Inhaled and systemic pulmonary vasodilators for ARDS

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:

• Question 4 from the second paper of 2019
• Question 14 from the first paper of 2006
• Question 2 from the first paper of 2004

In summary:

Rationale for the use of inhaled pulmonary vasodilators

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:

• Loss of surfactant, and collapse of alveoli
• The actual weight of the pus-filled lung, which (for an entire lobe) could be as much as 1 kg - this certainly contributes to the compression of the pulmonary vessels.

Failure of pulmonary vasoconstriction in response to hypoxia 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.

Inhaled nitric oxide

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:

• To decrease pulmonary vascular resistance:
  • This decreases right ventricular afterload and may improve the performance of a failing right ventricle
• To improve V/Q matching (for severe ARDS):
  • 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.

Administration

• via a uniquely designed gas mixer
• from its own tank
• start at 5-10 ppm, go up to 160ppm as needed
• usual dose is around 20 ppm

Monitoring

• Monitor PA pressures with PAC or serial TTE
• monitor response with arterial oxygenation
• regular CXR, watch for pulmonary haemorrhage
• Monitor for toxicity, particularly methaemoglobin levels
• Monitor for the formation of nitrogen dioxide (NO₂), which is toxic
• Observe strict handling safeguards, including ventilation precautions. The CICM answer (Question 4 from the second paper of 2019) actually mentions the need to park the patient in a room where 10-12 air exchanges per hour are taking place, to prevent exhaled nitric oxide from hanging around. Troncy & Blaise (1998) published an excellent discussion of these sort of pragmatic considerations in the management of the iNO-ventilated patient. Their take on this topic was something along the lines of "if you're concerned, figure it out yourself". Among several surveyed British ICUs, only 16.9% felt that it was necessary to monitor the environmental NO levels. Forty percent of the units used no scavenging whatsoever, and the rest adapted soda lime buckets and commercial scrubber systems without any specific rhyme or reason. Twenty years later, the situation remains essentially the same. Fortunately we now have some data to discuss. Qureshi et al (2003) explored the exposure of nursing staff to iNO while working with infants and found that the environmental levels of nitric oxide were high only within about 60cm of the patient's crib. There was only a minimal exposure of nursing staff working closely with these patients.

Mechanism of action:

• The pharmacology of nitric oxide is an interesting topic all on its own. One can devote an entire chapter to its wily charms. For now, it will suffice to say that nitric oxide is a potent vasodilator; it inhibits vasoconstriction by increasing the amount of cyclic GMP (cGMP) in the cytosol, thus decreasing the amount of cytosolic calcium ions available to sustain smooth muscle contraction.

  

Advantages

• Relatively non-toxic
• Does not require scavenging technology (though if it were used in higher concentration, it would require scavenging)
• Short-acting (thus, no systemic vasodilation - only pulmonary)
• Small molecule:
  • diffuses easily to the site of action
  • penetrates well into the alveoli (where aerosols do not)

Disadvantages

• Expensive
• Can actually decrease the oxygen-carrying capacity of the blood
• Though scavenging is not required, a high air flow rate in the room is called for.

Complications

• Methemoglobinaemia: one way or another, nitric oxide ends up as methaemoglobin and nitrate. Either it reacts with lung water, becoming nitrite (which reacts with oxyhemoglobin and generates methaemoglobin and nitrate) or it combines directly with oxyhaemoglobin, with the same results.
• Hypotension (maybe some of it does leak into the systemic circulation, or maybe this the effect of depressed LV function
• Rebound hypoxia after abrupt withdrawal
• Thrombocytopenia (in as many as 10% of patients)
• Increased susceptibility to pulmonary infections probably due to NO₂ formation and associated lung injury
• Renal failure, which appears to be more common with nitric oxide, and which appears to be due to its "altering the function of mitochondria, various enzymes", etc.

Contraindications

• Left ventricular failure: NO seems to cause lots of adverse effects in this group of patients- particularly, pulmonary oedema. In fact, halfway through one study, the investigators had to start excluding CCF patients from the trial because of these effects.
• Left to right shunting: NO will decrease the pulmonary (and thus the RV) pressure, increasing the amount of blood shunted via a septal defect.
• Uncontrolled haemorrhage: Though there is no human evidence, in animal studies NO had been shown to increase bleeding times.
• Existing methaemoglobinaemia: obviously, it will get worse.

Evidence
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. 
In summary:

• It is an effective pulmonary vasodilator. Nitric oxide decreases pulmonary artery pressure and pulmonary vascular resistance in a dose-dependent manner (Sim et al, 2010)
• It improves oxygenation in ARDS. Albert et al (2017) found that in ARDS patients with  FiO₂ around 80%, 20ppm of inhaled NO increased the PaO₂ by 39 mmHg on average.
• There does not appear to be a survival benefit. A good Cochrane analysis of the data for adults is available (up to 2010). The analysed trials, with a total of 1303 participants, demonstrated no benefit in mortality, and a statistically insignificant benefit in the duration of ventilation and length of ICU stay. Oxygenation did improve, to be sure- but the effect was only significant in the first 24 hours of therapy. A 2016 Cochrane review by Gebistorf et al  reappraised the data for iNO in ARDS and concluded that the evidence was "insufficient to support INO in any category of critically ill patients". The same study found that nitric oxide caused an apparent increase in the risk of renal failure (RR was ~ 1.59).
• However, many of the older trials on this application of nitric oxide were performed in the bad old days, before the advent of lung-protective ventilation.
• Addiitonally, in the neonatal and paediatric population there is some evidence of mortality benefit. Bronicki et al (2015) and Dowell et al (2017) found improved outomes in these groups.

Other applications

• Haemolysis: free haemoglobin liberated by haemolysis consumes NO, which leads to vasoconstriction. Inhaling NO converts some of this free haemoglobin to methaemoglobin, whcih prevents it from depleting systemic NO reserves. This has implications for patients expected to undergo massive haemolysis, eg. those who are undergoing cardiopulmonary bypass. Lei et al (2018) were able to demonstrate a marked improvement in the rates of renal failure (from 63% to 50%) among post-cardiac surgical patients receiving inhaled nitric oxide.
• Post-cardiac surgery pulmonary hypertension: There are several scenarios when one might need to decrease the RV afterload in post-op cardiac surgical patients, and in these scenarios iNO is at least as effective as inhaled prostacycline (McGinn et al, 2015).
• Sickle cell disease: the use of iNO in these patients has only ever improved symptoms of painful vascular crisis in the setting of case reports; a single trial of using iNO via nasal prongs did not demonstrate much improvement in symptoms (Gladwin et al, 2011)
• Cerebral malaria: iNO is supposed to decrease cerebral vasoconstriction and preserve the integrity of the blood brain barrier, but it does not seem to have much of an effect on the outcomes in this disease (Hawkes et al, 2015)

Inhaled epoprostenol (prostacyclin) in ARDS

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".