Sustained neuromuscular junction blockade in critical illness

This issue has yet to appear in any great detal in the CICM Part II. Question 21 from the first paper of 2016 asked about its use as a supportive strategey for ARDS, but that's about it. However, its one of those things the ICU trainee is expected to know about. If you're going to subject people to a perverse and unnatural therapy, you should know all about its advantages and disadvantages.

The primary sources of greatest utility for this brief summary included the following:

In brief:

Indications for NMJ blockade:

  • Mechanical ventilation:
    • To facilitate patient-ventilator synchrony
    • Use of very high, very low or inverse I:E ratios
    • Prone ventilation
    • Improvement of respiratory compliance
    • Tolerance of HFOV
    • Safety of ECMO
    • Evidence suggests that at least in ARDS mortality is improved by the use of NMJ blockade
  • Raised intracranial pressure:
    • Prevention of ICP-increasing noxious stimuli, such as cough.
    • Only boluses seem to be effective
    • Evidence suggests that sustained blockade is either useless or actually harmful.
  • Muscle spasm:
    • Tetanus
  • Decrease oxygen demand:
    • Shivering in hypothermia
    • Situations when oxygen supply is fixed and poor, eg. in severe ARDS
  • Decrease intra-abdominal pressure:
    • But not by much, maybe by 4mmHg

In detail:

Indications for sustained neuromuscular junction blockade

Unnatural mechanical ventilation

By this, one could mean a range of things. For instance, one could use neuromuscular junction blockade to facilitate patient-ventilator synchrony in situations when a profoundly unnatural pattern of ventilation is called for, particularly something involving unusual I:E ratios. Or, one might wish to ventilate the patient in a prone position. Alternatively, one might use paralysis to eliminate the contribution of thoracic and abdominal muscles to respiratory compliance, when the pulmonary compliance is poor (eg. in ARDS - discussed in greater detail in the chapter on non-ventilator supportive strategies for ARDS). Under extreme conditions, paralysis is required to allow the patient to withstand the nightmarish process of high frequency oscillatory ventilation, or to prevent them from accidentally dislodging their ECMO catheters.

Given that only the most severe respiratory disorders call for a ventilation strategy which might require NMJ blockade, it is not surprising that its use is associated with longer ventilation and increased mortality. But does it help in any way?

Perhaps. In one 2011 trial of 340 ARDS patients, the cisatracurium group performed better. The early use of NMJ blockers seemed to be associated with a decreased mortality (31.6% vs 40.7%), without any increase in the risk of ICU-acquired weakness. Similarly, among patients with sepsis a more recent (2014) retrospective cohort audit discovered a slight improvement of in-hospital mortality (from 31.9% to 38.3%).  Using reverse reasoning, to spare the NMJ blocker is to spoil the patient: a 2015 prospective study observed that ICU patients who are frivolously asychronous with their ventilator tend to have a higher in-hospital mortality. In contrast, Goligher et al (2017) found decreased mortality in ARDS patients who were breathing spontaneously, and the massive "Early neuromuscular blockade in the acute respiratory distress syndrome" study (NEJM 2019) found that there was 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.

Management of raised intracranial pressure

The utility of NMJ blockade in traumatic brain injury is classically attributed to the improvement in the precise control of minute ventilation (keeping the CO2 level at 25-40mmHg), and in the prevention of ICP-increasing reflex actions such as cough and strain of defaecation.

But then, one might argue that the respiratory drive and cough reflex (along with any response to any noxious stimuli whatsoever) could be ablated completely with a sufficiently large dose of opioid, eg. fentanyl. And who is going to be defaecating after several days of 200mcg/hr of fentanyl? Nobody. Therefore, some might contest the use of NMJ blockers for this indication. Others, in response, might contest the safety of such veterinary doses of fentanyl (dangerous, they daresay). The otherwise very useful Brain Trauma Foundation Guidelines are disappointingly vague in their recommendations, deferring meekly: "...the choice... should be left to the treating physician".

To resolve such conflict, one could turn to a good synopsis of (reasonably) contemporary evidence such as this 2014 meta-analysis from Neurocritical Care. In unsurprising concert with basic pharmacology, the data suggest that NMJ blockers have no intrinsic ICP-reducing effects; rather, selective boluses of the agent were effective in controlling an ICP increase due to procedures (eg. pressure area care or suctioning). In fact, the routine use of continuous NMJB infusion for all severe head injury patients was actually found to be harmful in one early 1994 study (ICU stay was prolonged, and there was an increased propensity to pneumonia, probably because of inability to cough).

More controversial reasons to use NMJB in traumatic brain injury do exist. For instance, if you have ignored or disagreed with the EUROTHERM results, you might still cosnider therapeutic hypothermia for TBI as an end-of-the-line solution, and will paralyse your hypothermic patients to prevent shivering. On an even wacker note, NMJBs may have some sort of antiinflammatory effect in the lung, and their use might decrease the "inflammatory cross-talk" between the lungs and brain, decreasing the cytokine-mediated disruption of the blood-brain barrier.

Management of muscle spasm

This is an interesting topic, as it relates to the management of severe muscle-damaging spasm arising from such prehistoric diseases as tetanus. Obviously controlling the spasm from status epilepticus is a purely cosmetic therapy, as it does nothing to protect the brain or treat the underlying problem, but an argument could be made for the use of NMJB in tetanus. This is very old-school (1980s). In those days, sustained NMJ blockade frequently had to be continued for 3-4 weeks, using gallamine which is probably an agent none of you young people have ever heard of. Other papers of the same vintage make mention of the more modern vecuroniumA more recent review from 2014 suggests that magnesium may be a better NMJ blocker in tetanus. The authors conclude that for mild cases, it may be effective as a sole agent.

Minimisation of oxygen consumption

Under certain circumstances, it may be beneficial to reduce the global bdy oxygen demand. Generaly speaking it is assumed that this happens anyway due to the action of NMJBs on the skeletal muscle, but very rarely does one actually prescribe paralysis for the explicit purpose of manipulating oxygen demand. Such a situation was presented in a 2014 case report, describing the use of hypothermia and paralysis to intentionally decrease the oxygen consumption of a critically anaemic Jehovah's Witness. She remained at 32° and paralysed for three days at a haemoglobin of 46. The authors of this case congratulated themselves when the tachycardia and oliguria resolved, taking this as a sign of improved O2 supply-demand matching. However, one should also acknowledge that the hypothermia itself has the effect of decreasing heart rate and increasing urine output. So do the neuromuscular junction blockers actually have any effect on total body oxygen demand?

Certainly, in the case of hypothermia they do. Shivering is known to increase oxygen consumption and carbon dioxide production in hypothermic patients- in fact, oxygen consumption may be doubled by shivering. To reason in reverse, the use of pancuronium in these post-bypass patients halved their oxugen demand.

Even in the absence of shivering, oxygen consumption is significantly reduced by NMJBs, both in foetal lamb and in human children. The figure in the paediatric study was about 8.7%. So, in conclusion, one would have to agree that if a situation calls for decreasing oxygen demand (rather than increasing supply), a neuromuscular junction blocker would be a good start.

Control of increased intra-abdominal pressure

The pressure in your post-laparotomy abdomen might be high for a great many reasons, not the least of which might be the effect of angry muscles spasming around the laparotomy wound. The Guidelines resulting from an international conference on this subject (2007) recommend the use of NMJ blockers for control of raised intra-abdominal pressure. Indeed one needs to actually paralyse the patient before one can measure it correctly.

In small scale trials, it certainly seems to be effective, but the magnitude of the effect is fairly small: it may decrease your IAP from 18mmHg to about 14mmHg. There may not be much change in the organ perfusion from such a modest improvement. Perhaps your IAP is 40mmHg; decreasing it to 36mmHg will do little to save the kidneys. At best, it buys some time while the surgeon is driving back to the hospital.

Agents used to sustain neuromuscular junction blockade

There is a vast armamentarium of NMJBs to choose from. In the ICU, however, the question is not "which of my many curare toxins shall I use", but rather "why not cisatracurium"?

Thus far, there is no evidence base to answer that question. Cisatracurium is probably the safest agent in the ICU population, purely because the speed of onset doesn't matter (they are intubated anyway) and because one does not rely on any working organs for its clearance (one could be totally anephric and anhepatic).

For whatever reason, the above-quoted Clinical Practive Guidelines make a Grade B recommendation for the use of pancuronium, and reserve cisatracurium for renal and hepatic failure patients. No satisfactory evidence-based reason for this is given: the authors merely state that "there is evidence in the literature that patients on pancuronium fare as well as or better than patients receiving any other NMBA". No references are offered. Perhaps tachyphylaxis develops more slowly to pancuronium in comparison to cisatracurium. Or perhaps somebody somewhere found its vagolytic activity helpful.


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