Partial Neuromuscular Blockade During Partial Ventilatory Support in Sedated Patients with High Tidal Volumes, by Jonne Doorduin et al .
We’re back! After two weeks of well-deserved rest, here we are again, ready to roll! And the 2017 début article will be a quite provocative one. In fact, it is a proof-of-concept study approaching a subject loved by intensivists around the globe: ARDS. Remember the last time you were ventilating a patient with ARDS? Well, probably your story will have something in common with this one. A 50y/o (70kg) patient with ARDS due pneumonia was just admitted, he was intubated, with a P/F ratio of 186, sedated with propofol (80mg/h) and fentanyl (30mcg/h), and receiving a small dose of noradrenaline (0,1mcg/kg/min). The ventilator parameters were: volume-assisted ventilation, PEEP=12cmH2O, FiO2=0.8, Vt=420ml, plateau-pressure=20cmH2O. However, as soon as you stepped in the room, two things got your attention: The patient was triggering the ventilator, and although the Vt was setted to 420ml, the actual Vt was 680ml. A combination of hypoxemia, hypercarbia, and light sedation was fucking up with your plan of lung protective ventilation. After your still hangovered neurons from the holidays make some synapsis, a few options pop-up in your once healthy I-eat-hangover-for-breakfest brain.
-Option 1: Go back to the nurse station and pretend that is not your problem.
-Option 2: Increase the level of sedation until the patient stops triggering the vent.
-Option 3: Put him on ECMO.
-Option 4: Give him meropenem + vancomycin.
Ok, since most of us, including myself, have limited brains capable of coming up with only these 4 options, it doesn’t seem a though decision at all. But every time I decide to deep our patients’ sedation, even for a noble reason, there is a price to pay. We all know about critical illness myopathy, and that both mechanical ventilation and sedatives play a role in its development, but here, I’d like to focus on the myopathy of a specific muscle: the diaphragm. We already know that diaphragm muscle fiber atrophy begins in the first days of mechanical ventilation, specially in controlled modes of ventilation. This is not a good thing, right? So, how to overcome this issue? What if I could combine the benefits of partial support ventilation, which has its benefits (lung recruitment and reduced risk of ventilator-induced diaphragm dysfunction) with the assurance of lung protective ventilation? In order to do that, some bright minds thought about a “pharmacologically induced partial neuromechanical uncoupling of the respiratory muscles”, i.e. I’ll give my patient a drug that allow him to trigger the vent, but will not allow him to make high Vt. Since a study from 80’s showed that curare could reduce maximum inspiratory pressure while maintaining spontaneous breathing, the use of a neuromuscular blocking agents (NMBAs) seems to be the right drug for this purpose.
All this rationale became a question in the mind of Jonne Doorduin and colleagues, culminating with an article  published last year in the American Journal of Respiratory and Critical Care Medicine. In order to answer this question, a proof-of-concept study was designed. Inclusion criteria were: Adult patients with ARDS who were able to trigger the ventilator and developed a Vt>8ml/kg during pressure support ventilation (PSV) of 12cmH2O. Exclusion criteria were: Recent use of NMBAs, pain or agitation, metabolic acidosis, high dose pressors and increased ICP. The study protocol consisted in three phases, as shoed below:
They selected two levels of PSV 12cmH2O and 6cmH2O. The former is a reasonable level of support, and the latter was chosen to confirm the high Vt under low level of support. The titration of rocuronium was performed in NAVA (neurally adjusted ventilatory assist) “because diaphragm activity and support are tightly linked in this mode”. A total of 10 patients were studied, most of them with moderate ARDS according to the Berlin definition. As expected, there were high variability in the number of rocuronium boluses and cumulative dose to achieve and maintain low Vt (≤6ml/kg). The graphs below show how the Vt changed during the study phases. We can see patients had higher Vt when in PSV-12 (9.8 ± 0.5 ml/kg) and NAVA (9.4 ± 0.6 ml/kg), and a reduction to PSV-6 resulted in a small Vt decrease. It is also shown that during titration and continuous infusion of rocuronium the Vt dropped considerably, as compared to baseline (stacked bar graph).
Also, they were able to show a decrease (not cessation) in the electrical activity of the diaphragm and work-of-breathing throughout the 3 phases. An increase in dynamic lung compliance during phase 2 was evident: from 26 ± 2 in the first minute to 42 ± 4.7 ml/cmH2O in the last minute (p < 0.0001). Two aspects that might have raised concerns were the hemodynamic response and blood gas values during the study period. During phase 2, there were a slightly increase in heart rate and mean arterial reassure, both without correlation with RASS (Richmond Agitation-Sedation Scale). Even with an increase in the respiratory rate during phases 2 and 3, there were a significant increase in PaCO2 and a decrease in pH during these phases.
The strategy of delivering lung protective ventilation while maintaining diaphragm activity is quite interesting, and this small study show us that it might be feasible. However, patients experienced changes in hemodynamic and PaCO2. Also, we know that NMBAs are highly related to critical illness myopathy, so, would the benefits of support ventilation be counteracted by this side effect? I don’t know. Maybe. But this was not the purpose of this study, this was a proof-of-concept study, and it did its job. The strategy of partial neuromuscular blockade does decrease the Vt while maintain diaphragm activity in ARDS patients ventilated in partial support modes. Will they be able to run a major RCT? Will it show any benefit? Let’s wait. For now, this might be the embryo of a really good idea, but we already saw good ideas sink before.
1. Doorduin J, Nollet JL, Roesthuis LH, et al. Partial Neuromuscular Blockade During Partial Ventilatory Support in Sedated Patients with High Tidal Volumes. Am J Respir Crit Care Med. 2016.
2. Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327-1335.
3. Campbell EJ, Gandevia SC, Killian KJ, Mahutte CK, Rigg JR. Changes in the perception of inspiratory resistive loads during partial curarization. J Physiol. 1980;309:93-100.