Failed experimental therapies for ARDS

High dose corticosteroids in ARDS

The excitement about using of corticosteroid use in ARDS was based on the idea that the pathology was so very inflammatory that surely anti-inflammatory agents would have some sort of beneficial effect.

Indeed, some endotoxin-damaged pigs faired rather well when treated with high dose methylprednisone, which led the early authors to call for human trials. However, that same year, a study of 81 ARDS patients which randomised half to high dose steroids did not demonstrate any benefit (and suggested that there may be an increase in infectious complications).

Subsequent attention became directed at the dreaded "fibroproloferative response" stage of ARDS. The argument is that corticosteroids increase the degradation of fibroblast collagen mRNA, and thus decrease the rate of collagen deposition in this final stage, decreasing the degree of fibrosis which ultimately cripples the respiratory function of these people.

However, randomised control trials trashed steroids again, with good evidence of harm rather than benefit. Not only did the methylprednisone group have increased mortality (29% vs 26%) - they were also weaker when they died, with (predictably) greater incidence of muscular weakness.

In spite of discouraging data, the debate continued. Perhaps the doses of steroids were simply too high, and the toxicity outstripped the useful effects? In coming years the pendulum of intensivist opinion began to swing back in favour of steroids. In 2009, Australia's own Ian Seppelt and Tony McLean joined several other critical care luminaries in a meta-analysis and review of the evidence behind the use of low dose steroids in ARDS. Admitting some heterogeneity, the authors were forced to conclude that there might be some mortality benefit (a relative risk of 0.62)- but cautioned that there are too few studies to make a convincing argument. Another article by Lamontagne's group analysed 12 trials, with a pooled N=966. Their conclusions were - again- that the evidence pool is too shallow. But, they did admit to finding a small decrease in all-cause mortality in the group who received the lowest doses, supporting the idea that maybe some sort of homeopathic corticosteroid dose is actually beneficial.

The debate continues. The most recent analysis of this appears to be Meduri et al (2016), with the excellent editorial by Bihari et al.  The study re-analysed individual patient outcomes from several studies to determine whether a longer course of lower dose steroids might be of any use. These data are discussed in greater detail in the chapter about the adjunctive management of ARDS, because this chapter is all about "failed therapies", and low dose steroids seem to work (at least according to Meduri et al). 

Ketoconazole in ARDS

Ketoconazole has been shown to have numerous non-fungus-related effects, which one would never guess at- for instance, it is an anti-androgen which blocks testosterone biosynthesis; it is also an androgen receptor blocker. This has resulted in its widespread use in the treatment of androgenic alopecia.

What ahs this got to do with ARDS, you might rightly ask. Well. The interest in this azole antifungal drug as a treatment for ARDS arose as a result of research which has demonstrated its tendency to act as an anti-inflammatory drug. The initial studies demonstrated that it was even superior to hydrocortisone (albeit, in the very limited arena of preventing UV-induced skin erythema in humans).

The mechanism for this seems to be the inhibition of 5-lipoxygenase , which (as of course everybody immediately remembers) is the other metabolic pathway for arachidonic acid. 5-lipoxygenase is responsible for the conversion of arachidonic acid into leukotrienes, whereas cyclo-oxygenase is responsible for its conversion into prostaglandins, prostacyclin and thromboxanes. And on top of that, ketoconazole seems to also affect the synthesis of thromboxane, by inhibiting thromboxane synthase.

The intensivist’s interest in leukotrienes, and anything that can block their production, then becomes more obvious.  , Azole drugs (like ketoconazole and to a lesser extent itraconazole) uniquely decrease leukotriene production, whereas   NSAIDs do nothing for them.
Leukotrienes are potent neutrophil chemokines. One can imagine that to reduce their level in the ARDS lung might result in a decrease of inflammatory exudate; the fewer neutrophils arrive on scene, the less your lung looks like a warzone. 

In a 1993 trial of 53 surgical ICU patients with sepsis demonstrated that early ketoconazole prophylaxis was associated with a marked decrease in the incidence of ARDS (from 64% to 15%). What sort of surgical ICU this was, where over half of the septic patients progress to ARDS, one cannot imagine. That notwithstanding, these results were encouraging, even though the length of ICU stay or duration of ventilation did not decrease in these people.

Then came disappointment. Well designed multicenter studies associated with the ARDS Network have so far failed to produce earthshattering results; not only that, but some have been stopped halfway by the Data and Safety Monitoring Board when it became abundantly clear that there was no positive effect.  They even measured serum ketoconazole levels – in spite of excessively high levels, no benefit to mortality (or oxygenation for that matter) was demonstrated.

In short, for ARDS, one cannot recommend ketoconazole with a straight face. This issue has been buried since at least 2001. But, as a champion of unusual substances, I would welcome the return of ketoconazole, if it ever wins favour from the Gods of Empirical Evidence.

Surfactant supplementation

The theory that a loss of alveolar surfactant is responsible for much of the horror in ARDS has been drawn largely from our knowledge of pre-term neonatal IRDS, where surfactant is genuinely lacking. This group has been treated since the  1980s with exogenous surfactants, with some considerable success.  Why not adults, one might ask? Why don’t the ARDS adult patients get some of this stuff nebulized?

What is that stuff, anyway? Normal human surfactant is a lipoprotein molecule, which contains the beautifully named lipid component dipalmitoylphosphatidylcholine. It is synthesized from phosphatidylcholine by alveolar cells. In the extra-alveolar world, clever scientists can cook up some of this stuff de novo. In the dark ages of molecular chemistry, synthesis was not an option, and some of the first infants to be treated with exogenous surfactant had to get their dose in a more macabre fashion. One has the choice of either lavaging the respiratory tracts of several cows, or draining the juice of minced pig lung.

But I digress. The interest in using this material for adults arose in 1987, when a case report was published detailing the rescue by surfactant of a drowned child with ARDS. Amazing improvement of gas exchange was reported. Interest was peaked around the world, and a flurry of trials followed. However, it seems the effect remains limited to children. An erudite meta-analysis of these trials, performed with the benefit of retrospect (2012), was forced to conclude that none of the adult studies really showed any sort of improvement, in mortality or in oxygenation.

To be fair, many of these studies pre-date the ARMA trial, and recall the era when intensivists were torturing their ARDS patients with cruel and ridiculous tidal volumes. Who knows, perhaps in the future, more enlightened ventilation strategies will unearth some sort of treatment effect in adults. But it seems unlikely.  The children, they die of respiratory failure and hypoxia, whereas adults with ARDS tend to die from multiorgan system failure. Pulmonary surfactant alone is unlikely to prevent MOSF, and this may be behind is tragic failure to improve mortality in adults.

Immunomodulatory nutrition for ARDS patients

The use of a patented immunomodulatory enteral formula in ARDS has certainly been a topic of great interest. A 1999 trial by Gadek et al and a 2003 study had found enough benefit in it that it has subsequently made its appearance as a Grade B recommendation in the 2006 iteration of the ESPEN guidelines for enteral nutrition.

Essentially, Omega-3 fatty acids and antioxidants were fed to these patients, and their lungs were lavaged every 3 days to evaluate the protein content, neutrophil count and cytokine levels. Not only did those decrease, but the investigators found an improvement in gas exchange after 4 days. However, treatment effect had diminished considerably after intention-to-treat analysis. In spite of the lukewarm endorsement by ESPEN and ASPEN, this practice has been met with some scepticism by the intensive care community, and more recent attempts to reproduce Gadek's results have actually suggested that there may be some harm in using excessive amounts of fish oil as a nutritional supplement.

In summary, fish oil for ARDS patients cannot be recommended with a straight face.

Experimental treatments in the pipeline

This is bat country. There has been a massive plethora of treatments suggested as "helpful adjuncts" for ARDS, which range from Vitamin C to activated Protein C. Numerous substances have been suggested, with fair-sounding rationale for their application. Here is a list. These adventurous treatments receive an excellent airing in a delightful review article, which is sadly trapped behind a paywall. I will only discuss these in brief.

• Ace inhibitors and Angiotensin Receptor Blockers

  • These (if anything) appear largely preventative. A retrospective analysis of 1553 ICU patients demonstrated that the chronically ACE-inhibited population were less likely to develop ARDS (or, depending on how you interpret their results, that those patients who did devlop ARDS ended up with less severe ARDS).

• Tetracyclines derivatives

  • Not your bog-standard teracyclines, but specially modified versions thereof, have been used to treat anaesthetised Yorkshire swine with ARDS. The specific substance is called incyclinide, and the cause of ARDS was clamp-induced mesenteric ischaemia. The swine did very well, even the severity of their septic shock was ablated somewhat.

• Thiazolidinediones (glitazones)- particularly rosiglitazone

  • These drugs are Peroxisome Proliferator Activated Receptor-Gamma(PPARγ) agonists, which normally find their use in the management of diabetes. Apart from doing good antihyperglycaemic work, these drugs also happen to decrease the synthesis of cytokines by inhibiting a leucocyte transcription factor, NF-kB. Thus far, only rats with pancreatitis have ben rescued from ARDS with rosiglitazone.

• Beta-2 adrenoceptor agonists

  • Rather than using them for their bronchodilating properties, one may throw beta-2 agonists at ARDS in order to improve the rate of fluid removal from the alveoli. The idea is to increase the activity of alveolar Na⁺/K⁺ ATPAse, thus increasing the net water movement (out of the alveolus and into the cells). This notion was explored in an RCT from 2006, which even merited an acronym (BALTI-1). PiCCO was used to calculate extravascular lung water - and indeed it did decrease with salbutamol, though this decrease did not translate into improved oxygenation, nor a mortality benefit. Encouraged, the investigators went on to stage BALTI-2, which imploded completely and had to be stopped because salbutamol was killing people. In fact, the mortality increase was substantial, from 23% to 34%.

• Antioxidants

  • Enteral omega-3 fatty acids (the OMEGA trial) were tested by the ARDSNet people - neither harm nor benefit were found, and the investigators blamed this on insufficient duration of therapy (only 12 hours). Thus far, nobody has taken a lot of notice of this modality. N-acetylcysteine, Vitamin C and Vitamin E have all been tested, with similarly disappointing results.

• HMG-CoA reductase inhibitors (statins)

  • There might be some animal evidence that statins decrease the degree of vascular "leakyness" and have some positive effect on inflammation. Retrospectively, small cohorts of patients on statins give the appearance of having less severe ARDS. A trial of statins in H1N1 ARDS patients broke down when the H1N1 epidemic subsided; another has commenced and is presently recruiting participants.

• Cytokine inhibitors

  • Both direct inhibitors and various targetted monoclonal antibodies have been investigated, without much success. One recalls the ARDSNet-driven LARMA trial, which was ceased in view of futility.

• Recombinant human platelet activating factor (PAF) acetylhydrolase

  • PAF is fiercely proinflammatory, and so it stands to reason that in ARDS we should be inhibiting it each chance we get. Thankfully, somebody has produce epafipase, a recombinant form of the enzyme which normally degrades PAF. Unlike a lot of the abovementioned alchemy, this one has made it to a Phase II clinical trial. Sadly, though it did improve mortality from sepsis (by half!), it didnt do much for ARDS per se. One can envision that the future of this substance may be in line with the history of activated protein C, though hopefully less expensively broken.

One could persist with listing failed pharmacotherapy for ARDS, but there are far too many.

In short, they just don't work.