Accepted Manuscript

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Neuromuscular Blockade in the 21 Century Management of the Critically Ill Patient

Julian deBacker, MSc, Nicholas Hart, MBBS, PhD, Eddy Fan, MD, PhD

PII: S0012-3692(16)62328-0
DOI: 10.1016/j.chest.2016.10.040
Reference: CHEST 785

To appear in: CHEST

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Please cite this article as: deBacker J, Hart N, Fan E, Neuromuscular Blockade in the 21 Century
Management of the Critically Ill Patient, CHEST (2016), doi: 10.1016/j.chest.2016.10.040.

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 ACCEPTED MANUSCRIPT

Neuromuscular Blockade in the 21st Century Management of the Critically Ill Patient

Julian deBacker MSc; Nicholas Hart MBBS, PhD; Eddy Fan MD, PhD

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From the Cleveland Clinic Lerner College of Medicine (JDB), Cleveland, Ohio; Lane Fox
Respiratory Service (NH), St. Thomas’ Hospital, Guy’s & St. Thomas’ NHS Foundation Trust,

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London, UK; and the Interdepartmental Division of Critical Care Medicine (JDB, EF), Toronto,
Canada

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Corresponding Author
Eddy Fan, MD, PhD
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Toronto General Hospital
585 University Avenue, PMB 11-123
Toronto, Ontario, Canada
M5G 2N2
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Email: eddy.fan@uhn.ca
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Word Count: 4,168 (manuscript text only)

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Keywords: airway management; critical care; intensive care units; mechanical ventilation;
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neuromuscular blocking agents

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The authors have no conflicts of interest to declare.

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ABSTRACT

Neuromuscular blockings agents (NMBAs) have a controversial role in the ventilatory

and medical management of critical illness. The clinical concern surrounding NMBA-induced

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complications stems from evidence presented in the 2002 clinical practice guidelines, but new

evidence from subsequent randomized trials and studies provides a more optimistic outlook

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about the application of NMBAs in the intensive care unit (ICU). Furthermore, changes in the

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delivery of critical care such as protocolized care pathways, minimizing or interrupting sedation,

increased monitoring techniques, and overall improvements in reducing immobility have created

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a modern, 21st century ICU environment whereby NMBAs may be administered safely. In this

paper we start with a review of the mechanism of action, side effects and pharmacology of
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commonly used NMBAs. We then address the rationale for NMBA use for an expanding number

of indications (endotracheal intubation, acute respiratory distress syndrome, status asthmaticus,

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increased intracranial and intra-abdominal pressure, and therapeutic hypothermia following

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cardiac arrest), with an emphasis on NMBA use in facilitating lung-protective ventilation for
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respiratory failure. We end with an appraisal over the importance of monitoring depth of

paralysis and the concerns of complications such as prolonged skeletal muscle weakness. In
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the context of adequate sedation and analgesia, monitored NMBA use (continuous or bolus

administration) can be considered for the small number of clinical indications in critically ill
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patients for which evidence currently exists.

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INTRODUCTION

Neuromuscular blockade, as an adjuvant therapy in the ventilatory and medical

management of common critical illnesses has an important, but increasingly controversial role,

in the delivery of 21st century care in the modern intensive care unit (ICU). Clinical practice

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guidelines published in 2002 cautioned against the use of neuromuscular blocking agents

(NMBAs), suggesting they only be used when “all other means have been tried without

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success”1. Yet, the evidence used in developing the guidelines was largely observational and, in

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light of evidence from more recent prospective and randomized controlled trials, an optimistic

outlook exists for NMBA use in the ICU. Using the latest evidence, this review summarizes the

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different NMBAs, pharmacological considerations, and the indications and rationale for use of
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these agents, with an emphasis on continuous NMBA infusions to optimize mechanical

ventilation and oxygenation in the treatment of respiratory failure. Finally, we review strategies
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for monitoring the depth of paralysis and an appraisal of the concerns over complications with

the use of these agents in the ICU.

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MECHANISMS OF ACTION, SIDE EFFECTS & PHARMACOKINETICS

NMBAs cause skeletal muscle relaxation by blocking the transmission of nerve impulses
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at the neuromuscular junction (NMJ) (Table 11–6). At the NMJ, acetylcholine (ACh) is released

from the presynaptic motor nerve terminus, diffuses across the synaptic cleft, and binds to
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ligand-gated nicotinic acetylcholine receptors (nAChRs) on the postsynaptic motor endplate.

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Binding of ACh increases membrane permeability to ions which decreases transmembrane

potential. If threshold potential is reached, the action potential is propagated over the surface of

the skeletal muscle cells resulting in contraction. The action of ACh is rapidly terminated by the

enzyme acetylcholinesterase2.

Depolarizing NMBAs

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Depolarizing NMBAs bind and activate nAChRs whilst non-depolarizing NMBAs bind

and competitively antagonize AChRs. Within the depolarizing class, succinylcholine is the only

agent used clinically. The rapid onset of succinylcholine and extremely short duration of action

makes it ideal for a rapid sequence intubation, but concerns for adverse effects have limited its

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use in the management of critically ill patients. Conditions that cause the proliferation of extra-

junctional ACh receptors, such as subacute or chronic upper and lower motor neuron lesions,

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myopathies and muscle trauma (i.e., crush injuries, rhabdomyolysis), burns, immobilization,

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intraabdominal infections and sepsis, may result in an exaggerated hyperkalemic response that

can lead to fatal cardiac arrhythmias7,8. Succinylcholine is a known trigger for malignant

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hyperthermia and it is the most common NMBA to cause an anaphylactic reaction. In addition to
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hyperkalemia, other adverse effects include cardiac dysrhythmias (through postsynaptic

activation of cardiac muscarinic AChRs), myalgias, increased intraocular and intracranial

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pressure and masseter spasm. Patients with atypical pseudocholinesterases may experience

prolonged neuromuscular blockade with succinylcholine and be at higher risk for adverse
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effects2.
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Non-Depolarizing NMBAs

The non-depolarizing classes of NMBAs are highly ionized, water-soluble compounds

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that competitively antagonize the nAChRs and prevent depolarization. Non-depolarizing NMBAs

are further divided into aminosterodial compounds (e.g., pancuronium, vecuronium, rocuronium)
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and benzylisoquinolinium compounds (e.g., atracurium, cisatracurium, mivacurium). The choice

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between agents in the ICU depends on both the indication and the patient’s comorbidities (e.g.,

renal failure, liver failure). Rocuronium is commonly used as an alternative to succinylcholine for

endotracheal intubation in the ICU given its rapid onset and intermediate duration of action, but

without the high potential for adverse effect in the critically ill population. Atracurium or

cisatracurium may be preferred agents for continuous infusions given that their metabolism is

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unrelated to renal or hepatic function. Furthermore, unlike succinylcholine, infusions of non-

depolarizing NMBAs may be used safely in critically ill patients with conditions that cause a

proliferation of the extra-junctional receptors without concern for sustained membrane

permeability and acute hyperkalemia2.

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Drug Handling

The pharmacokinetics and pharmacodynamics of NMBAs are influenced by the drugs

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used concomitantly and other features of critical illness, such as organ dysfunction, and may

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affect the duration or depth of paralysis. For example, older patients may have reduced drug

elimination, patients with liver or renal dysfunction are at risk for aminosteroid NMBA

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accumulation, and metabolic or electrolyte disturbances (e.g., hypothermia, hypokalemia,
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respiratory acidosis) may potentiate the duration of neuromuscular blockade and impair

pharmacological reversal3,9. Specific drugs such as antiepileptics (e.g., phenytoin,

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carbamazepine), ranitidine, caffeine and theophylline may cause resistance to NMBA actions.

Others drugs may enhance or prolong NMBA action including antibiotics (e.g., aminoglycoside,
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clindamycin, vancomycin), cardiovascular agents (e.g., furosemide, beta blockers, calcium

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channel blockers), immunosuppressants (e.g., cyclosporine, corticosteroids), lithium, and

inhaled and local anesthestics4,5,9. Tachyphylaxis has also been documented with NMBA use,
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but may be less common with bolus versus continuous administration, and clinical guidelines

recommend that patients who develop tachyphylaxis to one NMBA should try another drug if
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neuromuscular blockade is still required1.

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Reversal of Paralysis

In the modern era of critical care management, unlike in the operating room, rapid

reversal of paralysis is not common. Agents or infusions are usually discontinued and muscular

function is allowed to recover gradually as the NMBAs are metabolized and eliminated. If rapid

reversal of non-depolarizing NMBAs is required, anticholinesterase agents (e.g., edrophonium,

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neostigmine, pyridostigmine) with concomitant use of antimuscarinic agents (glycopyrrolate,

atropine) may be employed in a manner that reverses paralysis while preventing “recurarization”

(i.e., binding of residual NMBAs in circulation once anticholinesterase agent has been

eliminated which results in unexpected re-paralysis). Drugs such as edrophonium (0.5-1.0

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mg/kg), neostigmine (0.03-0.07 mg/kg) and pyridostigmine (0.1-0.4 mg/kg) are administered

with antimuscarinics, such as atropine and glycopyrrolate, to prevent the clinical effects of the

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parasympathetic activation, including bradycardia, bradyarrhythmias, bronchoconstriction and

excessive airways secretions, caused by the ACh increase at autonomic synapse2–5,10. A new

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drug, sugammadex, acts by forming tight complexes with aminosteroidal NMBAs in the plasma

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and can provide immediate reversal following rocuronium administration in patients where

emergency intubation has failed11.

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CLINICAL USES

In addition to facilitating endotracheal intubation, clinical guidelines recommend NMBA

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use in the adult ICU setting as an adjuvant for managing mechanical ventilation, decreasing
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oxygen consumption, managing increased intracranial pressure and treating muscle spasms1.

NMBAs have also been used to manage increased intra-abdominal pressure and for therapeutic
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hypothermia after out-of-hospital ventricular fibrillation (VF)-associated cardiac arrest5. A survey

of Canadian intensivists showed that the most common indications are for endotracheal
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intubation, unconventional modes of ventilation (e.g., high-frequency oscillation or jet

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ventilation), poor respiratory system compliance, and severe hypoxemia12.

Endotracheal Intubation

Emergent endotracheal intubation in the critically ill patient carries substantially more risk

than in the controlled environment of the operating room. While the experience of the operator

mitigates these risks, complications such as hypoxemia, hemodynamic collapse, and difficulty

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intubating occur at a rate exceeding 25%13. The use of NMBAs can reduce these risks and has

been associated with a lower prevalence of hypoxemia and procedure-related complications

and improved intubating conditions (with fewer attempts)14. Succinylcholine and rocuronium are

common NMBAs used for intubation given their short onset and duration of action (Table 1). A

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recent Cochrane review found succinylcholine (minimum dose 1 mg/kg) to be superior to

rocuronium (minimum dose 0.6 mg/kg) for achieving excellent intubation conditions, defined as

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good conditions recorded by the operator, open vocal cords that were immobile, and no

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response by the patient to intubation. There was no difference in intubation conditions when

succinylcholine was compared to higher doses of rocuronium (0.9-1.2 mg/kg), but the shorter

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duration of action with succinylcholine made it more favorable clinically8. However, given the
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extensive risks of succinylcholine administration in critically ill patients, clinicians may prefer

rocuronium15. Allergy to aminosteroid NMBAs is the only absolute contraindication for

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rocuronium, but its longer duration of action requires extreme caution in patients with anticipated

difficult airways at high risk for a “cannot intubate, cannot ventilate” situation. Rapid reversal of
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rocuronium may be achieved with sugammedex, which forms tight complexes with unbound
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steroid NMBA molecules, although physician familiarity, cost and availability have limited the

use of this agent16.

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Acute Respiratory Distress Syndrome (ARDS)

In ARDS, lung-protective ventilation strategies help mitigate ventilator-induced lung

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injury (VILI) and are associated with significantly lower mortality 17,18. NMBAs may help facilitate
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lung-protective ventilation and continuous infusions of NMBAs have been reported in 22% of

patients with ARDS and 38% in those with severe ARDS19. Mechanisms by which NMBAs may

help to achieve lung-protective ventilation occur through the prevention of spontaneous

respiratory efforts and by reducing oxygen consumption through decreasing work of breathing

and abolishing resting muscle tone20. NMBAs may prevent potentially injurious pendelluft

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(regional lung overinflation)21, occult “reverse triggering”22 and dynamic hyperinflation23 and

reduce pulmonary and systemic inflammatory-mediator release24. Three randomized controlled

trials (RCTs) showed significant improvement in a number of clinically-important outcomes with

a 48-hour infusion of cisatracurium. In the first RCT, patients randomized to the 48-hour

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cisatracurium infusion (initial rate 5 mcg/kg/min) group had lower FiO2 requirements by 24

hours, higher PaO2/FiO2 ratios by 48 hours, and decreased PEEP requirements by 72 hours

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compared to placebo group25. While a low PaO2/FiO2 ratio upon admission may not predict

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morality in adult ARDS studies, tracking changes in PaO2/FiO2 throughout the first week may be

useful in categorizing patients at higher risk for adverse outcomes or identifying patients failing

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conventional therapy26. In the largest RCT (340 patients with early ARDS diagnoses and
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PaO2/FiO2 <150), the group randomized to cisatracurium (37.5 mg/hour) had a significant

reduction in adjusted mortality (HR 0.68 [95% CI 0.48-0.98]) at 90 days. In addition, the
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treatment group had more ventilator-free and organ failure-free days, as well as less frequent

barotrauma (5% vs. 12%; p=0.03). There was no difference in ICU-acquired weakness (ICUAW)
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as measured by the Medical Research Council (MRC) scale for muscle strength between the
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treatment and placebo groups27. Despite these encouraging findings, potential limitations of this

landmark trial include that it was underpowered and there was no difference in crude 90-day
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mortality between groups. Furthermore, the survival curves did not separate until 18 days after

enrollment, which was more than two weeks following the cessation of administration of
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cisatracurium28. An explanation for this time lag in benefit could be due an NMBA-mediated
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reduction in pulmonary and systemic cytokines, which may have contributed to the prevention of

multi-organ dysfunction29. A small RCT showed a decrease in baseline inflammatory pulmonary

interleukin (IL)-8 and serum IL-6 and IL-8 concentration 48 hours following cisatracurium

infusion (initial rate 5 mcg/kg/min). Sustained improvements in oxygenation were also observed

after 24 hours of starting the NMBA infusion24. Finally, a meta-analysis of these 3 RCTs

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suggested that NMBA (cisatracurium) use early in the course of ARDS was associated with

decreased ICU and 28-day mortality, and decreased barotrauma without an increased risk of

ICUAW 30. More information regarding the safety and efficacy of early cisatracurium in patients

with moderate/severe ARDS will be available from the ongoing Reevaluation of Systemic Early

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Neuromuscular Blockade (ROSE) trial (ClinicalTrials.gov NCT02509078) from the Prevention

and Early Treatment of Acute Lung Injury (PETAL) Network.

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Status Asthmaticus

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Increased airway resistance in severe asthma leads to an obstruction in expiratory flow

and an increased work of breathing. The incomplete exhalation of tidal volume may result in

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static and dynamic lung hyperinflation and increased airway pressure. In these circumstances,
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positive pressure mechanical ventilation may cause barotrauma and/or subsequent

hemodynamic collapse as a consequence of adverse heart-lung interactions. Maintaining lower

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minute ventilation, which is a critical determinant of lung hyperinflation, may mitigate these

complications. Heavy sedation and NMBAs assist clinicians in achieving the desired minute
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ventilation through reducing ventilator dyssynchrony and airway pressures in order to optimize
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lung volume and respiratory rate. NMBAs have the additional benefit of reducing oxygen

consumption (VO2), carbon dioxide (CO2) production and lactate accumulation by paralyzing the
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overworked respiratory muscles31,32. Results from older retrospective studies have demonstrated

an increased odds ratio or correlation between myopathy and duration of muscle relaxation33,34.
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These observations contrast another retrospective study demonstrating that a marked reduction
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in exposure to NMBAs, with a shift towards deep sedation rather than continuous paralysis, did

not change the incidence of clinically-significant muscle weakness in status asthmaticus

patients35. Indeed it seems more likely that prolonged immobilization and muscle inactivity

(whether through NMBA administration or deep sedation) is the critical driver for prolonged

skeletal muscle weakness or myopathy in patients with severe asthma.

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Raised Intracranial Pressure

NMBAs have a number of applications in the context of elevated intracranial pressure

(ICP). They facilitate mechanical ventilation strategies that lower ICP (i.e., CO2 elimination,

lower PEEP), decrease metabolic expenditure, and limit surges in ICP after stimulating

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procedures (e.g., tracheal suction, coughing, movement), agitation and posturing36,37. An RCT

with 14 neurosurgical patients examined changes in baseline ICP, cerebral perfusion pressure

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(CPP) and cerebral blood flow (CBF) and mean arterial pressure (MAP) with atracurium and

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cisatracurium. After 3 bolus doses of atracurium there was a decrease in ICP, CPP, CBFV, and

MAP. The decreased CPP and CBFV may be attributed to the decreased MAP secondary to

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histamine-induced, vasodilatory effects (see Table 1). Cisatracurium, which provides greater

cardiovascular stability, showed no change in ICP, CPP, CBFV38, even at higher doses44. A
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small prospective study of traumatic brain injury (TBI) patients examined doxacurium bolus
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followed by infusion titrated to 1/4 peripheral nerve twitches (see monitoring) also failed to show

any significant change in BP or ICP and did not report any incidence of muscle weakness or
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adverse events. A retrospective study revealed a lower mortality with early (<14 hours within
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ICU admission) continuous (>12 hours) administration of NMBAs, but this group also had longer

ICU stays, higher occurrence of pneumonia, and higher incidence of vegetative or severely
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disabled survivors39. NMBA use in this population has the additional complication of masking

seizure activity and preventing neurological assessment. Although routine use of these agents
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in this patient population is not indicated, they may be considered when deep sedation is
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insufficient in preventing increased ICP.

Increased Intra-Abdominal Pressure

Intra-abdominal hypertension, which is a sustained intra-abdominal pressure (IAP)

greater than 12 mmHg, occurs in up to 32% of ICU patients. Abdominal compartment syndrome

(ACS) occurs when pressure exceeds 20 mmHg with concomitant signs of organ dysfunction

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and is reported in up to 4% of critically ill patients40,41. Reduced abdominal wall compliance,

whether from fluid overload/increased vascular permeability, tight abdominal closures, or pain,

may lead to dangerously high IAP. Through reducing abdominal muscle tone, NMBAs not only

reduce IAP, but can provide time for clinicians to manage the increased IAP (e.g., positioning,

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nasogastric/rectal decompression, diuresis, therapeutic paracentesis)41,42. A prospective study

demonstrated that bolus administration of cisatracurium caused a significant decrease in IAP

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that was sustained for 30 minutes without significant changes in hemodynamics43. While

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NMBAs may not be effective for severe IAH or patients who have progressed to ACS, brief trials

of NMBAs may be used as temporizing measure to reverse the negative effects of mild to

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moderate IAH44,45.
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Therapeutic Hypothermia after Cardiac Arrest

Individuals who experience an out-of hospital cardiac arrest were more likely to reach
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better cerebral performance category (CPC) scores during hospital stay and to survive to

hospital discharge when their core body temperature is lowered to 32-34oC for 12-24 hours46.
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Shivering is a consequence of therapeutic hypothermia which leads to heat production,

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increased metabolic rate, inflammation, increased intracranial pressure, decreased brain tissue

oxygen levels and muscle soreness. Both opioids and NMBAs may be used to reduce shivering
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although the ideal combination of agents and dosing strategy remains unclear47. Furthermore,

hypothermia induces alterations in both the pharmacodynamics and pharmacokinetics of these

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medications and blunts TOF monitoring of paralysis depth which further complicates
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management48,49. One retrospective study compared continuous (0.8 mcg/kg/min) versus

intermittent boluses (0.05 mg/kg every 2 hours) of vecuronium and found that both dosing

strategies were equally effective at maintaining a goal TOF response. However, the bolus group

reached the TOF goal earlier and at a lower dose and the continuous group had a shorter

median time to spontaneous respiration and extubation. Another retrospective study

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demonstrated increased survival with sustained (24 hour) paralysis within 24 hours of ROSC as

compared to no NMBA ( OR 7.23 [95% CI 1.56-33.38])50. A third retrospective study, which

adjusted clinical outcomes using a propensity score, found a non-significant trend towards

increased survival and a non-significant increase in early-onset pneumonia and ICU stay with

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continuous Cisatracurium infusions titrated to a TOF ≤151. American Heart Association

Guidelines suggest the short-acting, titrated use of sedation and analgesia to suppress

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shivering and the use of any NMBAs should be kept to a minimum or avoided altogether52,53.

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MONITORING

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The adequacy of sedation and analgesia may be monitored clinically through behavioral
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scales, changing vital signs (e.g., tachycardia, hypertension), diaphoresis, lacrimation, detection

of spontaneous breathing, and end-tidal CO2 waveforms and bodily movement54. The specific
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effects of NMBAs, however, may be measured through the stimulation of peripheral nerves

which evokes mechanical responses or “twitches” in the corresponding muscles. TOF

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monitoring, which involves a series of 4 electrical impulses (2 Hz) delivered to a peripheral

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nerve (i.e., facial nerve stimulation and orbicularis oculi twitch or ulnar nerve stimulation and

adductor policis twitch) result in a mechanically evoked response in the corresponding muscle
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group. As neuromuscular blockade increases so will the percentage of occupied AChRs and

there is a fade in amplitude of subsequent impulses. The amplitude of the 4th impulse divided by
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the amplitude of the 1st impulse may be quantified to determine the TOF-ratio. These techniques
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are seldom used in the ICU, but have become more popular in the context of detecting “residual

paralysis” post-operatively which is defined as a TOF ratio <0.9. For patients discharged to the

PACU or ICU postoperatively the incidence of residual neuromuscular blockade (from intra-

operative NMBA administration) varies widely from 2-64%, putting them at high risk for critical

respiratory events55. In the absence of quantitative monitoring, clinical signs of recovery from

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neuromuscular blockade (e.g., sustained head lift or leg lift, “normal” pattern of respiration,

sustained hand grip) often occur at TOF ratios <0.9 yet still provide physicians with enough

reassurance to extubate56,57. While the intensivist must be cautious about residual

neuromuscular blockade when extubating the postoperative patient, the incidence of critical

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respiratory events is low (<1%) and most patients seem to tolerate residual block of modest

extent without untoward results58,59, albeit clinical consideration must be given to those with pre-

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existing respiratory or neuromuscular disease. Visual and tactile measurement of TOF

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stimulation is more common in the ICU setting, whereby the disappearance of twitches (by sight

or by touch) correspond to AChR receptor occupancy (Table 23,60). An RCT found that in

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mechanically ventilated patients who required continuous NMBA administration, those who had
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TOF monitoring (titrated to 1 of 4 twitches) used less NMBA hourly and cumulatively and had

faster recovery of neuromuscular function (RR 1.85 [95% CI 1.02-3.35]) and spontaneous
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ventilation (RR 1.86 [95% CI 1.00-3.45])61. The 2002 clinical guidelines recommended that

paralysis be titrated to only 1-2 of 4 twitches1, which roughly correspond to 80-90% receptor
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occupancy60, yet some clinicians prefer to target the lowest dose that is clinically effective
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regardless of the TOF. Given that a number of factors may lead to incorrect TOF readings (i.e.,

peripheral edema, incorrect placement of electrodes, loss of skin adhesion) some clinicians
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recommend a combination of clinical and TOF monitoring68,69. Conversely, one prospective

study suggested that there is no difference in mean recovery time, total paralysis time or NMBA
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dose (cisatracurium) between patients with TOF monitoring and those with clinical monitoring
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(based on ventilator dyssynchrony and peak airway pressures)62. Another prospective study

found no difference between clinical or TOF monitoring with respect to NMBA dose (atracurium)

or clinical recovery time63. The landmark study by Papazian et al did not use any peripheral

nerve stimulation to monitor paralysis. Patients’ sedation was clinically titrated so they would

have no response to glabellar tap (Ramsay sedation score 6) before NMBA or placebo

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administration and using this protocol they demonstrated that early administration of

cisatracurium improved clinical outcomes without increasing muscle weakness (as measured by

MRC score for muscle strength)27. Given these observations, TOF monitoring of paralysis may

be unnecessary.

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COMPLICATIONS

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ICUAW results from a number of factors, including critical illness neuromyopathy and

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disuse atrophy that can lead to prolonged weakness that persists long after the patient has been

discharged from the ICU and hospital. The increasing recognition of the neuromuscular

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consequences of critical illness has led to greater attention being directed to the appropriate use

of NMBAs, although the attributable portion to NMBA use is controversial and under debate. A
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review by Puthucheary et al challenged the clinical view of an adverse relationship between

NMBAs and skeletal muscle weakness64. The authors highlighted the high incidence of
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corticosteroid use, which causes the well-described complication of steroid-induced myopathy65,

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limitations in defining and diagnosing skeletal muscle wasting and weakness and the variations
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in mechanical ventilation and sedative practice that accompany the early observational studies

from which the 2002 clinical guidelines were based64. A retrospective observational study in
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severe asthmatics demonstrated an increased incidence (30% vs. 10%) of skeletal myopathy

with NMBA administration (mean duration 3.1 ± 2.3 days), with myopathy only associated with
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duration of muscle relaxation33. Another retrospective study in severe asthmatic patients also
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demonstrated higher incidence of post-extubation skeletal muscle dysfunction and multiple

logistic regression analysis demonstrated that NMBAs were independent predictors of overall

morbidity34. A prospective study of septic patients demonstrated that NMBAs were an

independent risk factor for development of critical illness polyneuropathy, defined by

electrophysiological testing66. However, a direct relationship between electrophysiological

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abnormalities, skeletal muscle wasting, skeletal muscle weakness and functional outcome has

not been shown which add to the complexity in the overall interpretation of such studies.

Indeed, a prospective study by Fan et al found that in ALI patients the duration of bed rest

during critical illness, but not systemic corticosteroid nor use of NMBAs, was independently

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associated with prolonged muscle weakness67. Furthermore, an RCT by Papazian et al showed

no change in muscle strength testing at day 28 or at ICU discharge in patients receiving 48-hour

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cisatracurium infusions compared to placebo27. Price et al offer modifications to the 2002 clinical

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practice guidelines to decrease in incidence or risk of critical illness polyneuromyopathy6. They

report an evidence-based algorithm for the use of NMBAs that advocates for the use of

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cisatracurium infusions in early ARDS with PaO2/FiO2 ratios <120 and benzylisoquinolinium
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compounds for sepsis with multiorgan failure and suggest avoiding NMBAs if possible in this

population6. They also recommend keeping infusions to <48 hours and be vigilant of the
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potentiating effects of corticosteroids and aminoglycosides on muscle dysfunction6. Modern

critical care practice moving towards minimizing and interrupting sedation68 may offer further
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reductions the incidence of prolonged muscle weakness in the ICU by decreasing overall
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immobility.

Many complications from NMBA use are related to the effects of immobility. NMBA-
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induced paralysis is associated with pooling of blood in veins and stasis, which increases the

risk of venous thromboembolism. One study found NMBA use to be the strongest predictor of
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DVT incidence and encouraged procedures that reduce venous stasis (passive mobilization and
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elastic compression stockings) to increase the efficacy of pharmacological DVT prophylaxis in

paralyzed patients69. Paralysis results in impaired eyelid closure and loss of corneal reflex,

which place the cornea at risk for drying, scarring, ulceration and infection and may lead to

permanent visual loss. An RCT found that applying artificial tears, on a regular set schedule,

was more effect than passive eyelid closure alone at reducing the incidence of corneal

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abrasions70. Skin breakdown, slowed GI motility, peripheral muscle weakness, diaphragmatic

atrophy, and myositis ossificans are other complications of immobility that may be managed

with supportive care, changes in position and height-of-bed, and mobilization1,4. NMBAs are the

most common cause of anaphylaxis (IgE-mediated) in anesthesia, with succinylcholine (38%)

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and rocuronium (26%) as the most frequently culprits, and cross-reactivity between NMBAs

observed in >60% of cases71.

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Awareness during paralysis is major risk with NMBA use. This stresses the importance

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of providing adequate sedation and analgesia prior to and during paralysis to provide concurrent

amnesia and analgesia and prevent the incidence of traumatic recollections, negative

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experiences, dreams or thoughts72. Continuous, quantitative monitors of awareness, such as the
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bispectal index (BIS), are insufficient for clinical utility73, and advocate for careful clinical and

qualitative monitoring of patients for signs and symptoms suggesting inadequate sedation or
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analgesia.
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CONCLUSIONS
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Previous clinical guidelines that were largely based on observational studies have

exaggerated concern regarding NMBA administration in the delivery of critical care in the 21st
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century. Protocolized care pathways, minimizing or interrupting sedation, increased monitoring

techniques, and overall improvements in reducing immobility have created a modern ICU
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environment whereby NMBAs can be administered safely. While the indications for NMBA use
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are expanding, their use in the context of intubation and facilitating mechanical ventilation in

patients with respiratory failure dominate the clinical picture. Further research is required in

order to optimize NMBA administration in patients with acute respiratory failure in order to

achieve lung-protective ventilation. Uncertainties about the importance of monitoring and the

appropriate duration of NMBA administration will need to be addressed. Additionally, identifying

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NMBAs’ attributable portion of ICU-acquired weakness will be required to improve the safety of

these medications. Yet, at the present, in the context of adequate sedation and analgesia,

monitored NMBA use, whether continuous (<48 hours) or bolus administration, should be

considered safe and efficacious for the small number of clinical indications in critically ill patients

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for which the current evidence is robust.

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Table #1: Pharmacokinetic and pharmacodynamics of NMBAs

Class Depolarizing Non-depolarizing

Type Aminosteroid Benzylisoquinolinium

Agent Succinylcholine Pancuronium Vecuronium Rocuronium Atracurium Cisatracurium Mivacurium

ED95 (mg/kg) 0.5-0.6 0.07 0.05 0.3 0.2 0.05 0.08

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Dose: intubating 0.5-1 0.1 0.08-0.1 0.6-1 0.4-0.5 0.1-0.2 0.25

(mg/kg) (RSI: 1-1.2) (RSI: 0.9-1.2)

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Dose: Bolus doses 1.0 0.02 0.02 0.1 0.1 0.15-0.2 0.05

following intubation

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Dose: Continuous Not 0.8- 0.8-1.7ug/kg/min 8-12ug/kg/min 5-20ug/kg/min 1-3ug/kg/min 5-6ug/kg/min

infusion (ug/kg/min) recommended 1.7ug/kg/min

Onset (time to peak 30-60s 3-5min 3-5min 1-2min 3-5min 3-5min 2-3min

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effect)
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Duration Ultra short Long Intermediate Intermediate Intermediate Intermediate Short

(5-10min) (60-90min) (20-35min) (20-35min) (20-35min) (20-35min) (12-20min)

Metabolism/Elimination Plasma Renal >> Renal ≤ Hepatic Renal << Plasma esterase and Hofmann Plasma
cholinesterase* Hepatic Hepatic Hofmann elimination elimination cholinesterase
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*
Active Metabolites none 3-desacetyl- 3-desacetyl- none Laudanosine (possible none none

pancuronium vecuronium (50- CNS toxicity)

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(50% potency) 70% potency)

Effect on Cardiac Stimulates Blocks ++ None Blocks + None None None

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Muscarinic receptors**

Histamine release*** + None None None + None +

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Evidence for critical n/a +++ +++ + + + n/a

illness

polyneuromyopathy
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1–6
Sources for Table ; +minimal, ++moderate, +++ marked
ED95: the amount of NMBA required to reduce twitch height by 95%
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*patients with atypical or reduced pseudocholinesterase may experience prolonged NMBA blockade.
**effect on cardiac muscarinic receptors = atropine-like effect
***histamine release may cause hypotension and tachycardia

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Table 2: Monitoring technique and receptor occupancy

Monitoring technique Receptor Occupancy (%) Comment

TOF 4/4 twitches 70-75%

TOF 0/4 twitches >90%

Sustained 5-sec head lift (TOF 0.6) 50% Must be performed unaided with patient supine.

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Hand grip (TOF 0.7) 50% Sustained at a level qualitative similar to pre-induction baseline

Sustained bite (TOF~0.85) 50% Sustain jaw clench on tongue blade

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3,60
Adapted from
TOF = Train-of-Four

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REFERENCES

1. Murray MJ, Cowen J, DeBlock H, et al. Clinical practice guidelines for sustained
neuromuscular blockade in the adult critically ill patient. Crit Care Med. 2002;30(1):142–
156.

2. Miller R, Pardo MC. Neuromuscular Blocking Drugs. In: Basics of Anesthesia.

PT
Philadelphia, PA: Elsevier; 2011:143–161.

3. Naguib, M, Lien CA. Pharmacology of muscle relaxants and their antagonists. In: Miller’s
Anesthesia, 6th ed. Philadelphia, PA: Churchill Livingstone; 2005:481–572.

RI
4. Warr J, Thiboutot Z, Rose L, Mehta S, Burry LD. Current therapeutic uses, pharmacology,
and clinical considerations of neuromuscular blocking agents for critically ill adults. Ann
Pharmacother. 2011;45(9):1116–1126.

SC
5. Greenberg SB, Vender J. The use of neuromuscular blocking agents in the ICU: where are
we now? Crit Care Med. 2013;41(5):1332–1344.

U
6. Price D, Kenyon NJ, Stollenwerk N. A fresh look at paralytics in the critically ill: real
promise and real concern. Ann Intensive Care. 2012;2(1):43-52.
AN
7. Martyn JA, White DA, Gronert GA, Jaffe RS, Ward JM. Up-and-down regulation of skeletal
muscle acetylcholine receptors: Effects on neuromuscular blockers. Anesthesiology.
1992;76(5):822–843.
M

8. Tran DTT, Newton EK, Mount VAH, Lee JS, Wells GA, Perry JJ. Rocuronium versus
succinylcholine for rapid sequence induction intubation. Cochrane Database of Systematic
D

Reviews 2015, Issue 10. Art. No.: CD002788. DOI: 10.1002/14651858.CD002788.pub3.

9. Prielipp RC, Coursin DB. Applied pharmacology of common neuromuscular blocking

TE

agents in critical care. New Horiz. 1994;2(1):34–47.

10. Bevan DR, Donati F, Kopman AF. Reversal of neuromuscular blockade. Anesthesiology.
1992;77(4):785–805.
EP

11. Abrishami A, Ho J, Wong J, Yin L, Chung F. Sugammadex, a selective reversal medication

for preventing postoperative residual neuromuscular blockade. Cochrane Database of
Systematic Reviews 2009, Issue 4. Art. No.: CD007362. DOI:
C

10.1002/14651858.CD007362.pub2.
AC

12. Mehta S, Burry L, Fischer S, et al. Canadian survey of the use of sedatives, analgesics,
and neuromuscular blocking agents in critically ill patients. Crit Care Med. 2006;34(2):374–
380.

13. Jaber S, Amraoui J, Lefrant J-Y, et al. Clinical practice and risk factors for immediate
complications of endotracheal intubation in the intensive care unit: A prospective, multiple-
center study. Crit Care Med. 2006;34(9):2355–2361.

20
 ACCEPTED MANUSCRIPT

14. Wilcox SR, Bittner EA, Elmer J, et al. Neuromuscular blocking agent administration for
emergent tracheal intubation is associated with decreased prevalence of procedure-related
complications. Crit Care Med. 2012;40(6):1808–1813.

15. Booij L. Appropriate use of muscle relaxants in anaesthesia, intensive and emergency
care. Jurnalul Roman Anestezie Ter Intensiv. 2011;18(2):136–144.

16. Jones RK, Caldwell JE, Brull SJ, Soto RG. Reversal of Profound Rocuronium-induced

PT
Blockade with Sugammadex: A Randomized Comparison with Neostigmine.
Anesthesiology. 2008;109(5):816–824.

RI
17. The Acute Respiratory Distress Syndrome Network. Ventilation with Lower Tidal Volumes
as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute
Respiratory Distress Syndrome. N Engl J Med. 2000;342(18):1301–1308.

SC
18. Amato MBP, Meade MO, Slutsky AS, et al. Driving Pressure and Survival in the Acute
Respiratory Distress Syndrome. N Engl J Med. 2015;372(8):747–755.

19. Bellani G, Laffey JG, Pham T, et al. Epidemiology, Patterns of Care, and Mortality for

U
Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50
Countries. JAMA. 2016;315(8):788.
AN
20. Bishop MJ. Hemodynamic and gas exchange effects of pancuronium bromide in sedated
patients with respiratory failure. Anesthesiology. 1984;60(4):369–371.
M

21. Yoshida T, Torsani V, Gomes S, et al. Spontaneous effort causes occult pendelluft during
mechanical ventilation. Am J Respir Crit Care Med. 2013;188(12):1420–1427.
D

22. Akoumianaki E, Lyazidi A, Rey N, et al. Mechanical ventilation-induced reverse-triggered

breaths: a frequently unrecognized form of neuromechanical coupling. Chest.
2013;143(4):927–938.
TE

23. Pohlman MC, McCallister KE, Schweickert WD, et al. Excessive tidal volume from breath
stacking during lung-protective ventilation for acute lung injury. Crit Care Med.
2008;36(11):3019–3023.
EP

24. Forel JM, Roch A, Marin V, et al. Neuromuscular blocking agents decrease inflammatory
response in patients presenting with acute respiratory distress syndrome. Crit Care Med.
2006;34(11):2749–57.
C

25. Gainnier M, Roch A, Forel JM, et al. Effect of neuromuscular blocking agents on gas
AC

exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med.
2004;32(1):113–9.

26. Ware LB. Prognostic determinants of acute respiratory distress syndrome in adults: impact
on clinical trial design. Crit Care Med. 2005;33(3Suppl):S217-222.

27. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al.

Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med.
2010;363(12):1107–16.

21
 ACCEPTED MANUSCRIPT

28. Needham CJ, Brindley PG. The role of neuromuscular blocking drugs in early severe acute
respiratory distress syndrome. Can J Anesth. 2012;59(1):105–108.

29. Slutsky AS, Tremblay LN. Multiple System Organ Failure: Is Mechanical Ventilation a
Contributing Factor? Am J Respir Crit Care Med. 1998;157(6):1721–1725.

30. Neto AS, Pereira VGM, Esposito DC, Damasceno MCT, Schultz MJ. Neuromuscular
blocking agents in patients with acute respiratory distress syndrome: A summary of the

PT
current evidence from three randomized controlled trials. Ann Intensive Care. 2012;2(1)33-
40.

RI
31. Levy BD, Kitch B, Fanta CH. Medical and ventilatory management of status asthmaticus.
Intensive Care Med. 1998;24(2):105–117.

32. Leatherman J. Mechanical Ventilation for Severe Asthma. Chest. 2015;147(6):1671-1680.

SC
33. Behbehani NA, Al-Mane F, D’yachkova Y, Paré P, FitzGerald JM. Myopathy following
mechanical ventilation for acute severe asthma: the role of muscle relaxants and
corticosteroids. Chest. 1999;115(6):1627–1631.

U
34. Adnet F, Dhissi G, Borron SW, et al. Complication profiles of adult asthmatics requiring
AN
paralysis during mechanical ventilation. Intensive Care Med. 2001;27(11):1729–1736.

35. Kesler SM, Sprenkle MD, David WS, Leatherman JW. Severe weakness complicating
status asthmaticus despite minimal duration of neuromuscular paralysis. Intensive Care
M

Med. 2009;35(1):157–160.

36. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of

D

Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain
injury. VIII. Intracranial pressure thresholds. J Neurotrauma 2007;24 Suppl 1:S55-58.
TE

37. Rangel-Castillo L, Gopinath S, Robertson CS. Management of Intracranial Hypertension.

Neurol Clin 2008;26(2):521–541.

38. Schramm WM, Papousek A, Michalek-Sauberer A, Czech T, Illievich U. The cerebral and
EP

cardiovascular effects of cisatracurium and atracurium in neurosurgical patients. Anesth

Analg. 1998;86(1):123–127.

39. Hsiang JK, Chesnut RM, Crisp CB, Klauber MR, Blunt BA, Marshall LF. Early, routine
C

paralysis for intracranial pressure control in severe head injury: is it necessary? Crit Care
Med. 1994;22(9):1471–1476.
AC

40. Malbrain MLNG, Chiumello D, Pelosi P, et al. Incidence and prognosis of intraabdominal
hypertension in a mixed population of critically ill patients: a multiple-center epidemiological
study. Crit Care Med. 2005;33(2):315–322.

41. Malbrain MLNG, Cheatham ML, Kirkpatrick A, et al. Results from the International
Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment
Syndrome: Definitions. Intensive Care Med. 2006;32(11):1722–1732.

22
 ACCEPTED MANUSCRIPT

42. Luckianow GM, Ellis M, Governale D, Kaplan LJ. Abdominal Compartment Syndrome: Risk
Factors, Diagnosis, and Current Therapy. Crit Care Res Pract. 2012;2012:1–8.

43. De Laet I, Hoste E, Verholen E, De Waele JJ. The effect of neuromuscular blockers in
patients with intra-abdominal hypertension. Intensive Care Med. 2007;33(10):1811–1814.

44. The Pediatric Guidelines Sub-Committee for the World Society of the Abdominal
Compartment Syndrome, Kirkpatrick AW, Roberts DJ, et al. Intra-abdominal hypertension

PT
and the abdominal compartment syndrome: updated consensus definitions and clinical
practice guidelines from the World Society of the Abdominal Compartment Syndrome.
Intensive Care Med. 2013;39(7):1190–1206.

RI
45. Cheatham ML, Malbrain MLNG, Kirkpatrick A, et al. Results from the International
Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment
Syndrome. II. Recommendations. Intensive Care Med 2007;33(6):951–962.

SC
46. Arrich J, Holzer M, Havel C, Müllner M, Herkner H. Hypothermia for neuroprotection in
adults after cardiopulmonary resuscitation. Cochrane Database of Systematic Reviews
2016, Issue 2. Art. No.: CD004128. DOI: 10.1002/14651858.CD004128.pub4

U
47. Riker RR, Gagnon DJ, May T, Seder DB, Fraser GL. Analgesia, sedation, and
AN
neuromuscular blockade during targeted temperature management after cardiac arrest.
Best Pract Res Clin Anaesthesiol. 2015;29(4):435–450.

48. Heier T, Caldwell JE. Impact of hypothermia on the response to neuromuscular blocking
M

drugs. Anesthesiology. 2006;104(5):1070–1080.

49. van den Broek MPH, Groenendaal F, Egberts ACG, Rademaker CMA. Effects of
D

hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of

preclinical and clinical studies. Clin Pharmacokinet. 2010;49(5):277–294.
TE

50. Salciccioli JD, Cocchi MN, Rittenberger JC, et al. Continuous neuromuscular blockade is
associated with decreased mortality in post-cardiac arrest patients. Resuscitation.
2013;84(12):1728–1733.
EP

51. Lascarrou JB, Le Gouge A, Dimet J, et al. Neuromuscular blockade during therapeutic
hypothermia after cardiac arrest: Observational study of neurological and infectious
outcomes. Resuscitation. 2014;85(9):1257–1262.
C

52. Callaway CW, Donnino MW, Fink EL, et al. Part 8: Post–Cardiac Arrest Care: 2015
American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and
AC

Emergency Cardiovascular Care. Circulation. 2015;132(18suppl 2):S465–S482.

53. Peberdy MA, Callaway CW, Neumar RW, et al. Part 9: post-cardiac arrest care: 2010
American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care. Circulation. 2010;122(18Suppl 3):S768-786.

54. Loyola R, Dreher HM. Management of pharmacologically induced neuromuscular blockade

using peripheral nerve stimulation. Dimens Crit Care Nurs. 2003;22(4):157-64–6.

23
 ACCEPTED MANUSCRIPT

55. Murphy GS. Residual neuromuscular blockade: Incidence, assessment, and relevance in
the postoperative period. Minerva Anestesiol. 2006;72(3):97–109.

56. Grayling M, Sweeney BP. Recovery from neuromuscular blockade: a survey of practice.
Anaesthesia. 2007;62(8):806–809.

57. Kopman AF, Yee PS, Neuman GG. Relationship of the train-of-four fade ratio to clinical
signs and symptoms of residual paralysis in awake volunteers. Anesthesiology.

PT
1997;86(4):765–771.

58. Kopman AF. In response. Anesth Analg. 2011;112(2):483.

RI
59. Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS. Residual
neuromuscular blockade and critical respiratory events in the postanesthesia care unit.
Anesth Analg. 2008;107(1):130–137.

SC
60. Lee CM. Train-of-4 quantitation of competitive neuromuscular block. Anesth Analg.
1975;54(5):649–653.

U
61. Rudis MI, Sikora CA, Angus E, et al. A prospective, randomized, controlled evaluation of
peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking
AN
agents in critically ill patients. Crit Care Med. 1997;25(4):575–583.

62. Baumann MH, McAlpin BW, Brown K, et al. A prospective randomized comparison of train-
of-four monitoring and clinical assessment during continuous ICU cisatracurium paralysis.
M

Chest. 2004;126(4):1267–73.

63. Strange C, Vaughan L, Franklin C, Johnson J. Comparison of train-of-four and best clinical
D

assessment during continuous paralysis. Am J Respir Crit Care Med. 1997;156(5):1556–

1561.
TE

64. Puthucheary Z, Rawal J, Ratnayake G, Harridge S, Montgomery H, Hart N. Neuromuscular

blockade and skeletal muscle weakness in critically ill patients: time to rethink the
evidence? Am J Respir Crit Care Med. 2012;185(9):911–917.
EP

65. Schakman O, Gilson H, Thissen JP. Mechanisms of glucocorticoid-induced myopathy. J

Endocrinol. 2008;197(1):1–10.

66. Garnacho-Montero J, Madrazo-Osuna J, García-Garmendia JL, et al. Critical illness

C

polyneuropathy: risk factors and clinical consequences: A cohort study in septic patients.
Intensive Care Med. 2001;27(8):1288–1296.
AC

67. Fan E, Dowdy DW, Colantuoni E, et al. Physical complications in acute lung injury
survivors: a two-year longitudinal prospective study. Crit Care Med. 2014;42(4):849–859.

68. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in
critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342(20):1471–
1477.

69. Boddi M, Barbani F, Abbate R, et al. Reduction in deep vein thrombosis incidence in
intensive care after a clinician education program. J Thromb Haemost. 2010;8(1):121–128.

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70. Lenart SB, Garrity JA. Eye care for patients receiving neuromuscular blocking agents or
propofol during mechanical ventilation. Am J Crit Care. 2000;9(3):188–191.

71. Mertes PM, Laxenaire MC. Anaphylactic and anaphylactoid reactions occurring during
anaesthesia in France: Seventh epidemiologic survey. Ann Fr Anesthèsie Rèanimation.
2004;23(12):1133–1143.

72. Ballard N, Robley L, Barrett D, Fraser D, Mendoza I. Patients’ recollections of therapeutic

PT
paralysis in the intensive care unit. Am J Crit Care. 2006;15(1):86–94.

73. LeBlanc JM, Dasta JF, Pruchnicki MC, Gerlach A, Cook C. Bispectral index values,

RI
sedation-agitation scores, and plasma Lorazepam concentrations in critically ill surgical
patients. Am J Crit Care. 2012;21(2):99–105.

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