Apart from fancy ventilation strategies and cheating with pulmonary vasodilators, there are some pharmacological agents which are thought to be helpful in ARDS.Though the evidence for them is weak, there is some argument that many of the trials were perfomed prior to the era of low tidal volume ventilation, and that in this new enlightened age some sort of previously obscured subtle mortality benefit might surface.
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 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.
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.
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.
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.
One could persist with listing failed pharmacotherapy for ARDS, but there are far too many.
In short, they just don't work.
Burnham, Ellen L., et al. "The Fibroproliferative Response in ARDS: Mechanisms and Clinical Significance." European Respiratory Journal (2013).
Borg, T., B. Gerdin, and J. Modig. "Prophylactic and Delayed Treatment with High‐Dose Methylprednisolone in a Porcine Model of Early ARDS Induced by Endotoxaemia." Acta anaesthesiologica scandinavica 29.8 (1985): 831-845.
Weigelt, John A., et al. "Early steroid therapy for respiratory failure." Archives of Surgery 120.5 (1985): 536.
Steinberg, K. P., et al. "Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome." New England Journal of Medicine354.16 (2006): 1671-1684.
Tang, Benjamin MP, et al. "Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis*."Critical care medicine 37.5 (2009): 1594-1603.
Belvitch, Patrick, and Steven M. Dudek. "Corticosteroids and Acute Respiratory Distress Syndrome: The Debate Continues*." Critical Care Medicine 41.7 (2013): 1813-1814.
Witjes, Fred J., et al. "Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer." Urology 33.5 (1989): 411-415.
Rosen, Ted, Barbara J. Schell, and Ida Orengo. "Anti‐inflammatory activity of antifungal preparations." International journal of dermatology 36.10 (1997): 788-792.
Pierard-Franchimont, C., et al. "Ketoconazole shampoo: effect of long-term use in androgenic alopecia." Dermatology 196.4 (1998): 474-477.
Yu, Mihae, and GRACE TOMASA. "A double-blind, prospective, randomized trial of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome." Critical care medicine 21.11 (1993): 1635-1641.
Beetens, J. R., et al. "Ketoconazole inhibits the biosynthesis of leukotrienes in vitro and in vivo." Biochemical pharmacology 35.6 (1986): 883-891.
Cranshaw, J., M. Griffiths, and T. Evans. "The pulmonary physician in critical care c 9: Non-ventilatory strategies in ARDS." Thorax 57.9 (2002): 823.
Network TA. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network. JAMA 2000;283:1995–2002.
Kesecioglu, J., and M. M. J. van Eijk. "Surfactant therapy in acute lung injury/acute respiratory distress syndrome." (2012).
Tomoi, Masao, et al. "Polymer-Supported Bases. 10. Synthesis of Phosphatidylcholines Using Polymer-Supported or Free Acylimidazoles." Synthetic Communications 19.5-6 (1989): 907-915.
Lachmann, B. "The role of pulmonary surfactant in the pathogenesis and therapy of ARDS." Update 1987. Springer Berlin Heidelberg, 1987. 123-134.
Bosma, Karen J., Ravi Taneja, and James F. Lewis. "Pharmacotherapy for prevention and treatment of acute respiratory distress syndrome." Drugs 70.10 (2010): 1255-1282.
Trillo, C. A., et al. "Chronic Use of Angiotensin Pathway Inhibitors Is Associated with a Decreased Risk of Acute Respiratory Distress Syndrome." Am J Respir Crit Care Med 179 (2009): A4638.
Chen, Chen, et al. "Rosiglitazone attenuates the severity of sodium taurocholate-induced acute pancreatitis and pancreatitis-associated lung injury." Archives of medical research 40.2 (2009): 79-88.
Roy, Shreyas K., et al. "Chemically Modified Tetracycline 3 Prevents Acute Respiratory Distress Syndrome in a Porcine Model of Sepsis+ Ischemia/Reperfusion–Induced Lung Injury." Shock 37.4 (2012): 424-432.
Schuster, Daniel P., et al. "Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial*." Critical care medicine 31.6 (2003): 1612-1619.
Perkins, Gavin D., et al. "Beta Agonist Lung Injury TrIal-2 (BALTI-2) trial protocol: A randomised, double-blind, placebo-controlled of intravenous infusion of salbutamol in the acute respiratory distress syndrome." Trials 12.1 (2011): 113.
Smith, Fang Gao, et al. "Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial." The Lancet 379.9812 (2012): 229-235.
Sabater, Joan, et al. "Effects on hemodynamics and gas exchange of omega-3 fatty acid-enriched lipid emulsion in acute respiratory distress syndrome (ARDS): a prospective, randomized, double-blind, parallel group study." Lipids Health Dis 7 (2008): 39.
The ARDS Clinical Trials Network; National Heart, Lung and Blood Institute; National Institutes of Health. Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med. 2002; 30(1):1-6).