Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03896802 |
| Other study ID # |
ARDS-HEMO |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2018 |
| Est. completion date |
December 31, 2019 |
Study information
| Verified date |
March 2019 |
| Source |
University of Milan |
| Contact |
Davide Chiumello |
| Phone |
+390281844020 |
| Email |
chiumello[@]libero.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The purpose of this study is to assess the effect of different levels of PEEP on the
cardiocirculatory system in patients affected by the acute respiratory distress syndrome
(ARDS)
Description:
Introduction
Acute respiratory distress syndrome (ARDS) is a clinical syndrome defined by the association
of an acute onset of hypoxaemia and bilateral pulmonary infiltrates following a trigger
insult; it is characterized by inflammation of the pulmonary tissue, with subsequent
development of non-cardiogenic edema. The extent of edema may be such that the weight of the
lung may increase up to 2-3 times its original weight. As a consequence, the lung tends to
collapse on itself, more so in the dependent areas, i.e. the posterior/dorsal areas when the
patient in lying supine, with the consequent development of zones of atelectasis.
These areas, when perfused, are the main cause for the development of the severe form of
hypoxemia commonly seen in this condition. Hypoxemia, if severe enough, may bring by itself
to the death of the patient. It has to be noted that, despite the advances in the management
of critically ill patients, mortality attributable to ARDS currently is about 50%, with a
range between 30-70%.
The use of positive end-expiratory pressure (PEEP) has been reported ever since the first
description of the syndrome, as a tool to manage and correct hypoxemia. PEEP has thus been
used for 40 years, and is an essential part of the management of the syndrome. While the
effectiveness of PEEP in improving the oxygenation of the wide part of critically ill
patients with ARDS it is out of doubt, its efficacy with respect to outcomes such as
mortality has not, so far, been demonstrated. The question is then still open with regards to
the setting of an optimal level of PEEP in ARDS.
Frequently, ARDS is associated with the development of hemodynamic instability and shock, to
the extent that up to 2/3 of patients suffering from the syndrome require the infusion of
catecholamines or show signs of hypoperfusion; circulatory failure seems to be the factor
more strongly associated to mortality in these patients, and the strength of the association
is higher compared to that of the degree of hypoxemia. In ARDS shock is secondary to three
main factors: 1) acute cor pulmonale due to pulmonary hypertension secondary to microvascular
occlusion by thrombi or arteriolar remodeling and/or hypoxic pulmonary vasoconstriction; 2)
the deleterious hemodynamic effects of mechanical ventilation, especially on right cardiac
function; and 3) the possible development of septic myocardial depression.
Acute kidney injury (AKI) is common in critically ill patients and it is associated with poor
outcomes. An increasing body of evidence points to the existence of deleterious interactions
between kidney and lung dysfunctions in a vicious cross-talk. Several studies seem to suggest
that mechanical ventilation and ARDS may have adverse effects on kidney function via three
main mechanisms: 1) positive-pressure ventilation may lead to a reduction in cardiac output
and an increase central venous pressure, thereby diminishing renal blood flow, free water
clearance, and the glomerular filtration rate; 2) changes in arterial blood oxygen (O2) or
carbon dioxide (CO2) may influence renal vascular resistance, renal perfusion, or diuresis;
and, finally, 3) emerging data suggest that ventilator-induced lung injury may not only
affect the lung, but may also lead to further systemic inflammation via the systemic release
of inflammatory cytokines.
Indeed, the hemodynamic effect of PEEP depends on how much of the positive pressure applied
to the alveoli is transmitted to the mediastinal structures (heart and big vessels), and the
effect on renal function depends on how much this interferes with renal hemodynamic. The
transmission of airway pressure, in turn, depends on the mechanical characteristics of the
lung and the chest wall, which are known to be variably and unpredictably affected in ARDS.
The main question of this research project deals with the hemodynamic impact of PEEP in
patients with ARDS, in terms of effects on the cardiocirculatory system.
Rationale
Hemodynamic effects of mechanical ventilation The hemodynamic effects of mechanical
ventilation are mainly secondary to cyclic oscillations in pleural pressure (Ppl) and
transpulmonary pressure (Ptp). Variations in pleural pressure mainly interfere with inflow of
blood into the right ventricle, and with ejection of blood from the left ventricle. On the
other side, variations in transpulmonary pressure mainly affect the inflow of blood into the
left ventricle and ejection of blood from the right ventricle. While the large vessels of
systemic circulation are surrounded by the constant atmospheric pressure, central vessels of
the pulmonary circulation are surrounded by pleural pressure, which in turn may significantly
vary compared to atmospheric pressure during the whole respiratory cycle. Positive-pressure
mechanical ventilation exerts an effect which is opposed to the physiologic inspiratory
negativisation of pleural pressure. Indeed, the increase in pleural pressure secondary to
positive airway pressure reduces left ventricular afterload, while at the same time it
reduces right ventricular preload. Since the normal pressure gradient which drives blood from
periphery to the right heart lies in the range of 4-8 mmHg, even small increases in pleural
pressure may have a significant impact on venous return. Moreover, the presence of PEEP has a
hemodynamic effect during the whole respiratory cycle. As a rule of thumb, it is generally
estimated that up to about 50% of the variation in airway pressure is transmitted as a
variation in pleural pressure in patients with normally functioning lungs. This effect is
however likely reduced in case of an increased lung elastance (i.e. the presence of stiff
lungs, as in patients with ARDS), given that a reduced amount of airway pressure is
transmitted at the pleural level. However, this depends on the ratio between lung elastance
and respiratory system elastance, which may vary widely in ARDS. Moreover, as the right
ventricle generally displays a high level of compliance despite a limited myocardial
thickness and a reduced contractile force, this may be more affected from increments in
afterload rather than by variations in preload.
On the other side, the increase in mean airway pressure as a consequence of the application
of PEEP leads to an increase in the size of the lung (increase in end-expiratory lung
volume), mainly through the recruitment of previously closed and derecruited zones. However,
the application of PEEP may also lead to overdistention of already open and ventilated
pulmonary units, leading to a certain degree of vascular occlusion of the critical closing
pressure of those vessels is reached and overcome (as in the case of West zones I and II, in
which alveolar pressure in higher than arterial and venous pulmonary pressure, respectively).
The hemodynamic effect of PEEP might then be different, as a function of the amount of
pulmonary units that can be recruited. In conclusion, the knowledge of the effect on the
cardiocirculatory system of the application of a high or low level of PEEP may require the
measure or at least an estimate of the potential for lung recruitment.
Measurement and estimate of the potential for lung recruitment The gold standard for the
measurement of the potential for lung recruitment is represented by pulmonary CT scan. This
technique has been used together with quantitative analysis of regional and global lung
aeration by our group since 1987 for the analysis of parenchymal response to PEEP in patients
with ARDS. An estimate of the potential for lung recruitment may be inferred at the bedside
by the assessment of the effect of PEEP on the level of oxygenation, physiologic dead-space
and partitioned lung compliance, to be able to differentiate recruitment from overdistention.
Main hypothesis The main hypothesis behind the present research project is that critically
ill patients with ARDS and an elevated potential for lung recruitment will be less affected
by the hemodynamic effects of PEEP than patients with a lower potential for lung recruitment.
If this hypothesis was to be confirmed, the application of PEEP would be less troublesome, at
least for the concerns for the hemodynamic compromise, in patients with ARDS and a higher
potential for lung recruitment. This issue has so far never been investigated, and the
present research might significantly extend our knowledge on the topic.
