Acute respiratory distress syndrome (ARDS) is a lethal syndrome characterized by hypoxemia, bilateral infiltrates and diffuse alveolar damage.(1) Patients presenting with ARDS often require intubation and mechanical ventilation for hypoxemic respiratory failure.(2) Standard therapy includes low tidal volumes coupled with lower plateau pressures, which reduce mortality and increase ventilator-free days when compared to higher tidal volumes and plateau pressures.(3) However, volumes set by clinicians do not always correspond to the true volume delivered because of patient-ventilator dyssynchrony, which can occur despite the use of adequate analgesics and sedatives.(4,5) Patients may develop breath stacking, leading to higher tidal volumes and increased pressures delivered to the alveoli.(6) Thus, clinicians sometimes consider the use of neuromuscular blocking agents (NMBAs) to increase chest wall compliance and minimize work of breathing and patient-ventilator dyssynchrony.(5) This review examines the risks and benefits of using NMBAs for selected patients with ARDS.
Breath stacking and patient-ventilator dyssynchrony both may contribute to ventilator-induced lung injury. Light et al published the first report of NMBA effects in ARDS,(5) demonstrating that pancuronium boluses diminished hypoxia and cerebral damage, as well as lowered inspiratory pressures and the subsequent risk of pneumothorax. However, several studies that followed demonstrated disparate outcomes, and the benefits of NMBAs remained unclear.(7-10) These uncertainties were addressed by three prospective randomized trials examining the effect of 48 hours of cisatracurium infusion in patients with early, severe ARDS (defined in two of the studies as a PaO2
ratio less than 150) who were receiving mechanical ventilation.(11-13) In the first two trials,(11,12) patients treated with cisatracurium had an improved PaO2
ratio and reduced levels of proinflammatory cytokines (Table 1
7-9,11-13). In the largest of the three trials, ARDS et Curarisation Systematique (ACURASYS), patients treated with a high fixed dose of cisatracurium had an increased 90-day survival, more ventilator-free days and decreased barotrauma compared to the placebo-treated patients.(13) No difference was detected between groups in the development of ICU-acquired weakness. A higher number of patients in the cisatracurium group had pneumonia as the primary etiology of ARDS, while those who received the placebo had more intra-abdominal sepsis as the source.
The disadvantages of NMBAs are related to drug pharmacology and the secondary side effects of immobility, including corneal abrasions, venous thromboembolisms, myopathy, and polyneuropathy, which can persist for years after recovery.(14-17) Additionally, the use of NMBAs requires the use of sedative and analgesic agents at higher doses, both of which may prevent early physical and occupational therapies.(18,19) Figure 1
depicts some of the side effects and benefits of NMBA use.
Types of NMBAs
Neuromuscular blockers are categorized as depolarizing or non-depolarizing agents. Succinylcholine is a depolarizing NMBA that activates the cholinergic receptors of the motor end plate to depolarize postsynaptic cells.(20) Due to its rapid onset and short duration of action, succinylcholine is generally reserved for transient paralysis, such as during endotracheal intubation.(17) Conversely, the non-depolarizing NMBAs are reserved for prolonged muscle paralysis, as in patients with ARDS. These drugs competitively bind to cholinergic receptors and antagonize the actions of acetylcholine, causing decreased muscle responsiveness to presynaptic excitation.(17,21) They can be further classified by their chemical structure into aminosteroidal and benzylisoquinolinium compounds (Table 2
), which delineates how they are metabolized.(17,22)
The non-depolarizing paralytic agents differ in their duration of action (short-, intermediate-, and long-acting) as well. Vecuronium, rocuronium, atracurium, and cisatracurium are intermediate-acting drugs. With organ dysfunction, plasma concentrations of vecuronium and rocuronium may be increased, since both are hepatically metabolized and then renally excreted. Vecuronium’s active metabolite is 50% as active as its parent drug and has been associated with prolonged blockade after discontinuation because of decreased renal clearance.(22) Comparatively, rocuronium’s metabolite is 5% to 10% as active as its parent compound, making its accumulation less of a concern. Both agents possess few or no cardiovascular effects.(21) Atracurium and cisatracurium undergo elimination via ester hydrolysis and Hofmann elimination. Therefore, they are preferred for use in critically ill patients with multisystem organ failure. However, laudanosine, a neuroexcitatory metabolite of atracurium, can accumulate in organ dysfunction and may precipitate seizures.(17,22) Atracurium and cisatracurium have minimal cardiovascular effects, but histamine release is associated with higher doses of atracurium.(22) Pancuronium is a long-acting NMBA affected by renal and hepatic impairment with an active metabolite that is one-third to one-half as active as its parent drug.(22) It also has vagolytic effects, including an increase in heart rate of 10 or more beats per minute (in more than 90% of intensive care unit [ICU] patients).
Limited evidence supports the use of a single agent over another. The 2002 neuromuscular blockade guidelines published in Critical Care Medicine indicate that cisatracurium or atracurium are favored when there is evidence of hepatic or renal dysfunction and pancuronium should be avoided if vagolytic effects are of concern.(22) Subsequent surveys have found the decision-making process in NMBA choice is based on clinician experience and preference rather than on patient-related factors.(23) These surveys preceded the French studies establishing the promising results of cisatracurium.(11-13) Few trials have directly compared aminosteroids with benzylisoquinoliniums. One prospective, multicenter randomized trial compared recovery times in cisatracurium and vecuronium, and showed a significant reduction in recovery time to 70% response to train-of-four (TOF) for cisatracurium (68 min vs. 387 min, P = 0.02).(24) In another analysis of prospective trials in which the primary outcome under investigation was prolonged weakness, approximately 8% of patients who received aminosteroids had acute quadriplegic myopathy, whereas none of those receiving atracurium or cisatracurium did.(25)
The goals of monitoring NMBA therapy are efficacy and safety. To assess TOF response, periodic clinical assessment and peripheral nerve stimulation are recommended.(22) Clinical signs include spontaneous ventilation, eye opening and sustained five-second head lift. In TOF testing, four electrical impulses are delivered to the facial or ulnar nerve (preferred) with a goal of one or two of four twitches discernable by palpation or observation, corresponding to 80% to 90% of blocked receptors. However, the added value of TOF is uncertain. Rudis et al titrated vecuronium in patients with respiratory failure (approximately 13% of all randomized patients had ARDS) to 1/4 twitches and observed that the group monitored with TOF required less vecuronium and had more rapid recovery to 4/4 twitches and to spontaneous breathing when compared to clinical assessment alone.(26) Two other reports, using atracurium and cisatracurium, respectively, found no difference between groups, suggesting that clinical assessment alone can be performed.(27,28) The discordance in these conclusions can likely be attributed to the difference in the pharmacokinetic properties of the various agents. Regardless of the agent used, deep sedation must be achieved before initiating blockade to prevent awareness during induced paralysis. The bispectral index (BIS) is frequently used to quantitate level of consciousness, although studies have had mixed results concerning its correlation to sedation.(29-32)
When to Use
Generally, NMBAs are considered in patients with early, severe ARDS after they have failed conventional therapy with lung-protective mechanisms. At Emory University, we reserve their use in ARDS to patients presenting with a PaO2/FIO2 ratio less than 150 on conventional lung-protective strategies and will often attempt this before prone positioning. Cisatracurium is used in conjunction with TOF and BIS monitoring to ensure adequate sedation and analgesia and to minimize the dosing of NMBAs.
Altogether, the use of short-term neuromuscular blockade in patients with early, severe ARDS appears a reasonable option in patients who fail first-line therapy. The largest of the studies supporting its use employed cisatracurium, but it would seem reasonable to assume that alternate NMBAs would have similar effects. When patients receive NMBAs, clinical evaluation, peripheral nerve stimulation and BIS should be used in combination to minimize adverse effects.
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