Neuromuscular Blockade Improves Results in Acute Respiratory Distress Syndrome: A Mechanism May Be Prevention of Expiratory Muscle Activity, Which Allows More Lung Expansion

Neuromuscular blockers are now used in ∼40% of patients with severe acute respiratory distress syndrome (ARDS) (1). Evidence for their use is not unambiguous, however. One large trial found that continuous neuromuscular block for the first 48 hours of the ICU stay improved 90-day mortality in patients with severe ARDS (2), whereas a more recent trial found no survival benefit (3). Possible mechanisms by which neuromuscular blockers improve outcome are preventing vigorous patient effort and thus limiting tidal lung distension, limiting patient–ventilator interactions and improving oxygenation, direct anti-inflammatory effects, or reducing total body oxygen consumption (4–6). Further elucidating these possible mechanisms would help determine which patients might benefit most from neuromuscular block.

Summary of Findings by the Authors

Fortuitously, in this issue of the Journal, Plens and colleagues (pp. 563–572) noted that end-expiratory lung volume, estimated with electrical impedance tomography, increased in some patients with ARDS when they were administered muscle relaxants (7). Plens and colleagues hypothesized that this increase was caused by preventing expiratory muscle activity, and they systematically studied the prevalence and mechanisms of this phenomenon. They cleverly exploited the clinical requirement to provide “windows” in neuromuscular block: In this period, they made before-and-after measurements in each patient.

They found that responses to neuromuscular blockade were highly variable. In half of the patients, end-expiratory lung volume increased by more than 10% after reinstating neuromuscular blockers. Impedance measurements of regional ventilation suggested that these “responders” were using their expiratory muscles during the windows in neuromuscular block, whereas the “non-responders” were not. This was confirmed in a further patient sample by measuring esophageal pressure, which assesses respiratory muscle effort directly.

Pathophysiology of Expiratory Muscle Recruitment in ARDS: The “Anti-PEEP” Effect

Some studies suggest that moderate respiratory effort improves ICU outcomes (8), which contradicts findings that neuromuscular blockers can be advantageous. However, respiratory effort in early respiratory failure should not cause excessive lung stretch. Controlling respiratory effort is often difficult when ventilatory drive is excessive, which is often the case in critical illness: Reduced efficiency of gas exchange, hypercapnia and hypoxia, neural reflexes from pulmonary inflammation, and increased metabolism may all contribute. In patients in whom respiratory effort is difficult to control, neuromuscular blockade may be the only solution.

An almost universal method to reduce lung damage and improve gas exchange is to increase lung volume with positive end-expiratory pressure (PEEP). An increase in end-expiratory lung volume should prevent collapse of lung regions where the distending transpulmonary pressure is small. Moving the lung to a less harmful part of its pressure–volume relationship may also reduce elastic stress. However, the final effect of PEEP depends on the mechanical properties of the chest wall and the presence of expiratory muscle activity (Figure 1). Action of expiratory muscles will decrease lung volume, causing possible local collapse, and might thus contribute to lung injury by several pathways: greater lung elastance requiring increased driving pressures, impaired gas exchange, cyclic recruitment of alveoli, and increased lung inhomogeneity. It had been suspected in earlier studies that improved oxygenation after neuromuscular block might be caused by lung recruitment after cessation of abdominal muscle recruitment (9), but the effects of neuromuscular block on lung volumes had not been demonstrated as elegantly as in this paper. Plens and colleagues call the reduction in end-expiratory lung volume by expiratory activity an “anti-PEEP” effect, which is an insightful moniker, but it might be better to think that PEEP can restore the diminished lung volumes caused by active expiration.

Figure 1.

Fundamental findings of the present study: More than half the patients had increased end-expiratory lung volume when muscle paralysis was instituted and active expiration was abolished (left panel). The effect was more marked in patients who had received greater doses of fentanyl (right panel). A simple explanation of the consequences of active expiration (bottom cartoon):

• Step 1:
  Contraction of expiratory muscles
• Step 2:
  This increases abdominal pressure (P_ab).
• Step 3:
  When the diaphragm is relaxed in expiration, this increase in P_ab is transmitted to the pleural space (P_pl).
• Step 4:
  If the lung volume is unchanged, there will be an equivalent increase in alveolar pressure (P_alv).
• Step 5:
  If there were no flow out of the lung, then pressure at the airway opening would also increase (P_aw).
• Step 6:
  The only practical means of preventing a reduction in lung volume caused by expiratory activity is to apply a pressure at the airway opening equal to the expiratory pressure generated by the active expiratory muscles. Of note, this pressure would be needed in addition to any positive end-expiratory pressure that had been applied before the expiratory activity had started.

Fentanyl and Abdominal Muscle Recruitment, a Not-So-New Phenomenon

Plens and coworkers found that fentanyl dosage was related to the increase in end-expiratory lung volume after neuromuscular block and suggest that fentanyl promotes expiratory muscle recruitment in patients with ARDS. Fentanyl dose was not adjusted in their study, however, so causality cannot be derived from their data, but this effect has been noted in other circumstances. The mechanism appears to be central, does not affect only respiratory muscles, and certainly is not exclusively mediated by μ-opioid receptors. In animals, muscle rigidity caused by fentanyl can be reversed in a dose-dependent way by dexmedetomidine, which is an adrenergic α₂-agonist. This effect of dexmedetomidine is prevented by the centrally acting α₂-antagonist idazoxan, but not by α₂-adrenergic antagonists, which are predominantly peripherally active. Thus, opioid-induced muscle rigidity is a central effect, not mediated by an opioid-dependent mechanism alone (10). An interesting alternative strategy to reduce abdominal muscle recruitment apart from neuromuscular blockers would therefore be to use pharmacological agents such as α₂-adrenergic agonists, which have the added advantage of providing sedation.

The action of opioids on respiration interacts with other factors, particularly chemical drive (11). Chest wall movements have been measured in anesthetized patients, studied both paralyzed and breathing spontaneously, where recovery from neuromuscular block and the onset of spontaneous breathing was associated with a decrease in end-expiratory volume (12). The dimensions of the lower rib cage and upper abdomen decreased, consistent with active expiratory abdominal muscles. When respiration was stimulated with carbon dioxide, the end-expiratory volumes of the rib cage and abdomen decreased further, and subsequent reversal of the opioid with naloxone increased the chest wall volumes (11, 12).

Detecting Expiratory Activity at the Bedside

This study emphasizes the importance of abdominal muscles in critically ill patients. Abdominal muscle recruitment can be difficult to detect (13). Clinical examination is a good place to start: Place a hand on the flank or stomach of the patient, and feel whether the muscles underneath stiffen rhythmically. In patients who are breathing spontaneously from a simple circuit with valves, active expiration can be convincingly shown by measuring airway pressure during transient occlusion of the expiratory pathway. If active expiration is present, this is seen as a plateau toward the end of the expiratory period (14). Dedicated techniques such as abdominal pressure measurement or abdominal muscle electromyography are seldom applied outside of research studies (1). However, most patients in intensive care will have convenient tubes in places that could be used to measure intraabdominal pressure, such as the stomach or the bladder. A simple display of pressures in these cavities, viewed at the same time as the volume display of the ventilator, will provide a good indication of the gradual onset and sudden offset of abdominal muscle activity during each respiratory cycle.

Implications for Clinical Practice and Future Research

Should we now use neuromuscular blockade only in patients with abdominal muscle recruitment? As is often the case, more studies are required. The present study did not indicate if patients with expiratory muscle recruitment (“responders”) showed improved oxygenation after neuromuscular block, nor did it indicate improved outcomes compared with “non-responders.” Moreover, studies on lung-protective ventilation have not related improved oxygenation to improved mortality (15). If patients with abdominal muscle activity are those who benefit from neuromuscular block, then other patients might experience disadvantages such as respiratory muscle atrophy.

This study also reminds us that opioids have these effects on respiratory muscle activity in many patients, increasing expiratory muscle recruitment. Regularly monitoring for expiratory muscle activity in our patients might help us to better appreciate these side effects. Monitoring would also allow clinicians to gain practical experience with interventions to reduce abdominal muscle recruitment and to learn from the immediate effects of these interventions on lung stresses and oxygenation at the bedside.