Supportive non-ventilation strategies for ARDS

ARDS is a favourite topic of CICM examiners. The following past paper SAQs involve the ventilation of ARDS:

• Question 21 from the first paper of 2016 (use of paralysis)
• Question 20 from the second paper of 2014
• Question 13 from the first  paper of 2011
• Question 4 from the first  paper of 2009
• Question 4 from the first paper of 2008

For the majority of these, the college asked a broad question along the lines of "how'd you ventilate that?" Adjunctive non-ventilator management strategies have never really enjoyed much attention because everybody is all focused on driving pressure and the selection of an optimum PEEP.  However, management of ARDS is not all flashy physiology and pressure-volume circus tricks. There are numerous supportive strategies which help the ARDS patient, working quietly in the background. 

In brief summary, these are the non-ventilator adjunctive therapies for ARDS:

A good but somewhat dated Thorax article by Cranshaw et al (2002) also digresses into the territory of some of the failed experimental strategies for ARDS. What do people actually do? Munshi et al (2017) performed an audit of over 500,000 patients to answer that question (turns out, more epoprostenol and ECMO is being used of late, with people still using neuromuscular junction blockers and nitric oxide like it's 1998).

Minimization of dead space ventilation in ARDS

When one hears it said that the hypercapnia is "permissive", and when people mention that it has no ill effects in the long run, one is left with the impression that everything is ok and we should just ignore the PCO₂. However, this is not the case; respiratory acidosis in ARDS is in fact far from desirable.

There are four major causes of hypercapnea in ARDS:

This has negative consequences. Your respiratory centres, bathed in such acidic body fluid, will produce a powerful urge to breathe. This is counterproductive, as the whole ventilation strategy revolves around breathing less, not more. The consequences of this are escalating sedation requirements.

Not only that, but increased alveolar CO₂ decreases the concentration of other gases, most notably oxygen - so your FiO₂, fresh and pure at the ventilator valve, may be diluted by the time it gets to the business end of the endotracheal tube.

So, how does one defeat these causes of hypercapnia? First of all, you can't do much about the low tidal volumes. Those are a priority.  Furthermore, you can't do much about the respiratory rate (the minute volume needs to stay within a reasonable range). And usually you won't be able to adjust the I:E ratio to improve expiratory time because this will sacrifice oxygenation (by decreasing inspiratory time). However, you can prune away the plastic dead space.

1) Remove the heat-moisture exchanger, and replace it with a humidifier.

This move can save you about 10-20ml of dead space; it seems to result in a small but statistically significant reduction in PaCO₂, about 5mmHg. Several authors have concluded that it is a safe and cost-effective technique for decreasing hypercapnia in ARDS.

2) Get rid of as much ventilator tubing as you can.

This can also save you about 30ml of dead space, and decrease your PaCO₂ by about 6mmHg on average.

3) Use ASPIDS

This is a slightly fancier technique involving aspirating tracheobronchial gas and then flushing the circuit with fresh gas at the end of expiration. It seems to work very well, decreasing PaCO₂ by up to 40% even at a respiratory rate of 60 breath per minute (at least in healthy Swedish pigs). However, this may require you to purchase a ventilator pimped out with the appropriate gear.

Now, how to decrease the rate of CO₂ production in the patient? This is a question of energy supply and energy demand.

Adjusting nutrition to satisfy requirements while decreasing CO₂ production

Being affected by ARDS is hard work. Its certainly an interesting weight loss strategy. The inflammatory response results in a greatly increased rate of metabolism. And, because (conventionally) most human metabolism is aerobic, this results in a corresponding increase in CO₂ production. One study from the 90s suggests that hypermetabolism-related CO₂ excess accounts for about 50% of the increased ventilation demands in ARDS patients.

So, how to overcome this problem? On one hand, these people need optimal nutrition. On the other, we cant let them turn into churning CO₂ factories. 

Well, the first step is not to OVER-feed them. There is at least one case report of hypercapnea being exacerbated by hypercaloric feeding. As for using those enteral nutrition formulae which have increased ratio of fat, hoping to decrease CO₂ production by limiting carbohydrate intake... The scientific foundation of this has been discussed elsewhere. The empirical evidence in support of this practice is far from solid.

Somehow, much greater attention has been directed at feeding ARDS patients some sort of immunomodulatory cocktail, hoping to modify the inflammatory process and to decrease the oxidative damage in the lung.

Neuromuscular blockade for ARDS patients

The use of neuromuscular junction blockers in ARDS is a pretty standard response to poor lung compliance. This was asked about in Question 21 from the first paper of 2016, as a "critically evaluate" question, and is therefore subjected to the usual treatment.

Rationale for the use of neuromuscular blockade in ARDS

• Improve chest wall compliance: The lung compliance is already poor enough; removing chest wall compliance from the equation helps to prevent absurdly high peak pressures
• Improved patient-ventilator synchrony: Many of these patients end up ventilated with such perverse pressure/volume combinations that without paralysis there would be a constant and counterproductive battle of patient versus ventilator. True, this is something one could achieve with haemodynamically disastrous doses of sedation, but ... why would you?
• Recruitment manoeuvres  generally require paralysis for the abovementioned reasons; if the patient tries to exhale or cough during one of these manoeuvres, a pneumothorax may occur. In the post-ART era, you won't be doing those anyway.
• Prone ventilation usually requires paralysis
• Decrease skeletal muscle metabolism: this is a hidden benefit, which is frequently overlooked. Neuromuscular blockade prevents the skeletal muscle from performing anything but the very barest baseline of metabolic work; the ATP production in the muscle fibres drops to whatever is required to maintain ionic concentration gradients. This decreases the oxygen extraction ratio for a large percentage of your patients tissues. Oxygenated blood, formerly directed into muscles, is redistributed into splanchnic vascular beds. Indeed, in a study performed on ICU patients with respiratory failure, the oxygen extraction ratio was found to by decrease by 5% (from 36% to 31%).
• Improved assessment of respiratory mechanics: without the interference of respiratory muscles, the lung compliance can be assessed more correctly, and the pressure-volume loops are more meaningful

Disadvantages of a sustained neuromuscular blockade

• This strategy is contrary to the normal strategy of ventilating patients with the most spontaneous mode possible, to preserve their muscle strength and to increase their comfort.
• Longer duration of ventilation and longer ICU stay (Arroliga et al, 2005)
• Increased risk of critical illness polyneuromyopathy
• Increased risk of pressure areas
• Increased risk of DVTs
• Accumulation of paralytic agents (unless you use something like cisatracurium)
• Risk of paralysed awareness
• Increased nursing care

Interestingly, it seems there is some evidence that it matters which muscle relaxant you use. Specifically, it appears that the steroidal agents (any "(x)curonium", including rocuronium vecuronium and pancuronium) are to blame for higher rates of critical illness polyneuromyopathy. The data we have to support this assertion is not super-robust, but the tendency to use the "(x)-curium" group of substances is now a well-established ICU trope, extending beyond their advantages as drugs which degrade spontaneously without requiring organ metabolism. One example of this from the literature is the rat study by Testelmans et al (2007) which discovered that diaphragm muscle tends to become weaker with the sustained use of rocuronium, as compared to cisatracurium. Human data is also available, in the form of studies like Murray et al (1995) which compared doxacurium (an ancient relative of mivacurium) and pancuronium. 

Evidence for the efficacy of neuromuscular blockade in ARDS

• Blanch et al, 2015 - a prospective study which observed that ventilator asynchrony is associated with a higher in-hospital mortality. This study does not specifically recommend neuromuscular blockade as a means of controlling asynchrony- one has many other ways of dealing with asynchrony - but in the ARDS patient, NMJ blockers would be the natural response to asynchrony.
• Papazian et al, 2010 -  a 48 hour course of cisatracurium early in the progress of severe ARDS. The authors found a 10% absolute risk reduction of 90-day mortality (31.6% vs 40.7%) associated with the use of neuromuscular blockade, without any increase in the risk of ICU-acquired weakness.  This would place cisatracurium in the rare category of things which have been supported by positive trials, alongside low tidal volume ventilation and low delta-P.  Unfortunately, as the college mention in their answer to Question 21 from the first paper of 2016, the study has several weak points:
  • Papazian et al only enrolled 25% of the eligible patients. 10% of patients excluded due to 'other reason', whatever that means.
  • 21% of the patients had PA catheters, which is totally contrary to modern Australian practice
  • 30% of the patients received nitric oxide, which has since fallen into disuse.
  • Papazian et al used a surprisingly low PEEP, around 9 cmH₂O on average.
  • The groups differed in their use of steroids (39% in treatment arm, 45% in placebo)
  • The mortality from ARDS was much lower than predicted, which underpowered the study.
• "Early neuromuscular blockade in the acute respiratory distress syndrome" study (NEJM 2019) was much larger than the Papazian trial, using more modern PEEP levels, and a more robust methodology overall. They found no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets.

Deep sedation for ARDS patients

There are several advantages to using deep sedation in ARDS, most of which can be summed up as "it lets us do whatever we want". 

• It allows the use of neuromuscular junction blockers. Once you start using neuromuscular blockers, you are sort of obliged to sedate the patients heavily. It would not do to add PTSD to their already harrowing experience of the ICU, by allowing them to experience everything from inside a motionlessly unresponsive body.
• It decreases patient-ventilator dyssynchrony, which can wreck your careful ventilation strategy
• It decreases cardiac output requirements (respiratory workload is shouldered by the ventilator)
• It improves tolerance of low tidal volume ventilation.
• It improves tolerance of prone ventilation
• In the same way as neuromuscular blockade decreases the oxygen extraction ratio, so sedation decreases whole body oxygen demand (particularly in patients who aren't paralysed).

 The following consequences of deep sedation are non-beneficial:

• Decreased cough - clearance of secretions basically depends on postural drainage and suction, which are not ideal (for example, suction is generally eschewed in ARDS because it can generate a negative pressure in the respiratory circuit, thereby cauysing de-recruitment)
• Consequences of prolonged immobility will develop, including diaphragmatic dysfunction (though one might argue that a patient with ARDS is staying in bed for a long time, no matter what is being done with their sedation).
• Suppression of spontaneous breathing may actually be a disadvantage in ARDS, because diaphragmatic contraction can improve the ventilation of dependent lung. As dependent lung ends up being the most consolidated in ARDS, one could make the argument that spontaneous ventilation is beneficial in terms of

The latter point, that spontaneous ventilation is somehow beneficial in ARDS, is a contentious topic. Some studies looking at retrospective data (eg. Goligher et al, 2017) have demonstrated some mortality difference associated with spontaneous ventilation. ARDS patients who are well enough to merit a break from paralysis obviously end up breathing spontaneously and of course their outcomes are better (for reasons perhaps unrelated to the spontaneous mode of ventilation). For severe ARDS, mandatory modes and deep sedation still appear to be the standard of care.

Thus, one might conclude that sedation in ARDS is a good thing. As always, use in moderation.

Fluid management in ARDS

Keep them dry. Yes, of course, the disorder is by definition not related to fluid overload or heart failure, but the capillary permeability is high. With such permeable capillaries, a lower hydrostatic pressure is required to push fluid out into the interstitium. Thus, one would not wish to be cavalier with one's fluid management in these people.

This is supported by at least one trial. The ARDSNet people (FACTT trial, NEJM, 2006) compared two fluid management strategies in a thousand ARDS patients. One group got flooded, the other got dried. And on the seventh day, the difference between them was almost exactly 7000ml.  The patients randomised to a "conservative" fluid strategy had less ventilated days and better gas exchange, though hard outcomes remained the same (60-day mortality was 25.5% in the dry group, versus 28.4% in the wet). However, the trial had some crippling weirdness about it, which limits its applicability to ICU in Australia.

It was an odd design. Fluid management was guided by CVP measurements. The "liberal" group targeted a CVP over 10-14mmHg, and the "conservative" group targeted a CVP under 10mmHg. So naturally the "liberal" group was about 7 litres positive at the end. This could be because in the protocol, the "liberal" patients with good urine output cardiac index and MAP still ended up getting a fluid bolus if the CVP dropped below 10mmHg.

Surely, this is bizarre fluid management. On one hand, the principle is probably sound. So perhaps the CVP is not a very good parameter to hang your fluid management on, but the use of PiCCO to watch over the extravascular lung water seems to be associated with a more intelligent fluid resuscitation strategy in severe sepsis, and with less progression to ARDS. On the other hand, these patients with a seven litre positive balance: if the extra water is so bad, how come they aren't dead?  Also, excessive drying can lead to a volume-depleted state which accentuates shunt and leads to haemodynamic instability with the sort of high PEEP and high driving pressures required for this group. In early septic shock complicated by ARDS, patients whose fluid resuscitation is conservative often appear to have paradoxically increased mortality, at least upon inspection of retrospective data (Murphy et al, 2009).

There's virtually no evidence and minimal sensible opinion out there to guide you. Overall, the prevailing opinion is that one ought to aim for a goal of neutral fluid balance, and fluid resuscitation should be guided by sophisticated haemodynamic monitoring. This clever-sounding assertion is based on virtually nothing. Even highly paid medical experts seem to come up short.  Springer's Acute Respiratory Distress Syndrome (2017) contains within it a (paywalled) chapter on fluid management by Hanidzar & Bittner (p.113) which is so generic that it may as well consist of blank paper. "Fluid management in ARDS continues to be a source of great controversy", they conclude; much discussion takes place of well-trodden fluid management assessments like passive leg raises and IVC ultrasonography. The authors make recommendations like "maintaining the mean arterial pressure above the lower autoregulatory threshold for perfusion of the most vulnerable organs (heart, brain, kidneys) is essential."

A slightly more scientific approach was taken by Silversides et al (2017) in a meta-analysis of RCT evidence, comparing liberal and conservative fluid resuscitation strategies. No effect on mortality was noticed; or rather, no studies looked at 90-day mortality.  However, a conservative of "de-resuscitation" strategy resulted in fewer days of ventilation and shorter ICU stay. The average dry ARDS patient spent 10 days (vs. 12 days) ventilated, and got out of ICU 2 days sooner. Some authors even reported an association between lower mortality and diuretic dose. "The majority of studies did not attempt to use specific physiological or time criteria to determine readiness for conservative fluid management or deresuscitation", the authors complain. All that can be said is that among those who make an effort to limit fluid overload, that effort is made somewhere between the first and the fourth day after randomisation. 

So, what is the CICM exam candidate to write in the response to the inevitable future SAQ on fluid management in ARDS? One would have to hedge in some way. One's question may be getting marked by a "dry" examiner or a "wet" one, but the answer should ideally pleasure both of them equally.  The following gibberish has self-assembled spontaneously after the author digested an unregulated quantity of coffee and literature:

• Evidence for fluid management in ARDS is of poor quality, but appears to support a conservative strategy, which is associated with:
  • No change in mortality (Silversides et al, 2017)
  • No change in the risk of AKI (FACTT trial, 2006)
  • Decreased length of ICU stay and shorter duration of ventilation (Silversides et al, 2017)
• In early and severe ARDS fluid resuscitation should aim to counteract the haemodynamic consequence of ventilation with high positive pressure
• With resolution of the acute phase of ARDS, a negative fluid balance should be aggressively pursued to accelerate ventilator weaning.
• The transition between resuscitation and de-resuscitation should be guided by a multimodal assessment of haemodynamic and respiratory performance

Corticosteroids for ARDS

The rationale for 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. An excellent 2023 review by Kuperminc et al is worth reading before the CICM exams. One might summarise it like so:

• ARDS is a largely inflammatory condition, and so logically immunomodulation may help, like it probably helps in severe sepsis.
• There may be hyperinflammatory phenotypes in which it helps the most (although we are somewhat distant from a time when we can confidently offer personalised phenotype-specific treatment)
• This condition also has a late "fibroproloferative response" stage. 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.
• There are promising animal models: some endotoxin-damaged pigs faired rather well when treated with high dose methylprednisone, which led the early authors to call for human trials.

Evidence for high dose steroids is conflicted. An early 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). However, DEXA-ARDS (2020) blasted their patients with 20mg of dexamethasone for 5 days, and then 10mg for another 5 days, with a markedly improved number ventilator-free days (12.3 vs 7.5) and mortality (21% vs 36%) in the treatment group.

Evidence for low dose steroids late in the disease process is unsupportive. When ARDSNET people gave 0.5mg/kg of methylpred in an RCT with n=180, there was no mortality benefit; and when the steroids were given very late (after 14 days) the methylprednisone group had increased mortality (29% vs 26%) and a predictably greater incidence of muscular weakness.

Evidence for low dose steroids in early ARDS is cautiously optimistic.  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. Meduri et al (2016) also analysed some trials which were largely giving 1-2mg/kg of methylprednisolone, and it looked like mortality improved by 13% (from 33% to 20%) and the patients had fewer days of ICU stay and a shorter period of ventilation. However, there were a few problems with this meta-analysis. Of the total number of patients analysed, 56% came from one trial, which actually didn't find any benefit from steroids. Many of the studies were not using lung-protective volumes, i.e. they were not representative of modern standards.

Evidence for moderate dose steroids in other respiratory disease is very supportive. Pneumonia, particularly severe pneumonia with very high inflammatory markers, seems to benefit from solid doses of prednisone (Blum et al, 2015;  Torres et al, 2015; and of course CAPE COD, 2023). To say nothing for extremely good effect from rather high doses of dexamethasone in COVID19 ( RECOVERY trial, in 2020, demonstrated a mortality improvement from 40.7% to 29% in ventilated patients).

International society guidelines are in disagreement. On the basis of all these conflicting data, we (the scientific community "we") remain divided on whether steroids should be offered to ARDS patient, or when. Of the international ARDS guidelines, only the 2022 Japanese guidelines are currently supportive of the use of steroids (for seven days, in early ARDS, and using only 1-2mg/kg/day of methylpred).  The old 2017 SCCM/ESICM guidelines were fairly very pro-steroids ("We suggest use of corticosteroids in patients with early moderate to severe acute respiratory distress syndrome"). They suggested starting within 72 hours, and giving 1mg/kg of methylprednisolone. In contrast, the British FICM guidelines (2018) sat on the fence; "the group believed that a position of equipoise exists", more research is required, etc. This attitude had subsequently crossed the channel, as the 2023 ESICM guidelines don't even mention anything about steroids.

What do the CICM examiners think? Difficult to say. Question 22 from the first paper of 2008 was the last time these depths were explored in the Part II exam. No opinion or summary statement was offered, only one-liners about the published studies. Since then, much more material has been published, including the abovementioned meta-analysis and all the various guidelines. However, no new advice has been issued, and it is unclear which way the prevailing winds are blowing. If one had to make a safe summary statement about the use of steroids in ARDS, one would be forced to say that they cannot be recommended for routine use because the current evidence in support of this practice is weak and conflicted. However, steroids are still indicated for some selected conditions (eosinophilic pneumonitis, PJP, etc) which also happen to cause ARDS.