A fresh look at paralytics in the critically ill: real promise and real concernRocuronium, Vecuronium, Pancuronium Cisatracurium, Atracurium. Metabolism and excretion is Hepatic. Non -FDA trenbolone adverse effects aoporoved uses. Special considerations to NMBs. Aminoglycosides Tetracyclines Steroids Furosemide Beta blockers Calcium channel blockers Selective antiarrhythmics procainamide, quinidine. Optimal clinical practice paralytics and steroids administering analgesic and sedative drugs prior to and during neuromuscular paralttics, with the goal of achieving deep sedation. T NMB guidelines - good practice statement.
Neuromuscular-blocking drug - Wikipedia
Despite the publication of guidelines on the use of NMBAs in the ICU in , clinicians have needed more direction to determine which patients would benefit from NMBAs and which patients would be harmed. Recently, new evidence has shown that paralytics hold more promise when used in carefully selected lung injury patients for brief periods of time.
When used in early acute respiratory distress syndrome ARDS , NMBAs assist to establish a lung protective strategy, which leads to improved oxygenation, decreased pulmonary and systemic inflammation, and potentially improved mortality. It also is increasingly recognized that NMBAs can cause harm, particularly critical illness polyneuromyopathy CIPM , when used for prolonged periods or in septic shock.
In this review, we address several practical considerations for clinicians who use NMBAs in their practice. Ultimately, we conclude that NMBAs should be considered a lung protective adjuvant in early ARDS and that clinicians should consider using an alternative NMBA to the aminosteroids in septic shock with less severe lung injury pending further studies.
This review begins by contrasting the guidelines with current practice patterns related to NMBAs. We ultimately suggest clinicians to consider NMBAs as part of a lung protective strategy, especially in patients with more severe lung injury. Specifically, we use human as well as preclinical studies to raise concern about the routine use of NMBAs, especially aminosteroid NMBAs, in septic shock.
Finally, we synthesize this data for clinicians by offering a suggested alternative algorithm to the one presented in the guidelines. Neuromuscular blocking agents act on the skeletal muscle postsynaptic nicotinic acetylcholine ACh receptor. This class of medications is broken down into depolarizing and nondepolarizing blockers.
Depolarizing NMBAs, the prototype being succinylcholine, are rarely used in critically ill patients because of the risk of hyperkalemia and malignant hyperthermia and will not be further addressed in this review. Nondepolarizing NMBAs competitively bind the alpha subunits of the intra-junctional ACh receptor on the skeletal muscle postsynaptic membrane leading to inhibition of current through the receptor and thus flaccidity [ 2 ].
The guidelines identify indications for NMBAs and offer a simple algorithm for selecting an agent [ 1 ]. Recent surveys and cohort studies of clinical practice show a more detailed picture of actual NMBA use. Whereas the agents used and the indications for use are similar to the guidelines, these studies show a practice pattern of NMBAs used disproportionately on the sickest patients.
Pancuronium, rocuronium, and vecuronium are the most commonly used NBMAs [ 3 , 4 ]. In their survey of U. When asked about decision-making, clinicians responded that they were more likely to choose a NMBA based on their clinical experience and preference then on patient-specific factors. The surveys found that surgical ICU patient are more likely to receive pancuronium, whereas medical ICU patients are more likely to receive vecuronium.
As for administration, clinicians are more likely to give vecuronium and cisatracurium as continuous infusions, whereas all other agents are mostly given as intermittent boluses [ 3 ].
The indications reported by Rhoney and Murry [ 3 ] and Mehta et al. Beyond endotracheal intubation, the facilitation of mechanical ventilation is the most common indication for NMBAs with half reporting routine or frequent use of NMBAs for this reason. Less commonly cited indications include dosing to decrease metabolic demand, control of intracranial pressure, and decrease agitation.
Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Reprint with permission from [ 1 ]. Use was associated with patients on full ventilatory support with an odds ratio OR of 3. A subsequent study by Arroliga et al.
Finally, the duration of NMBA use is variable but favors shorter duration of use. Before these trials, NMBAs were thought to be beneficial in ARDS [ 2 , 10 ], but there was insufficient evidence to support a mechanism or demonstrate a benefit.
The hypothetical mechanism for this sustained improvement in oxygenation is likely a combination of reduced oxygen consumption [ 11 , 12 ] as well as homogenous distribution of PEEP and tidal volume limiting disproportionate barotrauma [ 9 ] and worsening of ARDS. These effects appear to occur in the absence of improved pulmonary mechanics [ 13 , 14 ]. Reduced oxygen consumption was previously postulated as a mechanism for improved oxygenation in a severe ARDS patient with an arterial partial pressure of oxygen to inspired oxygen P: F ratio of 58 and elevated respiratory rate [ 10 ].
Reduced oxygen consumption is an immediate effect, however, whereas the improvements in oxygenation elsewhere reported were seen after 24 hours [ 7 , 8 , 15 ]. This delayed improvement in oxygenation is better explained by slowing of disease progression. This decreased stress likely potentiates the lung protective effect of low tidal volume, because it leads to more homogenous distribution of ventilation [ 16 ]. Cisatracurium was again administered to the experimental group to abolish train of four responses.
Although the mechanism is unknown, it is possible that NMBAs eliminate excessive intrathoracic pressure changes and decrease alveolar overdistention, a phenomenon that is known to release proinflammatory cytokines in animal models [ 17 - 21 ].
IL-6 levels measured in the original lung protective trial [ 15 ] were significantly lower in the lung protective group. This decrease in inflammatory cytokines with lung protective tidal volumes was previously studied [ 22 , 23 ], with Parson et al.
With the administration of a NMBA and the decreased mechanical stress and improved homogenation discussed above, there is less inflammatory response and less likelihood of this inflammation becoming systemic. In , Papazian et al. This result was in contrast to a prior retrospective cohort study [ 6 ] that showed no mortality benefit.
Building on the work by Gainnier and Forel, Papazian randomized patients to 48 hours of cisatracurium versus placebo and was able to show a day mortality benefit after adjusting for baseline P: There was not, however, a significant difference in crude mortality between the study groups Beyond the improved oxygenation and anti-inflammatory mechanism mentioned above, the etiology of this adjusted mortality benefit from NMBAs can be inferred from the subgroup analysis. Patients in the cisatracurium group had more ventilator-free days 53 vs.
The greatest benefit, moreover, was seen with a P: F ratio less than Given the weakly significant p value associated with adjusted mortality, it is worth noting that this study was underpowered for the mortality rate it ultimately saw in its control group.
Critical illness polyneuromyopathy CIPM is a term that describes two separate diseases: Whereas CIP mainly affects motor and sensory nerve fibers leading to degeneration of the skeletal muscle, CIM directly affects myosin leading to muscle necrosis. CIP has been associated with increased in-hospital mortality [ 25 ], longer duration of mechanical ventilation [ 26 , 27 ], increased days in the ICU [ 28 ], and longer hospital stays [ 26 ].
For the purpose of this review, CIPM will be used to describe clinically significant weakness that is not further defined, whereas CIP and CIM will be used when authors provide sufficient EMG, muscle biopsy, and clinic data on sensory involvement to make a distinction.
The relationship between NMBAs and CIPM is not that simple, however, but a number of animal and human studies have helped to illuminate the connection and alert clinicians about which patients are at highest risk for CIPM.
Aminosteroid NMBAs have been associated with CIPM in patients receiving corticosteroids [ 26 , 27 , 30 ], sepsis with multiorgan failure [ 25 , 31 ], in multiple animal models of NMBA use [ 32 , 33 ], and with both a dose- and time-dependent relationship [ 27 , 31 , 34 ]. Conversely, only case studies of benzylisoquinolinium agents with concomitant corticosteroids for at least 6 days have linked this class of NMBAs to CIPM [ 35 - 38 ]; a link that could be explained by use of corticosteroids alone.
In a general population of ICU patients, de Jonghe et al. Rather, CIPM was associated with corticosteroid administration, duration of mechanical ventilation, and number of days with dysfunction in more than two organs. If clinically necessary, however, limiting the duration of using these medications together can minimize CIM. When time paralyzed is factored in, however, these numbers tell a different story. In the Douglass study, the patients with CIM were paralyzed for an average of 5 days compared with an average of 1 day in the CIM-free group.
In neither of these studies was incidence of CIM adjusted for severity of underlying illness. In contrast, when Behbehani et al. They did, however, find an association between duration of muscle paralysis and development of CIM with an odds ratio of 2. Six of the nine patients with CIP received vecuronium, whereas the other three received atracurium. Both of these patients had ARDS from septic shock. Animal model studies support this clinical finding of sepsis as a potent contributor to CIPM.
Whereas mechanical ventilation was consistently shown to decrease muscle compound muscle action potential amplitudes CMAP , sepsis was independently associated with a dramatic decrease in force generation capacity, a finding not seen with NMBAs. It should be noted that when all interventions were involved intubated and sedated, septic, corticosteroids, and NMBA , importantly, the degree of decline in CMAP was greatest. After 10 days of sepsis, the fast-twitch extensor digitorum longus muscle has a smaller cross-sectional area, increased fatigability, and reduction in maximal twitch contraction among other abnormalities.
Before the initiation of NMBAs, clinicians must ensure appropriate sedation and patient comfort. Practically, clinicians can provide sedation and analgesic until the patient is unconscious before administration of an NMBA [ 1 ].
Once properly sedated, accurate monitoring of NMBAs allows clinicians to get the maximum benefit while limiting the amount of medication used. Secondary to underlying organ dysfunction and intrinsic characteristics, patients require different amounts of NMBA to achieve the same level of paralysis.
For example, Circeo et al. In a study of septic rats, conversely, atracurium has a shorter onset and wore off quicker than in nonseptic rats [ 46 ]. The depth of paralysis, however, remains controversial.
Targeting a TOF of two of four rather than zero of four has been shown to be beneficial. In a prospective, randomize, open-labeled study [ 48 ] of ARDS patients randomized to shallow or deep paralysis for a median duration of F ratio, lower plateau pressure, and perhaps most importantly, received less total NMBA and had shorter recover time. Moreover, the guidelines, as discussed above, also recommend targeting a TOF of one to two of four.
This paper brings to light multiple clinical questions that require further experimentation to clarify. Although there is some evidence [ 47 , 48 ] as well as guidelines [ 1 ] available that targeting a TOF of two of four is beneficial, these authors chose a greater depth of paralysis. Perhaps the small mortality benefit shown by Papazian would have been larger with less paralytic.
Moreover, we offered evidence to support a mechanism for the improvement in oxygenation and inflammation seen in the studies by Gainnier and Forel, respectively, but additional studies are needed to investigate these hypothetical mechanisms. More studies are needed to address the use of NMBAs in patients with sepsis, and more specifically, septic shock. Achieving a mortality benefit from use of NMBAs comes with a small margin for error. Future studies of these agents need to build on the body of evidence suggesting that NMBAs can improve outcomes in patients with lung injury.
The following conclusions should be kept in mind. Use of NMBAs should be targeted. F ratio less than have the greatest mortality benefit. Suggested modifications to clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Bolded text represents suggested modifications to guidelines. The less NMBA used the better. This conclusion applies more to time paralyzed than to depth of paralysis. There is evidence, moreover, that less than 48 hours of NMBAs, either 24—36 hour may be even more beneficial.