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Use of muscle relaxants in ARDS patients

Articolo

Autore: Jean‑Michel Arnal, Munir Karjaghli

Data: 09.04.2020

Should muscle relaxants be used in ARDS patients?

The ROSE trial

The recent ROSE trial (National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997‑2008. doi:10.1056/NEJMoa19016861​) investigated the difference in 90‑day mortality rates between mechanically ventilated ARDS patients who received an early and continuous infusion of neuromuscular blocking agent (NMBA) with concomitant deep sedation and those who received usual care with no routine NMBA and lighter sedation targets. All patients were suffering from moderate‑to‑severe ARDS and being treated with a strategy involving high PEEP. The background for the trial was uncertainty about the benefits of early continuous neuromuscular blockade in ARDS patients receiving mechanical ventilation. Results published in 2019 showed no difference in 90‑day mortality between the two groups. These results are in direct conflict with results of the ACURASYS trial (Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. doi:10.1056/NEJMoa10053722​) published several years earlier, which showed a lower mortality rate in those patients who received muscle relaxants early on in their treatment.

In addition to showing no difference in mortality rates, results showed that the early use of a NMBA was associated with less physical activity, as well as a greater number of serious adverse cardiovascular events.

Comparing the ROSE and ACURASYS trials

It is important to recognize the difference between the two trials. In the ROSE study, the investigators:

  • Compared light sedation in the control group versus deep sedation and paralysis in the intervention group, while the ACURASYS trial compared deep sedation in the control group versus deep sedation and paralysis in the intervention group.  The use of the lighter sedation strategy in the control group of the ROSE study may have decreased mortality in that group.
  • Used higher PEEP than in the ACURASYS trial. This in itself could reduce the mortality rate in moderate‑to‑severe ARDS patients and thus negate the potential treatment effect of the early NMBA.
  • Used the prone position much less frequently than in the ACURASYS trial. Prone positioning may reduce the risk of death in patients with ARDS and although it is not known whether use of early NMBA is more effective with prone positioning, it is a possible explanation for the difference in results from the two trials.
  • Ended up with higher mortality rates overall, but found no difference between the control and the intervention groups.

A question of ventilation strategy

Bearing these differences in mind, the question is not necessarily one of sedation strategy, but of ventilation strategy.

Prone positioning has been demonstrated as an effective treatment for ARDS (moderate‑to‑severe) patients.  A recent study showed that prone positioning had an immediate beneficial effect on lung mechanics and a late lung recruitment effect independent of the PEEP strategy (Mezidi M, Parrilla FJ, Yonis H, et al. Effects of positive end-expiratory pressure strategy in supine and prone position on lung and chest wall mechanics in acute respiratory distress syndrome. Ann Intensive Care. 2018;8(1):86. Published 2018 Sep 10. doi:10.1186/s13613-018-0434-23​). However, as prone positioning requires deep sedation, this strategy should include the use of muscle relaxants.

The clinician therefore has two options:

  1. Keeping the patient in a supine position with light sedation and appropriate PEEP
  2. Using deep sedation, paralysis, and prone positioning

Which of these options is more lung protective is no doubt dependent on various factors, including the severity of ARDS, the size of the aerated lung, recruitability, etc. This question is currently the subject of further research.

Note

Bibliografia

  1. 1. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997‑2008. doi:10.1056/NEJMoa1901686
  2. 2. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107‑1116. doi:10.1056/NEJMoa1005372
  3. 3. Mezidi M, Parrilla FJ, Yonis H, et al. Effects of positive end‑expiratory pressure strategy in supine and prone position on lung and chest wall mechanics in acute respiratory distress syndrome. Ann Intensive Care. 2018;8(1):86. Published 2018 Sep 10. doi:10.1186/s13613‑018‑0434‑2

Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome.

National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997‑2008. doi:10.1056/NEJMoa1901686



BACKGROUND

The benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear.

METHODS

We randomly assigned patients with moderate‑to‑severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end‑expiratory pressure [PEEP] of ≥8 cm of water) to a 48‑hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual‑care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical‑ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in‑hospital death from any cause at 90 days.

RESULTS

The trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, -0.3 percentage points; 95% confidence interval, -6.4 to 5.9; P = 0.93). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. There were no consistent between-group differences in end points assessed at 3, 6, and 12 months.

CONCLUSIONS

Among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, 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. (Funded by the National Heart, Lung, and Blood Institute; ROSE ClinicalTrials.gov number, NCT02509078.).

Neuromuscular blockers in early acute respiratory distress syndrome.

Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107‑1116. doi:10.1056/NEJMoa1005372



BACKGROUND

In patients undergoing mechanical ventilation for the acute respiratory distress syndrome (ARDS), neuromuscular blocking agents may improve oxygenation and decrease ventilator‑induced lung injury but may also cause muscle weakness. We evaluated clinical outcomes after 2 days of therapy with neuromuscular blocking agents in patients with early, severe ARDS.

METHODS

In this multicenter, double-blind trial, 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS within the previous 48 hours were randomly assigned to receive, for 48 hours, either cisatracurium besylate (178 patients) or placebo (162 patients). Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FIO2) of less than 150, with a positive end-expiratory pressure of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day in-hospital mortality rate), adjusted for predefined covariates and baseline differences between groups with the use of a Cox model.

RESULTS

The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P=0.04), after adjustment for both the baseline PaO2:FIO2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P=0.08). Mortality at 28 days was 23.7% (95% CI, 18.1 to 30.5) with cisatracurium and 33.3% (95% CI, 26.5 to 40.9) with placebo (P=0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups.

CONCLUSIONS

In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. (Funded by Assistance Publique-Hôpitaux de Marseille and the Programme Hospitalier de Recherche Clinique Régional 2004-26 of the French Ministry of Health; ClinicalTrials.gov number, NCT00299650.)

Effects of positive end‑expiratory pressure strategy in supine and prone position on lung and chest wall mechanics in acute respiratory distress syndrome.

Mezidi M, Parrilla FJ, Yonis H, et al. Effects of positive end‑expiratory pressure strategy in supine and prone position on lung and chest wall mechanics in acute respiratory distress syndrome. Ann Intensive Care. 2018;8(1):86. Published 2018 Sep 10. doi:10.1186/s13613‑018‑0434‑2



BACKGROUND

In acute respiratory distress syndrome (ARDS) patients, it has recently been proposed to set positive end‑expiratory pressure (PEEP) by targeting end‑expiratory transpulmonary pressure. This approach, which relies on the measurement of absolute esophageal pressure (Pes), has been used in supine position (SP) and has not been investigated in prone position (PP). Our purposes were to assess Pes‑guided strategy to set PEEP in SP and in PP as compared with a PEEP/FIO2 table and to explore the early (1 h) and late (16 h) effects of PP on lung and chest wall mechanics.

RESULTS

We performed a prospective, physiologic study in two ICUs in university hospitals on ARDS patients with PaO2/FIO2 < 150 mmHg. End-expiratory Pes (Pes,ee) was measured in static (zero flow) condition. Patients received PEEP set according to a PEEP/FIO2 table then according to the Pes-guided strategy targeting a positive (3 ± 2 cmH2O) static end-expiratory transpulmonary pressure in SP. Then, patients were turned to PP and received same amount of PEEP from PEEP/FIO2 table then Pes-guided strategy. Respiratory mechanics, oxygenation and end-expiratory lung volume (EELV) were measured after 1 h of each PEEP in each position. For the rest of the 16-h PP session, patients were randomly allocated to either PEEP strategy with measurements done at the end. Thirty-eight ARDS patients (27 male), mean ± SD age 63 ± 13 years, were included. There were 33 primary ARDS and 26 moderate ARDS. PaO2/FIO2 ratio was 120 ± 23 mmHg. At same PEEP/FIO2 table-related PEEP, Pes,ee averaged 9 ± 4 cmH2O in both SP and PP (P = 0.88). With PEEP/FIO2 table and Pes-guided strategy, PEEP was 10 ± 2 versus 12 ± 4 cmH2O in SP and 10 ± 2 versus 12 ± 5 cmH2O in PP (PEEP strategy effect P = 0.05, position effect P = 0.96, interaction P = 0.96). With the Pes-guided strategy, chest wall elastance increased regardless of position. Lung elastance and transpulmonary driving pressure decreased in PP, with no effect of PEEP strategy. Both PP and Pes-guided strategy improved oxygenation without interaction. EELV did not change with PEEP strategy. At the end of PP session, respiratory mechanics did not vary but EELV and PaO2/FIO2 increased while PaCO2 decreased.

CONCLUSIONS

There was no impact of PP on Pes measurements. PP had an immediate improvement effect on lung mechanics and a late lung recruitment effect independent of PEEP strategy.