Question 21

College Answer

Rationale & Theoretical Benefits

• In general will reduce O₂ consumption & CO₂ production
• Avoids patient ventilator dys-synchrony
• Allows evaluation of respiratory mechanics
• Generally required to perform a recruitment manoeuvre
• In patients with pronounced spontaneous respiratory effort:
  • They may draw large spontaneous tidal volumes well in excess of appropriate ARDSnet values (pulmonary stress)
  • They may generate large spontaneous negative trans-pulmonary pressures during controlled breaths (pulmonary strain)
  • Spontaneous respiratory activity is difficult to otherwise supress (with sedation only), particularly in the setting of permissive hypercapnia
• Observationally improves oxygenation in the short term
• May reduce cytokine release and biotrauma
• Facilitates prone positioning

Theoretical Problems

• Contradicts strategies of maintaining spontaneous efforts and respiratory muscle strength.
• May unmask poor compliance in patients who were generating very negative inspiratory pressures while breathing spontaneously, with consequent difficulties maintaining adequate tidal volume.
• Potential for awareness during paralysis
• Risks of ‘Critical Illness Weakness’ associated with use of NMBA. 
• Risks of accumulation of NMBA drug in critical illness. 
• Increased risk of positive fluid balance and thromboembolic risks.

Practical Issues

• Timing / duration of paralysis not known – Papazian used 48 hr
• Which NMB – non-steroid based may be better for reducing risk of weakness (Papazian used cisatracurium)
• Train of four monitoring needed

Best Evidence                                                                                                         

• Single French RCT (Papazian, NEnglJM Sept 2010) 
• Severe ARDS, P/F < 150
• Showed mortality improvement at 90 days with paralysis for 48 hrs in early severe ARDS hours (hazard ratio for death 0.68).  No increase in weakness.
• Evidence for improved oxygenation beyond period of paralysis. 
• Criticisms:
  • 25% of eligible patients enrolled, limits external validity
  • study used low levels of PEEP (lower than the control of several high vs. low PEEP
  • trials)

Practice statement

Anything reasonable – for example:

I do not use NMBs routinely in severe ARDS but in selected patients e.g. those difficult to ventilate / oxygenate I use cistracurium infusion with train of four monitoring

Discussion

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.
• 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 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 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

Evidence for the efficacy of neuromuscular blockade in ARDS

• 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 places cisatracurium in the rare category of things which have been supported by positive trials.  Alongside low tidal volume ventilation and low delta-P, this is one of the strategies which can be strongly recommended. Unfortunately, as the college mention, 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 been thoroughly discredited in the literature and has fallen into disuse in Australia
  • 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.
• Blanch et al, 2015 - a prospective study which observed that ventilator asynchrony is associated with a higher in-hospital mortality.
• ROSE trial (2019), by the PETAL clinical trial network (lol), 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.

Papazian, Laurent, et al. "Neuromuscular blockers in early acute respiratory distress syndrome." N Engl J Med 363.12 (2010): 1107-1116.

Neto, Ary Serpa, et al. "Neuromuscular blocking agents in patients with acute respiratory distress syndrome: a summary of the current evidence from three randomized controlled trials." Annals of intensive care 2.1 (2012): 1-8.

National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. "Early neuromuscular blockade in the acute respiratory distress syndrome." New England Journal of Medicine 380.21 (2019): 1997-2008.