Slide 1

Thank you Mr Chairman. Good morning Ladies and Gentlemen. I first would like to thank the organisers of this meeting for their kind invitation. They challenged me with the question what the nephrologist should know about mechanical ventilation.

Slide 2

My first thought was nothing because mechanical ventilation that is the task of the intensivist but I suppose that this is not what the organisers had in mind.
20 minutes is far too short to give you a meaningful primer of mechanical ventilation and I therefore, decided to keep the focus on the kidney. So after a few basic concepts I will mainly concentrate on possible interactions between mechanical ventilation and the kidney.

Slide 3

Mechanical ventilation is the most common treatment used in intensive care medicine. It is a supportive treatment that however can often be life saving by improving gas exchange and by decreasing the work of breathing.

Slide 4

We have several forms of mechanical ventilation that have resulted in our own mechanical ventilation alphabet. The most common form of mechanical ventilation is controlled mechanical ventilation where a preset tidal volume is delivered at regular intervals. In the assist-control ventilation this tidal volume is delivered with every inspiratory effort of the patient which means that the patient can trigger the machine. Pressure support ventilation is also a very popular modality of mechanical ventilation, it is also triggered by the patient but instead of a preset volume the machine delivers a certain pressure.

Slide 5

Pressure controlled ventilation as is the name is a completely controlled form of ventilation but this time not the volume is controlled but the inspiratory pressure.
PEEP stands for positive end expiratory pressure which means that at the end of the expiration the pressure in the airway and alveoli does not return to atmosphere pressure.
CPAP is the spontaneous ventilation mode with continuous positive airway pressure.

Slide 6

There are many more modalities of mechanical ventilation that each may have their indication in specific patient populations but I will not bother you with this.

Slide 7

The major indication is acute respiratory failure. This can be in acute pulmonary conditions as pneumonia, ARDS, cardiogenic pulmonary oedema, airway diseases such as CPOD exacerbations, ventilatory failure such as Guillan-Barré or drug overdose, systemic illnesses can also be an indication such as shock or sepsis.
What is important to know is that the decision to start mechanical ventilation is almost never based on blood gases alone it is mostly based on clinical judgement that takes into account the work of breathing, in other words the respiratory rate, the use of accessory muscles, cardiac reserve of the patients, consciousness and of course, also blood gases.

Slide 8

A very common condition in ICU is acute lung injury or ARDS. It can be defined as a severe respiratory distress with one or more risk factors such as sepsis, pancreatitis, trauma and so on.
It is a clinical syndrome characterised by inflammatory pulmonary oedema, severe hypoxemia, reduced lung compliance and diffuse endothelial and epithelial injury that are the structural counterparts of an increased permeability.
Criteria for diagnosis are PO2 or an arterial PO2/FiO2 which is the inspiratory oxygen fraction, the ratio below 200 for ARDS and below 300 for ALI which is a less severe from. In addition to that the patient should have bilateral infiltrates and --- pressure below 18 mmHg or no clinical signs of increased left atrial pressure.

Slide 9

In clinical practice of intensive care medicine there is definitely a link between the lung and the kidney. Many patients have both acute lung injury and acute kidney injury, a combination that continues to have a very high mortality. It is also intriguing that these patients do not die from hypoxemia nor from hyperkalemia but mostly from an unresolved multiple organ dysfunction, the pathogenesis of which is not completely clear.

Slide 10

Over the past years it has become increasingly clear that patients with acute lung injury that receive mechanical ventilation that in these patients mechanical ventilation by itself might induce damage to the kidney especially to the injured kidney and this phenomenon is called VILI or ventilator-induced lung injury. We will see whether mechanical ventilation might also damage the kidney and result in what we could call ventilator-induced kidney injury.

Slide 11

Ventilator-induced kidney injury maybe directly related to the VILI, it can be the result of heart-lung interactions or in other words of the hemodynamic effects of mechanical ventilation and mechanical ventilation may also affect the kidney through humoral effects but I will mainly concentrate on the first 2.
When I speak of ventilator-induced lung injury most of you will think of ventilator associated pneumonia or barotraumas or pneumothorax, however far more important than barotraumas are these recent concepts of volutrauma, atelectrauma and biotrauma.

Slide 12

Already more than 20 years ago Dreyfuss showed that when you ventilate rat lungs with high volume and high pressure, you can induce pulmonary oedema. Already after 5 minutes there are focus zones of atelectasis and after 20 minutes the lungs of these rats were markedly enlarged and congestive with oedema fluid in the tracheal canula.

Slide 13

At the microscopic level this corresponds with interstitial oedema, enlarged perivascular cuffs and after 20 minutes with widespread alveolar oedema.

Slide 14

The same author then performed a very elegant experiment. He divided rats in 5 groups. The first group ventilated with low pressure and low volume. The second group with high pressure and high volume. The third group with the same pressure but with a PEEP of 10 cm of H2O which resulted in a lower tidal volume. The fourth group was ventilated with the same high pressure but lower tidal volume and this was obtained by strapping the thorax and the abdomen of these animals. The fifth group was ventilated with a sort of an iron lung resulting in a negative inspiratorial pressure but with the same high tidal volume.

Slide 15

Pulmonary oedema was measured by extravascular lung water and microvascular permeability by the dry lung weight and distribution space of labelled albumin. The lungs of the rats with high pressure and low volume were almost no different from control. But the two groups ventilated with a high tidal volume had marked permeability oedema and diffuse alveolar damage at microscopic examination.

Slide 16

These changes could be partially prevented by PEEP but it’s not clear from this experiment whether this is the PEEP by itself or the lower tidal volume in this group.
These and other experiments led to the term volutrauma indicating that it’s not the inspiratory pressure but the high volume with overdistension of lung units that is deleterious.

Slide 17

When you look at the x-ray of a patient with acute lung injury or ARDS, you get the impression that they have a diffuse pathology but this is not the case if you look at a CT scan. These patients mostly have pathologic dependent regions with more normal appearing non-dependent regions. This means that the volume of the lung that is available for gas exchange is reduced. This led Gattinoni to introduce the concept of the baby lung. When a baby lung is ventilated with normal tidal volumes, it will be overdistended. The sicker the lung, the smaller the volume that is available and the more it will be overdistended. So the danger of volutrauma is greater with a sick lung.

Slide 18

Another pathway of ventilator-induced lung injury is the so-called atelectrauma. It refers to the sheer injury that results from repeated opening and closing of small lung units in the so-called recruitable part of the lung. This has led to the concept of open-lung. This means that recruitment manoeuvres are used to open up the collapsed lung unit followed by the application of PEEP to keep these units open and thus prevent repeated opening and closing and associated atelectrauma.

Slide 19

The mechanical trauma by volutrauma and atelectrauma causes the so-called biotrauma with upregulation and release of inflammatory mediators in the lung. These inflammatory mediators may spill over into the circulation and may initiate and propagate a systemic inflammatory response.

Slide 20

Herrera demonstrated a concept of VILI and biotrauma in a clinically relevant experimental model of sepsis in rats. After introducing sepsis he divided the animals in 4 groups ventilated with high or low tidal volume, with or without PEEP. This slide shows you the lung injury score. As you can see, the injury in the lung is lowest in the animals ventilated with a low tidal volume and PEEP and highest in the two groups with the high tidal volumes.

Slide 21

He also looked at gene expression of inflammatory mediators in then lung and found a similar pattern; lowest expression in the group with low tidal volume and PEEP and highest expression in the group with a high tidal volume. Also in the systemic circulation the group with a high tidal volume had the highest systemic levels of TNF and IL-6 indicating that the way you ventilate in this case the animals may have an impact or an inflammatory reaction in the circulation.

Slide 22

In order to avoid this ventilator-induced lung injury, the so-called lung protective ventilatory strategies have been developed. These include the use of a low tidal volume to avoid volutrauma.

Slide 23

Lung recruitment manoeuvres and PEEP to avoid atelectasis and atelectrauma and since a higher priority in this strategy is assigned to avoiding injurious ventilation than maintaining normal levels of ventilation or oxygenation, these lung protective strategies are often associated with what is called permissive hypercapnia or hypoxia.

Slide 24

5 prospective randomised trials have compared conventional and lung protective ventilation. The first trials were small and could not find a difference but the ARDS network trial showed that patients that were ventilated with a tidal volume of 6 ml/kg and a maximal plateau pressure of 30 mmHg had a significantly better survival than patients ventilated with 12 ml/kg of tidal volume and a maximal plateau pressure of 50 mmHg. These patients also had a lower IL-6 level on their tree which is a clinical proof of the concept of biotrauma.

Slide 25

Could there be a relation between biotrauma and the kidney? Imai has performed a very elegant experiment where rabbits with acid aspiration lung injury were ventilated with an injurious strategy with high tidal volume and low PEEP or a non-injurious strategy. The investigators corrected for a difference in PO2 or PCo2 and they also infused saline to exclude for a possible different hemodynamic effect of the two strategies. After 8 hours the injurious group had a higher serum creatinine and more apoptotic tubular epithelial cells.

Slide 26

Investigators then took the plasma of these animals and incubated proximal tubular cells with it. When they used the plasma of the injuriously ventilated rabbits, this plasma could induce more apoptosis that could be reduced by blocking Fas ligand. They also took serum samples from a previous prospective randomised clinical trial and showed that the plasma of patients that were ventilated with a lung protective strategy had lower levels of the soluble Fas ligand and that is correlated with serum creatinine.

Slide 27

So this animal experiment suggests that the way you ventilate a lung if you use an injurious strategy you may induce apoptosis in the kidney and soluble pro-apoptotic factors may play a role in this.

Another experiment where a rat model, rats were ventilated for 2 hours with low tidal volume, high tidal volume or high tidal volume with correction of hypertension. The rats with high tidal volume with or without hypertension had more eNOS expression and more microvascular leakage in the lung and the kidney. Again, an indication that mechanical ventilation may affect the kidney.

Slide 28

This is clinical evidence. There is a small prospective randomised trial that compared conventional and lung protective strategies and showed that there was less organ failure in the lung protective strategy and this difference was most pronounced for the kidney. Also in the large ARDS network trial the patients with a lung protective strategy had less renal failure, had more renal failure free days. But in clinical trials it is always difficult to determine whether this is an effect of what we can call biotrauma or whether it is due to the hemodynamic effects of mechanical ventilation.

Slide 29

This brings us to the second part. Heart-lung interactions may be divided in those induced by changes in intrathoracic pressure or intrathoracic volume. Changes in intrathoracic pressure may affect systemic venous return or left ventricular afterload. Changes in volume may affect pulmonary vascular resistance or may induce mechanical heart-lung interactions.

Slide 30

When intrathoracic pressure increases, this causes an increase of the right atrial pressure and since the right atrial pressure is the back pressure for venous return, venous return will decrease. This decreases the preload of the right ventricle and since the right and the left ventricle are linked in series, the cardiac output will decrease. This is the most common effect of mechanical ventilation on hemodynamics. But the increase of intrathoracic pressure also sort of compresses the left ventricle and results in a decrease of wall tension or in other words of afterload and this may result in an increase of cardiac output, especially in patients that have a left ventricular dysfunction and that are afterload dependent and this explains why patients with acute cardiogenic pulmonary oedema may benefit from mechanical ventilation.

Slide 31

Pulmonary vascular resistance is minimal at resting long volume or functional residual capacity. It will increase with higher lung volumes by compression of alveolar vessels and it will increase at lower volume by collapse of extra-alveolar vessels and hypoxic pulmonary vasal constriction. Most patients with acute lung injury have a low lung volume and also here and often have an increased pulmonary vascular resistance. To the extent that mechanical ventilation can open lung units it may induce a decrease of pulmonary vascular resistance but when it overdistends healthy lung parts it may increase pulmonary vascular resistance.

Slide 32

Changes in pulmonary vascular resistance represent a change in the afterload of the right ventricle. A normal right ventricle can tolerate these changes but if you have a compromised right ventricular function, this will affect right ventricular output and therefore also the left ventricular output. These 2 ventricles are not only linked in series but they are also contained in the same pericardial sack and this leads to what is called ventricular interdependence which means that when the volume of one of these 2 ventricles changes, it will affect the compliance of the other. If there is an acute dilatation of the right ventricle, this will shift the septum to the left and the compliance of the left ventricle will decrease.

Slide 33

Mechanical heart-lung interactions by a compression of the heart between the two lungs can also result in a decreased diastolic compliance.
So in summary, the increases of lung volume and intrathoracic pressure induced by mechanical ventilation may affect preload, afterload and diastolic compliance of both the right and the left ventricle either directly or via ventricular interdependence. The final effect will depend on intravascular volume, myocardial contractility of right and left ventricle, the presence of lung injury and lung compliance and the modality of mechanical ventilation and this explains why studies on this issue have given contradictory results in the past.
The most common effect is a decrease of the systemic venous return that can easily be corrected with fluid resuscitation, patients with left ventricular dysfunction may benefit from a decreased afterload. Most injurious is a patient with a compromised right ventricular function that cannot tolerate an acute increase of afterload.

Slide 34

It is obvious that the way you ventilate a lung will also affect the hemodynamic effects. So these lung protective strategies not only have less biotrauma but will also induce less hemodynamic effects except when you use very high PEEP levels or very aggressive recruitment manoeuvres.

Slide 35

I wanted to say something about permissive hypercapnia but I think there is no time anymore and we can leave that for discussion and go directly to the conclusions that lung-protective ventilation strategies have beneficial effects not only on the lung but also on the kidney and you should know that the hemodynamic effects of mechanical ventilation are very complex and depend on the underlying condition of the patient.
I thank you.