Executive Summary: Society of Critical Care Medicine Guidelines for the Administration of Neuromuscular Blockade in Adults With Acute Respiratory Distress Syndrome

These guidelines involving the use of neuromuscular blockade (NMB) in critically ill patients are the fourth of a series with previous versions published in 1995, 2002, and 2016 (1–3). Previous versions dealt with a wide range of NMB-related topics including indications, details of specific NMB agents (NMBAs), and prevention or amelioration of adverse events. The panel elected to focus on acute respiratory distress syndrome (ARDS) since this is the most common indication for the sustained administration of NMB in critically ill patients and is associated with high mortality (4). A large multicenter, prospective study of critically ill patients without ARDS at onset of ventilation found that 30% of patients receiving mechanical ventilation in ICU settings were at risk for ARDS (5). For a detailed description of methodology, results, and rationale, the reader is referred to the complete guidelines (6). RECOMMENDATIONS The panel generated five conditional recommendations for this clinical practice guidelines that addressed five Population, Intervention, Comparison, and Outcome (PICO) questions (see full online version for all recommendations developed for these guidelines [6]). One recommendation is to use NMBAs in adults with moderate to severe ARDS. For the other recommendations, there was equipoise in the recommendation for and against using titratable vs. fixed-dose NMBAs dosing, a monitoring-based strategy for monitoring depth of sedation and analgesia in adults with ARDS before initiating or while receiving NMB and administration of NMBAs for patients who are proned due to overall lack of evidence in critically ill patients and due consideration of patient safety and experience concerns. Two conditional recommendations are highlighted in this executive summary and are presented below. Among adult patients with ARDS, should NMB vs. no NMB be administered to improve outcomes? Recommendation We suggest using NMBAs over not using NMBAs in adults with ARDS with Pao2/Fio2 less than 150 who are persistently hypoxemic and/or not achieving mechanical ventilation targets on sedation (conditional recommendation for, low certainty of evidence). Remarks We emphasize ventilator and/or sedation optimization to achieve lung-protective ventilation, mitigate dyssynchrony, and improve oxygenation before considering NMB. If used, NMB should be limited in duration and not routinely exceed 48 hours. Rationale Mortality A meta-analysis of seven randomized controlled trials (RCTs) (7–13) demonstrated a decreased risk of 28-day mortality, relative risk (RR) of 0.74 (95% CI, 0.56–0.98), with NMBAs compared with control irrespective of severity of hypoxemia. Subgroup analysis of these RCTs demonstrated a decrease in 28-day mortality irrespective of severity of hypoxemia. The certainty of evidence was downgraded to low for high risk of bias and inconsistency due to significant heterogeneity across trials. A meta-analysis of four RCTs (7–9,12) demonstrated a decreased risk of ICU mortality, RR of 0.73 (95% CI, 0.58–0.93), with NMBA compared with control. Subgroup analysis of these RCTs demonstrated a decrease in ICU mortality irrespective of severity of hypoxemia. The certainty of the evidence was downgraded to moderate due to imprecision associated with small sample size. An analysis of one RCT (12) subgrouped by length of stay in all randomized patients and survivors demonstrated a mean decrease of –1.80 days (95% CI, –5.93 to 2.33 d) and –2.90 days (95% CI, –7.86 to 2.06 d), respectively, with NMBA compared with control. The certainty of the evidence was downgraded to low due to serious imprecision (small sample size and wide CI). Mechanical Ventilation A meta-analysis of six RCTs (7–9,11–13) demonstrated a mean increase in ventilator-free days of 0.57 (95% CI, –0.43 to 1.57) with NMBA compared with control. The certainty of evidence was downgraded to moderate for imprecision. A meta-analysis of three RCTs (7,8,12) demonstrated a mean decrease in duration of mechanical ventilation in all randomized patients of –1.21 days (95% CI, –4.23 to 1.81 d) with NMBA compared with control. The certainty of evidence was downgraded to very low for inconsistency due to heterogeneity across the trials and imprecision. Adverse Events A meta-analysis of four RCTs (7,8,11,12) demonstrated a decreased risk of barotrauma, RR of 0.55 (95% CI, 0.35–0.85), and an increased risk of ICU-acquired weakness, RR of 1.16 (95% CI, 0.98–1.37), with NMBA compared with control. A meta-analysis of these RCTs (7,8,11,12) also demonstrated an increased risk of total adverse events, RR of 1.63 (95% CI, 0.98–2.72), with NMBA compared with control. The adverse events included pneumothorax, ventilator-associated pneumonia, neuromyopathy, septic shock, ICU-acquired paresis, bradycardia, barotrauma, ileus, paralysis awareness, hyperkalemia, myopathy, methemoglobinemia, and a variety of cardiac, respiratory, and nervous system events. The overall certainty of evidence was low due to either inconsistency in findings, risk of bias, and imprecision. The panel discussed associated considerations, including dosing (intermittent vs. bolus), agent selection, and duration of use and concluded that further research is needed before making formal recommendations on these details (14,15). The panel judged that the costs associated with the use of NMBA are moderate and can vary geographically. There are direct costs such as the acquisition of NMBAs and co-administered drugs (e.g., sedatives). There are indirect costs such as post-ICU rehabilitation, lost productivity, and length of stay. The panel was uncertain regarding the impact on health equity. The panel judged that the use of NMBA is feasible and probably acceptable to key stakeholders. While receiving NMBAs in adult patients with ARDS, is there a role for monitoring depth of analgesia and sedation vs. not monitoring depth of analgesia and sedation to improve patient outcomes? Recommendation We suggest the use of either a monitoring-based strategy or no monitoring of depth of analgesia and sedation in adults with ARDS who are receiving NMBAs (conditional recommendation for, very low certainty of evidence). Remarks Given the evidence limitations, clinicians should consider patient characteristics, availability of and local expertise with monitoring tools for evaluating depth of sedation and analgesia, and associated costs (direct and indirect) when deciding whether to implement a monitoring-based strategy beyond usual clinical assessments. Adequate depth of analgesia and sedation during administration of NMBAs should be ensured, with the goal of maintaining patient safety and minimizing distress, despite lack of evidence. Rationale Analyses of relevant studies demonstrated no significant difference in analgesia rate adjustment (16), delirium/coma-free days (16), ICU-free days (16), ICU length of stay (17,18), duration of mechanical ventilation (18), 90-day mortality (16–18), self-extubation (16), and ventilator-free days (16,17) with monitoring depth of sedation compared with no monitoring in patients with ARDS who were receiving NMBA. The overall quality of evidence was very low due to risk of bias associated with study design, and imprecision attributed to small sample size and wide CIs. The balance of benefits and harms did not favor either a monitoring-based strategy or a nonmonitoring-based strategy as more sedation and analgesia adjustments may have positive and negative implications. The panel judged that there would probably be no uncertainty in how much patients value the outcomes of sedation/analgesia monitoring. The panel was uncertain regarding the resources required to implement monitoring-based strategies and its impact on healthcare equity. The panel judged that the acceptability of a monitoring-based strategy to key stakeholders would vary, but probably feasible to implement in clinical practice. RESEARCH AGENDA Future research is needed on all topic areas covered by these guidelines (6), particularly those for which recommendations could not be made due to insufficient or limited evidence. Research priorities are presented in Table 1 of this summary. TABLE 1. - Research Priorities for Topics With Insufficient or Limited Evidence Topic Research Priorities Titration/dosing of NMBAs Mechanism of benefit of NMBAs (could impact dosing strategy) Recognition that frequent IV intermittent dosing results in blood concentrations (i.e., relatively flat concentration vs. time curve) like IV infusion Drug cost (much higher with high-dose IV infusion with no monitoring) Adverse effects including use of IV fluids (more with high-dose infusion) How different modes of mechanical ventilation may influence use of NMBAs Most appropriate drug dosing strategies Studies to evaluate outcomes associated with lower dosing Scale-based strategies for clinical evaluation of depth of analgesia and sedation Differences in the specific drugs uses for analgesia and sedation Specific endpoints for analgesia and sedation When to use single vs. combination drugs Analgesia and sedation goals prior to blockade Combining NMBAs with other ARDS therapies Synergistic or antagonistic effect of NMBAs when combined with prone positioning, corticosteroids, or higher positive end-expiratory pressure Impact of combining NMBAs with other acute respiratory distress syndrome therapies on adverse effects Factors influencing outcomes with combination therapies (e.g., patient characteristics, timing, duration) NMBAs = neuromuscular blockade agents.