The use of pulmonary vasodilators in ARDS is an attempt to manipulate pulmonary bloodflow in a way which improves gas exchange and right heart function. Unfortunately, it does not seem to improve survival, only oxygenation. The college showed some interest in these therapies, for some reason specifically in nitric oxide. Detailed discussions have come up repeatedly in the first decade of the 21st century, and then randomly again in 2019:
- The rationale is to improve V/Q matching
- Only ventilated regions of lung receive the inhaled agent; therefore pulmonary vessels will only be dilated in the well-ventilated regions of the lung; therefore blood flow will be preferentially directed to those regions
- In heterogeneous lung disease (eg. ARDS) this may improve the shunt caused by the reversal of normal hypoxic vasoconstriction.
- An ideal agent is, therefore, one which has a short half-life and minimal recirculation (i.e. the effect is limited to the pulmonary circulation)
- Options for agents include:
- Nitric oxide
- Neither agent improves mortality.
- Nitric oxide and prostacyclin at least improve oxygenation.
- By most, these are viewed as "second line" therapies
The discussion of the rationale must first start with a brief digression on the topic of the acute hypoxic pressor response of normal pulmonary arteries. A pulmonary artery reacts to hypoxia in a sensible fashion. If it is travelling through a hypoxic region of lung, the blood it carries will not become sufficiently oxygenated; it will benefit the organism if this blood were diverted to another portion of the lung - one with better oxygenation. Thus, the pulmonary artery will vasoconstrict, which increases the resistance to flow- and flow, being a fickle hydrodynamic phenomenon, will divert along a path of least resistance into other, more accommodating arteries.
Thus, the lung has some capacity to automatically improve the matching of ventilation and perfusion. This phenomenon, called the Acute Hypoxic Pressor Response, is an idiosyncrasy of the pulmonary circulation, well known since the cat experiments by Euler and Liljestrand. The site of this activity seems to be little muscular pulmonary arteries at the level of the terminal bronchioles.
This is all fine and good if you have a large proportion of healthy lung tissue into which this flow can be diverted. But, let us consider a situation (like pneumonia) where half or more of the lung tissue is filled with pus and has practically no oxygen.
The pulmonary arteries crushed inside this pus-filled lung will dutifully constrict, and the blood flow diverted to the few remaining well-oxygenated regions. However, this has significant implications for the total pulmonary artery resistance. Obviously, it will increase. The feeble right ventricle will only compensate for this for a certain range of pressures; as the pressure increases it will dilate, and decompensate, losing contractility. The ensuing right heart failure produces a low flow state in the pulmonary circulation. The total amount of pulmonary blood flow will decrease.
Apart from hypoxia, here are several other factors which contribute to increased pulmonary vascular resistance in ARDS:
Thus far, the discussed phenomena have been constructive. Ultimately, they are adaptive responses to hypoxia, and they result in an improvement of the ventilation/perfusion mismatch. However, in states of severe inflammation, these mechanisms break down. One is reminded that the normal milieu of inflammatory mediators are all largely vasodilatory. All the arachidonic acid metabolites, the products of degranulating platelets, and bacterial endotoxin, for instance. This is bad.
The pulmonary arteries travelling through such an inflamed lung will fail to appropriately constrict, allowing an embarrassingly large amount of blood to travel through them, picking up no oxygen whatsoever. This is counterproductive, as it robs the well-oxygenated portions of lung of their richly deserved blood flow. The result is a massive shunt. Of the blood arriving into the left atrium, let's say half is essentially mixed venous blood, with whatever saturation it had (say 75%); thus one can imagine that the arterial saturation will end up 87% or so.
Therein lies the allure of the inhaled pulmonary vasodilator agents.
If one is able to affect the vascular smooth muscle tone of the arteries in well-oxygenated regions, one can hopefully work to decrease the shunt fraction - as blood will be diverted from the poorly oxygenated regions into the free-flowing well oxygenated regions. Of course, as the agent is inhaled, it will never reach the pus-filled non-aerated lung, and will only settle in the normal alveoli.
On occasion, CICM trainees have been asked to "critically evaluate" nitric oxide. The answer offered here is tailored to Question 4 from the second paper of 2019, and is therefore not specific to the management of ARDS.
Rationale for the use of inhaled nitric oxide:
Mechanism of action:
In short, there is little high-quality evidence. What we do know is that there is no benefit in mortality. This molecule, like activated protein C, is a beautiful dream which never came true.
Prostacyclin (PGI2) is a prostacyclin derivative of arachidonic acid, with several available synthetic analogues. It has two mechanisms of action, one of which involves pulmonary (an systemic) vasodilation. The other effect is the inhibition of platelet activation.
A Cochrane review, in 2010, concluded that the use of inhaled prostacyclin cannot be recommended; however the rigorous process of trial filtration excluded all but one (pediatric) trial, which casts a shadow over the meta-analysis.
That notwithstanding, the literature has been unkind to prostacyclin. A 2013 study comparing it to nitric oxide reports that it is no better (though about 17 times cheaper) than nitric oxide. Given that nitric oxide is next to useless, this dampens the spirit of the prostacyclin enthusiast.
However, smaller trials which unfocus from hard outcomes and fixate on physiological parameters, such as oxygenation- such as this one from Chest, 2013 - applaud the efficacy of prostacyclin nebs in improving oxygenation in ARDS. It seems to increase PaO2 by 10% in ARDS patients within the first 4 hours of treatment.
Chapter 29 of Oh's Manual (by Anthony Bersten) echoes the above sentiments. Neither inhaled NO nor prostacyclin has ever been shown to convincingly improve outcome in ARDS.
However, the bottom line is this: prostacyclin does indeed improve oxygenation. Though this might not translate into a very obvious mortality benefit, one cannot sit idly while one's patients turn blue. In such situations, to quote Cherian et al (2018), "clinicians may resort to other measures with less robust evidence".
Chapter 29 of Oh's Manual (by Andrew Bersten) is a thorough treatment of ARSD in general, and devotes a good amount of space to discussion of the inhaled pulmonary vasodilators.
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