essentially 2 different degrees of severity of ARDS and then the definition was simple to apply in the clinical setting.

Slide 9

These are two very important points but nevertheless, there were essentially 3 weaknesses of this set of criteria because first of all, they did not take into account the relevance of the precipitating condition because as we will see, prognosis depends on the aetiology of lung injury.
Then the most appropriate system of interpretation of chest radiograph was not defined even if it is not easy to give a univocal definition of a chest radiograph.
Finally, they failed to standardise the strategy of mechanical ventilatory support to be used when the calculation of the ratio between PaO2 and FiO2 was quantified.

Slide 10

The first point is maybe the most important, as we can see acute lung injury and ARDS mortality depend essentially on the aetiology because when pneumonia is the case of ARDS mortality is maybe 2/3 than the mortality we encounter during septic shock pulmonary source.

Slide 11

Anyway from the histopathological point of view ARDS is characterised by inflammation of the microcirculation in the alveoli that causes a migration of neutrophils

Slide 12

and production of mediators of inflammation that causes sloughing of both the bronchial and alveolar epithelial cells and then the formation of protein rich hyaline membranes.

Slide 13

In the clinical setting this causes impaired gas exchange and the refractory hypoxemia. Refractory means that even if you give 100% oxygen to these patients and you mechanically ventilate them, they remain hypoxic mainly because there is a strong ventilation perfusion mismatch that means that a large part of the lungs is perfused but not ventilated. Above all these lungs are stiff. It is very, very difficult to ventilate these patients, as we will see.

Slide 14

The syndrome evolves

Slide 15

and when the patient is going to survive through an exudative and inflammatory state, he encounters a fibroproliferative state and after the water is drained again from the alveoli, fibrosis of the alveoli is seen.

Slide 16

The incidence of acute lung injury and ARDS is quite high because it has been calculated in about 190.000 cases per year in the US and about half of these patients die.
The pathology is very aggressive because we know that the lighter form of lung injury, ALI will evolve to ARDS in more than half of cases.

Slide 17

We need to differentiate ARDS from cardiogenic oedema and acute interstitial pneumonia, this is very important for treatment reasons and above all for therapeutic and research reasons.

Slide 18

Investigations to diagnose acute lung injury and ARDS are obviously chest radiograph, arterial blood gases, echocardiography above all to differentiate acute lung injury from cardiogenic pulmonary oedema. Above all computed tomography that has been increasingly used in recent years especially to monitor the effects of the recruiting manoeuvre on our patients.

Slide 19

Therapeutic strategies.

Slide 20

We see general supportive measures like nutrition, early provision of enteral nutrition is desirable in all critically ill patients obviously but recently a randomised controlled trial interestingly observed that adding eicopentaenoic acid, gamma linoleic acid and antioxidants to enteral nutrition improve significantly survival. Mainly because these molecules have very potent anti-inflammatory properties.

Slide 21

Then as we have already seen, fluid management is very important. Fluid restriction in a large randomised trial allowed to increase the number of days without ventilation even if unfortunately, no significant difference in mortality was seen.

Slide 22

In the same dataset of patients another study told us that there was no difference between monitoring these patients with the pulmonary artery catheter or with a normal central venous catheter.

Slide 23

So at the moment we are not authorised to routinely use the pulmonary artery catheter to monitor ARDS patients.

Slide 24

Ventilatory management which is one of the most important, which we’ve already seen this morning. Lung protection is the basis of ventilatory management. Lung injury distributes on the dependent part of the lung, so we know that ventilating these patients we run the risk to ventilate mostly, to over distend the unaffected part of the lungs. So volutrauma is risked and the opening and closing of the damaged lung is thought to generate pro-inflammatory mediators.

Slide 25

A recent study proposed to ventilate patients with low tidal volume ventilation 6 ml/kg of predicted body weight and they realised that there was a significant improvement in mortality with respect to standard ventilation. Obviously in this way we tended to have lower intrathoracic pressures in our patients but we have to expect a relative high degree of hypoxemia and a relative degree of hypercapnia.

Slide 26

The authors considered that this hypercapnia could be acceptable as long as pH of patients was maintained above 7.2.

Slide 27

Again on ventilatory management the use of positive and expiratory pressure. We know that the rational of PEEP in ARDS patients is to improve oxygenation and increase functional residual capacity and to recruit small airways. But we know that an excessive utilisation of PEEP may result in over distension and again volutrauma.

Slide 28

There are 3 very important and large randomised controlled trials, two of these compared low levels of PEEP with high levels of PEEP in two populations of ARDS patients both ventilated with low tidal volumes and a third randomised controlled trial compared the simultaneous utilisation of low tidal volume, recruiting manoeuvres and high levels of PEEP. All of these studies concluded that this aggressive management of ARDS patients did improve secondary end points like for example, oxygenation and ventilator-free days but none of these studies again showed a significant improvement in mortality.

Slide 29

So far it remains reasonable to set a PEEP level just above the lower inflection point that is the point where the associating between volume and pressure in our diseased lungs approach normality.

Slide 30

Prone ventilation. The rational of prone ventilation is that as we saw, the damaged lungs are in the dependent part of the thorax so if we put the patient upside down, maybe we could afford to ventilate the damaged part of lungs and no very large randomised controlled trials have been conducted on this but there is an interesting systematic review that came out this year and again it was shown that oxygenation did improve but mortality of these patients was not improved by this manoeuvre.

Slide 31

This was not without risks in these such complicated patients. High frequency ventilation is another option, I will go ahead

Slide 32

and there are other non-ventilatory approaches some of these are pharmacologic and some are extracorporeal as we will see.

Slide 33

Methylprednisolone has been used frequently in acute respiratory distress syndrome patients and a recent large trial focusing on the use of corticosteroids in late fibroproliferative ARDS showed that patients had an increased number of ventilatory shock free days but nonetheless, these patients had a higher rate of neuromuscular weakness and maybe a higher risk ratio for mortality.

Slide 34

Another systematic review on the use of steroids on ARDS patients showed that the role of corticosteroids has not been established yet. The possibility of reduced mortality when the steroids are started after the onset of ARDS is possible but the use of preventive steroids possibly increases the incidence of ARDS in critically ill adults.

Slide 35

The point with all these randomised controlled trials is that maybe it is very difficult to enrol the same kind of patients because of the difficult criteria that was set more than 15 years ago.

Slide 36

So one of the interesting therapeutic approaches that has been proposed is to start with a ventilatory strategy which is the one that has been surely accepted

Slide 37

and then accept an oxygenation between 85 and 90% of saturation. Then see if the patient remains stable for 48-72 hours. Then if the patient will improve we will try to start weaning manoeuvres and if the patients does not, we will consider rescue therapies like prone positioning and other drugs.

Slide 38

Let me go to the conclusion just touching upon the so-called pulmonary renal syndrome. In this case too we have already seen something but from the study of Uchino and co-workers we’ve seen that all, not all but more than 70% of patients affected by acute kidney injury come to the ICU with mechanical ventilation. We know that hypercapnia, hypoxia, the mechanical ventilation, the barotrauma and the release of inflammatory mediators all affect kidney function, as well as it happens when the kidney function is primarily damaged and then from many experimental models we know that lungs can be affected especially in the fluid handling and permeability of the alveolar epithelium.

Slide 39

So what can be the therapeutic strategy when the lungs and kidneys are simultaneously affected? As we’ve seen, there is no clear idea on what to do about fluids but what has been understood in recent years is that fluid can have a high physiological price but maybe after a – directed therapy in the ICU there should be an early goal directed fluid restriction.

Slide 40

When the kidneys are affected, maybe the use of initiation of CVVH can be suggested. Even because we know from institutional reports and case reports that sometimes CVVH improves lung function even when zero balanced ultrafiltration is used.

Slide 41

From a recent study dealing with patients treated with a protocol of high volume hemofiltration protocol with zero balance for 6 hours and then a standard protocol, this approach improved mortality of septic patients but above all it significantly improved the PaO2:FiO2 ratio between patients treated with this protocol and patients who were not.

Slide 42

Short-term outcomes as we’ve seen are bad especially when co-morbidities are present.

Slide 43

Long-term outcomes also are bad. Survivors of ARDS feel a low quality of life at 1 year.

Slide 44

In conclusion, acute lung injury needs extreme manifestation of ARDS and are severe forms of acute respiratory failure. They may represent the lung component of an early multi-organ failure. Early admission to intensive care unit is mandatory. Protective techniques of mechanical ventilatory support reduce mortality. Application of supportive measures is likely to improve outcome which has improved in the last 10 years. Although death rates are falling nevertheless, long-term debility in survivors is still considerable. Thank you very much.